COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY

Abstract
In one aspect, compounds of Formula AA, or a pharmaceutically acceptable salt thereof, are featured: or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula A can be as defined anywhere herein.
Description
TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound that modulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that are useful, e.g., for treating a condition, disease or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g., a condition, disease or disorder associated with NLRP3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.


The present disclosure also relates to, in part, methods and compositions for treating anti-TNFα resistance in a subject with an NLRP3 antagonist. The present disclosure also relates, in part, to methods, combinations and compositions for treating TFNα related diseases and anti-TNFα resistance in a subject that include administration of an NLRP3 antagonist, an NLRP3 antagonist and an anti-TNFα agent, or a composition encompassing an NLRP3 antagonist and an anti-TNFα agent.


BACKGROUND

The NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the cryopyrin associated periodic syndromes (CAPS). The inherited CAPS Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal onset multi-system inflammatory disease (NOMID) are examples of indications that have been reported to be associated with gain of function mutations in NLRP3.


NLRP3 can form a complex and has been implicated in the pathogenesis of a number of complex diseases, including but not limited to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn's disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as Osteoarthritis , osteoporosis and osteopetrosis disorders eye disease, such as glaucoma and macular degeneration, diseased caused by viral infection such as HIV and AIDS, autoimmune disease such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis, Addison's disease, pernicious anemia, cancer and aging.


In light of the above, it would be desirable to provide compounds that modulate (e.g., antagonize) NLRP3.


Several patients having inflammatory or autoimmune diseases are treated with anti-TNFα agents. A subpopulation of such patients develop resistance to treatment with the anti-TNFα agents. It is desirable to develop methods for reducing a patient's resistance to anti-TNFα agents. In light of the this, it would also be desirable to provide alternative therapies for treating inflammatory or autoimmune diseases (for example NLRP3 inflammasome inhibitors) to avoid or minimise the use of anti-TNFα agents.


Intestinal bowel disease (IBD), encompassing Ulcerative Colitis (UC) and Crohn's disease (CD), are chronic diseases characterized by barrier dysfunction and uncontrolled inflammation and mucosal immune reactions in the gut. A number of inflammatory pathways have been implicated in the progression of IBD, and anti-inflammatory therapy such as tumor necrosis factor-alpha (TNF-a) blockade has shown efficacy in the clinic (Rutgeerts P et al N Engl J Med 2005; 353:2462-76). Anti-TNFα therapies, however, do not show complete efficacy, however, other cytokines such as IL-113, IL-6, IL-12, IL-18, IL-21, and IL-23 have been shown to drive inflammatory disease pathology in IBD (Neurath M F Nat Rev Immunol 2014; 14;329-42). IL-1β and IL-18 are produced by the NLRP3 inflammasome in response to pathogenic danger signals, and have been shown to play a role in IBD. Anti-IL-1β therapy is efficacious in patients with IBD driven by genetic mutations in CARD8 or IL-10R (Mao L et al, J Clin Invest 2018; 238:1793-1806, Shouval D S et al, Gastroenterology 2016; 151:1100-1104), IL-18 genetic polymorphisms have been linked to UC (Kanai Tet al, Curr Drug Targets 2013; 14:1392-9), and NLRP3 inflammasome inhibitors have been shown to be efficacious in murine models of IBD (Perera A P et al, Sci Rep 2018;8:8618). Resident gut immune cells isolated from the lamina propria of IBD patients can produce IL-113, either spontaneously or when stimulated by LPS, and this IL-1β production can be blocked by the ex vivo addition of a NLRP3 antagonist. Based on strong clinical and preclinical evidence showing that inflammasome-driven IL-1β and IL-18 play a role in IBD pathology, it is clear that NLRP3 inflammasome inhibitors could be an efficacious treatment option for UC, Crohn's disease, or subsets of IBD patients. These subsets of patients could be defined by their peripheral or gut levels of inflammasome related cytokines including IL-1β, IL-6, and IL-18, by genetic factors that pre-dispose IBD patients to having NLRP3 inflammasome activation such as mutations in genes including ATG16L1, CARDS, IL-10R, or PTPN2 (Saitoh T et al, Nature 2008; 456:264, Spalinger M R, Cell Rep 2018; 22:1835), or by other clinical rationale such as non-response to TNF therapy.


Though anti-TNF therapy is an effective treatment option for Crohn's disease, 40% of patients fail to respond. One-third of non-responsive CD patients fail to respond to anti-TNF therapy at the onset of treatment, while another third lose response to treatment over time (secondary non-response). Secondary non-response can be due to the generation of anti-drug antibodies, or a change in the immune compartment that desensitizes the patient to anti-TNF (Ben-Horin Set al, Autoimmun Rev 2014; 13:24-30, Steenholdt C et al Gut 2014; 63:919-27). Anti-TNF reduces inflammation in IBD by causing pathogenic T cell apoptosis in the intestine, therefore eliminating the T cell mediated inflammatory response (Van den Brande et al Gut 2007: 56:509-17). There is increased NLRP3 expression and increased production of IL-1β in the gut of TNF-non-responsive CD patients (Leal R F et al Gut 2015; 64:233-42) compared to TNF-responsive patients, suggesting NLRP3 inflammasome pathway activation. Furthermore, there is increased expression of TNF-receptor 2 (TNF-R2), which allows for TNF-mediated proliferation of T cells (Schmitt H et al Gut 2018; 0:1-15). IL-1β signaling in the gut promotes T cell differentiation toward Th1/17 cells which can escape anti-TNF-α mediated apoptosis. It is therefore likely that NLRP3 inflammasome activation can cause non-responsiveness in CD patients to anti-TNF-α therapy by sensitizing pathogenic T cells in the gut to anti-TNF-α mediated apoptosis. Experimental data from immune cells isolated from the gut of TNF-resistant Crohn's patients show that these cells spontaneously release IL-1β, which can be inhibited by the addition of an NLRP3 antagonist. NLRP3 inflammasome antagonists—in part by blocking IL-1β secretion—would be expected to inhibit the mechanism leading to anti-TNF non-responsiveness, re-sensitizing the patient to anti-TNF therapy. In IBD patients who are naive to anti-TNF therapy, treatment with an NLRP3 antagonist would be expected to prevent primary- and secondary-non responsiveness by blocking the mechanism leading to non-response.


NLRP3 antagonists that are efficacious locally in the gut can be efficacious drugs to treat IBD; in particular in the treatment of TNF-resistant CD alone or in combination with anti-TNF therapy. Systemic inhibition of both IL-1β and TNF-α has been shown to increase the risk of opportunistic infections (Genovese M C et al, Arthritis Rheum 2004; 50:1412), therefore, only blocking the NLRP3 inflammasome at the site of inflammation would reduce the infection risk inherent in neutralizing both IL-1β and TNF-α. NLRP3 antagonists that are potent in NLRP3-inflammasome driven cytokine secretion assays in cells, but have low permeability in vitro in a permeability assay such as an MDCK assay, have poor systemic bioavailability in a rat or mouse pharmacokinetic experiment, but high levels of compound in the colon and/or small intestine could be a useful therapeutic option for gut restricted purposes.


The present invention also provides alternative therapies for the treatment of inflammatory or autoimmune diseases, including IBD, that solves the above problems associated with anti-TNFα agents.


SUMMARY

This disclosure features chemical entities (e.g., a compound that modulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that are useful, e.g., for treating a condition, disease or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g., a condition, disease or disorder associated with NLRP3 signaling).


In some embodiments, provided herein is a compound of Formula AA




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or a pharmaceutically acceptable salt thereof, wherein the variables in Formula AA can be as defined anywhere herein.


This disclosure also features compositions as well as other methods of using and making the same.


The present invention is also relates to the Applicant's discovery that inhibition of NLRP3 inflammasomes can increase a subject's sensitivity to an anti-TNFα agent or can overcome resistance to an anti-TNFα agent in a subject, or indeed provide an alternative therapy to anti-TNFα agents.


Provided herein are methods of treating a subject that include: (a) identifying a subject having a cell that has an elevated level of NLRP3 inflammasome activity and/or expression as compared to a reference level; and (b) administering to the identified subject a therapeutically effective amount of an compound of Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.


Provided herein are methods for the treatment of inflammatory or autoimmune disease including IBD, such as UC and CD in a subject in need thereof, comprising administering to said subject a therapeutically effective amount a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof, wherein the NLRP3 antagonist is a gut-targeted NLRP3 antagonist.


Provided herein are methods of treating a subject in need thereof, that include: (a) identifying a subject having resistance to an anti-TNFα agent; and (b) administering a treatment comprising a therapeutically effective amount of a compound for Formula I, or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to the identified subject.


Provided herein are methods of treating a subject in need thereof, that include: administering a treatment comprising a therapeutically effective amount of a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof to a subject identified as having resistance to an anti-TNFα agent.


Provided herein are methods of selecting a treatment for a subject in need thereof, that include: (a) identifying a subject having resistance to an anti-TNFα agent; and (b) selecting for the identified subject a treatment comprising a therapeutically effective amount of a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof.


Provided herein are methods of selecting a treatment for a subject in need thereof, that include selecting a treatment comprising a therapeutically effective amount of a compound for Formula I or a pharmaceutically acceptable salt, solvate, or co-crystal thereof for a subject identified as having resistance to an anti-TNFα agent.


In some embodiments of any of the methods described herein, the treatment further includes a therapeutically effective amount of an anti-TNFα agent, in addition to the NLRP3 antagonist.


An “antagonist” of NLRP3 includes compounds that inhibit the ability of NLRP3 to induce the production of IL-1β and/or IL-18 by directly binding to NLRP3, or by inactivating, destabilizing, altering distribution, of NLRP3 or otherwise.


In one aspect, pharmaceutical compositions are featured that include a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) and one or more pharmaceutically acceptable excipients.


In one aspect, methods for modulating (e.g., agonizing, partially agonizing, antagonizing) NLRP3 activity are featured that include contacting NLRP3 with a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). Methods include in vitro methods, e.g., contacting a sample that includes one or more cells comprising NLRP3, as well as in vivo methods.


In a further aspect, methods of treatment of a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease are featured that include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).


In a further aspect, methods of treatment are featured that include administering to a subject a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same), wherein the chemical entity is administered in an amount effective to treat a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease.


Embodiments can include one or more of the following features.


The chemical entity can be administered in combination with one or more additional therapies with one or more agents suitable for the treatment of the condition, disease or disorder.


Examples of the indications that may be treated by the compounds disclosed herein include but are not limited to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn's disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as osteoarthritis , osteoporosis and osteopetrosis disorders, eye disease, such as glaucoma and macular degeneration, diseases caused by viral infection such as HIV and AIDS, autoimmune disease such as rheumatoid arthritis, systemic Lupus erythematosus, autoimmune thyroiditis; Addison's disease, pernicious anemia, cancer and aging.


The methods can further include identifying the subject.


Other embodiments include those described in the Detailed Description and/or in the claims.


Additional Definitions


To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.


As used herein, the term “NLRP3” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP3 molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.


The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.


“API” refers to an active pharmaceutical ingredient.


The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound exhibiting activity as a modulator of NLRP3, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof;) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.


The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.


The term “pharmaceutically acceptable salt” may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term “pharmaceutically acceptable salt” may also refer to pharmaceutically acceptable addition salts prepared by reacting a compound having an acidic group with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.


The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.


The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.


The terms “treat,” “treating,” and “treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.


The term “prevent”, “preventing” or “prevention” in connection to a disease or disorder refers to the prophylactic treatment of a subject who is at risk of developing a condition (e.g., specific disease or disorder or clinical symptom thereof) resulting in a decrease in the probability that the subject will develop the condition.


The terms “hydrogen” and “H” are used interchangeably herein.


The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).


The term “alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, saturated or unsaturated, containing the indicated number of carbon atoms. For example, C1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tent-butyl, n-hexyl.


The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.


The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH3).


The term “carbocyclic ring” as used herein includes an aromatic or nonaromatic cyclic hydrocarbon group having 3 to 10 carbons unless otherwise noted, such as 3 to 8 carbons, such as 3 to 7 carbons, which may be optionally substituted. Carbocyclic rings may be monocyclic or bicyclic, and when bicyclic, can be fused bicyclic, bridged bicyclic, or spirocyclic. Examples of carbocyclic rings include five-membered, six-membered, and seven-membered carbocyclic rings.


The term “heterocyclic ring” refers to an aromatic or nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. When heterocyclic rings are bicyclic or tricyclic, any two connected rings of the bicycle or tricycle may be fused bicyclic, bridged bicyclic, or spirocyclic. Examples of heterocyclic rings include five-membered, six-membered, and seven-membered heterocyclic rings.


The term “cycloalkyl” as used herein includes an nonaromatic cyclic, bicylic, fused, or spiro hydrocarbon radical having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, wherein the cycloalkyl group which may be optionally substituted. Examples of cycloalkyls include five-membered, six-membered, and seven-membered rings. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.


The term “heterocycloalkyl” refers to an nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring, fused, or spiro system radical having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkyls include five-membered, six-membered, and seven-membered heterocyclic rings. Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.


The term “aryl” is intended to mean an aromatic ring radical containing 6 to 10 ring carbons. Examples include phenyl and naphthyl.


The term “heteroaryl” is intended to mean an aromatic ring system containing 5 to 14 aromatic ring atoms that may be a single ring, two fused rings or three fused rings wherein at least one aromatic ring atom is a heteroatom selected from, but not limited to, the group consisting of O, S and N. Examples include furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like. Examples also include carbazolyl, quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, triazinyl, indolyl, isoindolyl, indazolyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl. phenazinyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, isobenzofuran and the like.


The term “hydroxy” refers to an OH group.


The term “amino” refers to an NH2 group.


The term “oxo” refers to O. By way of example, substitution of a CH2 a group with oxo gives a C═O group.


As used herein, the terms “the ring A” or “A” are used interchangeably to denote




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in formula AA, wherein the bond that is shown as being broken by the wavy line custom-character connects A to the S(O)(NHR3)═N moiety of Formula AA.


As used herein, the terms “the ring A′” or “A′” are used interchangeably to denote




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in formula AA-1, wherein the bond that is shown as being broken by the wavy line custom-character connects A′ to the S(O)(NHR3)═N moiety of Formula AA-1.


As used herein, the terms “the ring A′” or “A′” are used interchangeably to denote




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in formula AA-2, formula AA-3, and formula AA-4, wherein the bond that is shown as being broken by the wavy line custom-character connects A″ to the S(O)(NHR3)═N moiety of formula AA-2, formula AA-3, or formula AA-4.


As used herein, the terms “the ring B” or “B” are used interchangeably to denote




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in formula AA wherein the bond that is shown as being broken by the wavy line custom-character connects B to the NHC(O) group of Formula AA.


As used herein, the terms “the ring B′” or “B′” are used interchangeably to denote




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in formula AA-4 wherein the bond that is shown as being broken by the wavy line custom-character connects B′ to the NHC(O) group of Formula AA-4.


As used herein, the terms “the ring B″” or “B″” are used interchangeably to denote




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in formula AA-5 wherein the bond that is shown as being broken by the wavy line custom-character connects B″ to the NHC(O) group of Formula AA-5.


As used herein, the term “the optionally substituted ring A” is used to denote




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in formula AA, wherein the bond that is shown as being broken by the wavy line custom-character connects A to the S(O)(NHR3)═N moiety of Formula AA.


As used herein, the term “the optionally substituted ring A′” is used to denote




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in formula AA-1, wherein the bond that is shown as being broken by the wavy line custom-character connects A′ to the S(O)(NHR3)═N moiety of Formula AA-1.


As used herein, the term “the optionally substituted ring A″” is used to denote




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in formula AA-2,




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in formula AA-3, and




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in formula AA-4, wherein the bond that is shown as being broken by the wavy line custom-character connects A″ to the S(O)(NHR3)═N moiety of Formula AA-2, formula AA-3, or formula AA-4.


As used herein, the term “the substituted ring B” is used to denote




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in formula AA and




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in formula AA-1, wherein the bond that is shown as being broken by the wavy line custom-character connects B to the NHC(O) group of Formula AA and Formula AA-1.


As used herein, the term “the substituted ring B′” is used to denote




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in formula AA-4, wherein the bond that is shown as being broken by the wavy line custom-character connects B′ to the NHC(O) group of Formula AA-4.


As used herein, the term “the substituted ring B″” is used to denote




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in formula AA-5, wherein the bond that is shown as being broken by the wavy line custom-character connects B″ to the NHC(O) group of Formula AA-5.


As used herein, the recitation “S(O2)”, alone or as part of a larger recitation, refers to the group




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In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 13C and 14C.


The scope of the compounds disclosed herein includes tautomeric form of the compounds. Thus, by way of example, a compound that is represented as containing the moiety




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is also intended to include the tautomeric form containing the moiety




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In addition, by way of example, a compound that is represented as containing the moiety




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is also intended to include the tautomeric form containing the moiety




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Non-limiting exemplified compounds of the formulae described herein include a stereogenic sulfur atom and optionally one or more stereogenic carbon atoms. This disclosure provides examples of stereoisomer mixtures (e.g., racemic or scalemic mixture of enantiomers; mixture of diastereomers). This disclosure also describes and exemplifies methods for separating individual components of said stereoisomer mixtures (e.g., resolving the enantiomers of a racemic mixture). In cases of compounds containing only a stereogenic sulfur atom, resolved enantiomers are graphically depicted using one of the two following formats: formulas A/B (hashed and solid wedge three-dimensional representation); and formula C (“flat structures with *-labelled stereogenic sulfur).




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In reaction schemes showing resolution of a racemic mixture, Formulas A/B and C are intended only to convey that the constituent enantiomers were resolved in enantiopure pure form (about 98% ee or greater). The schemes that show resolution products using the formula A/B format are not intended to disclose or imply any correlation between absolute configuration and order of elution.


Analogous formulas are used for compounds containing both stereogenic sulfur and carbon atoms.


Some of the compounds shown in the tables below are graphically represented using the formula A/B format. However, unless otherwise indicated (e.g., when the compound is synthesized from enantiomerically enriched starting materials (see e.g., compound 964a, Example 573), the stereogenic center is assigned based on the starting materials), the depicted stereochemistry at sulfur shown for each of the tabulated compounds drawn in the formula A/B format is a tentative assignment and based, by analogy, on the absolute stereochemistry assigned to compound 162bb herein (see FIG. 5).


In some embodiments, for two enantiomers or two epimers of Formula AA compounds which differ in the stereochemical configuration at the sulfur atom of the S(O)NHR3(═N) moiety, one of the two enantiomers or epimers has greater NLRP3 antagonistic activity than the other.


In certain embodiments, when R3═H, for two enantiomers or two epimers of Formula AA compounds which differ in the stereochemical configuration at the sulfur atom of the S(O)NHR3(═N) moiety, the enantiomer or epimer with (R)-stereochemical configuration at the sulfur atom has greater NLRP3 antagonistic activity than the enantiomer or epimer with (S)-stereochemical configuration at the sulfur atom. For example, the enantiomer or epimer with (R)-stereochemical configuration at the sulfur atom exhibits a lower ICso value in the hTHP-1 assay described herein.


The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.





DESCRIPTION OF DRAWINGS


FIG. 1: Expression levels of RNA encoding NLRP3 in Crohn's Disease patients who are responsive and non-responsive to infliximab.



FIG. 2: Expression levels of RNA encoding IL-1β in Crohn's Disease patients who are responsive and non-responsive to infliximab.



FIG. 3: Expression levels of RNA encoding NLRP3 in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab.



FIG. 4: Expression levels of RNA encoding IL-1β in Ulcerative Colitis (UC) patients who are responsive and non-responsive to infliximab.



FIG. 5 depicts ball-and-stick representations of two crystallographically independent molecules of compound 162bb in the asymmetrical unit.





DETAILED DESCRIPTION

In one aspect, provided herein is a compound of Formula AA




embedded image


wherein


m=0, 1, or 2;


n=0, 1, or 2;


o=1 or 2;


p=0, 1, 2, or 3; wherein the sum of o and p is from 1 to 4;


wherein


A is a 5- to 10-membered heteroaryl or a C6-C10 aryl;


B is a 6-membered heteroaromatic ring containing 1-3 N atoms, or an N-oxide thereof; wherein at least one R6 is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA;


R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,


wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);


wherein each C1-C6 alkyl sub stituent and each C1-C6 alkoxy sub stituent of the R1 or R2C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9, or oxo;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one monocyclic or bicyclic C4-C12 carbocyclic ring or at least one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein:


a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and


b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13 S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and


wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, hydroxy, oxo, CN, NO2, COC1—C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, NH, NR13, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R10 is C1-C6 alkyl;


each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, (C═NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR11R12;


or R8 and R9 taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


R13 is C1-C6 alkyl, C1-C6 haloalkyl, or —(Z1—Z2)a1—Z3;


each of R11 and R12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, and —(Z1—Z2)a1—Z3;


a1 is an integer selected from 0-10 (e.g., 0-5);


each Z1 is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;


each Z2 is independently a bond, NH, N(C1-C6 alkyl), —O—, —S—, or 5-10 membered heteroarylene;


Z3 is independently C6-C10 aryl, C2-C6 alkyenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


R3 is selected from hydrogen, cyano, hydroxy, CO2C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, and




embedded image


wherein the C1-C2 alkylene group is optionally substituted with oxo;


R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R6;


R15 is —(Z4—Z5)a2—Z6;


a2 is an integer selected from 1-10 (e.g., 1-5 (e.g., 2-5));


each Z4 is independently selected from —O—, —S—, —NH—, and —N(C1-C3 alkyl)-;


provided that the Z4 group directly attached to R1 or R2 is —O— or —S—;


each Z5 is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and


Z6 is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C1-C6 alkoxy), or an optionally substituted group selected from the group consisting of:


C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


with the proviso that the compound of Formula AA is not a compound selected from the group consisting of:




embedded image


embedded image


or a pharmaceutically acceptable salt thereof.


In one aspect, provided herein is a compound of Formula AA:




embedded image


wherein


m=0, 1, or 2;


n=0, 1, or 2;


o=1 or 2;


p=0, 1, 2, or 3; wherein the sum of o and p is from 1 to 4;


wherein


A is a 5- to 10-membered heteroaryl or a C6-C10 aryl;


B is a 6-membered heteroaromatic ring containing 1-3 N atoms, or an N-oxide thereof;


wherein at least one R6 is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA;


R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,


wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);


wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy sub stituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9, or oxo;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one monocyclic or bicyclic C4-C12 carbocyclic ring or at least one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein:


a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and


b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13 S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and


wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1—C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6 and R7 are each optionally substituted with one or more substituents, independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, NH, NR13, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R10 is C1-C6 alkyl; each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, (C═NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR11R12;


or R8 and R9 taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


R13 is C1-C6 alkyl, C1-C6 haloalkyl, or —(Z1—Z2)a1—Z3;


each of R11 and R12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, and —(Z1—Z2)a1—Z3;


al is an integer selected from 0-10 (e.g., 0-5);


each Z1 is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;


each Z2 is independently a bond, NH, N(C1-C6 alkyl), —O—, —S—, or 5-10 membered heteroarylene;


Z3 is independently C6-C10 aryl, C2-C6 alkyenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


R3 is selected from hydrogen, cyano, hydroxy, CO2C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, and




embedded image


wherein the C1-C2 alkylene group is optionally substituted with oxo;


R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R6;


R15 is —(Z4—Z5)a2—Z6;


a2 is an integer selected from 1-10 (e.g., 1-5 (e.g., 2-5));


each Z4 is independently selected from —O—, —S—, —NH—, and —N(C1-C3 alkyl)-; provided that the Z4 group directly attached to R1 or R2 is —O— or —S—;


each Z5 is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and


Z6 is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C1-C6 alkoxy), or an optionally substituted group selected from the group consisting of:


C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


with the proviso that the compound of Formula AA is not a compound selected from the group consisting of:




embedded image


or a pharmaceutically acceptable salt thereof.


In one aspect, provided herein is a compound of Formula AA




embedded image


wherein

  • m=0, 1, or 2;
  • n=0, 1, or 2;
  • o=1 or 2;
  • p=0, 1, 2, or 3;
  • wherein the sum of o and p is from 1 to 4;
  • wherein
  • A is a 5- to 10-membered heteroaryl or a C6-C10 aryl;
  • B is a 6-membered heteroaromatic ring containing 1-3 N atoms, or an N-oxide thereof;
  • wherein
  • at least one R6 is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA;
  • R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH—(C═NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,
  • wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
    • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;
  • R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1—C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1—C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,
  • wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;
  • R10 is C1-C6 alkyl;
  • each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, (C═NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl or 3- to 7-membered heterocycloalkyl; or R8 and R9 taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;
  • R13 is C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; each of R11 and R12 at each occurrence is independently selected from hydrogen and C1-C6 alkyl; and
  • R3 is selected from hydrogen, cyano, hydroxy, CO2C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, and




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wherein the C1-C2 alkylene group is optionally substituted with oxo; R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R6;

  • with the proviso that the compound of Formula AA is not a compound selected from the group consisting of:




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or a pharmaceutically acceptable salt thereof.


In another aspect, provided herein is a compound of Formula AA




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wherein the compound of Formula AA is selected from




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wherein


m=0, 1, or 2;


n=0, 1, or 2;


m′=0, 1, or 2;


n′=0, 1, or 2; wherein the sum of m′ and n′ is 0, 1, or 3;


m″=0, 1, or 2;


n″=0, 1, or 2; wherein the sum of m″ and n″ is 2;


m′″=1;


n′″=1;


o=1 or 2;


p=0, 1, 2, or 3; wherein the sum of o and p is from 1 to 4;


wherein


A′ is selected from:


a 6- to 10-membered heteroaryl,


a C6-C10 aryl,


a 5-membered heteroaryl comprising 2 or more heteroatoms,


a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR1, and


a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety;


A″ is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety;


B is a 6-membered heteroaromatic ring containing 1-3 N atoms, or an N-oxide thereof;


B′ is 2-pyridyl, 3-pyridyl, or an N-oxide thereof;


B″ is 4-pyridyl or an N-oxide thereof;


wherein


at least one R6 is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-2, Formula AA-3, and Formula AA-4;


at least one R6′ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-5;


at least one R6″ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-1;


R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,


wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);


wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9, or oxo;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, are each optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein:


a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and


b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13 S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and


wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9,


wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R1′ and R2′ are each independently selected from C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, Cl, Br, I, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,


wherein the C2-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);


wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1′ or R2′ C3-C7 cycloalkyl or of the R1′ or R2′ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9, or oxo;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R1′ and R2′ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9,


wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R2″ is F or CH3; or


when the compound of Formula AA is a compound of Formula AA-4, one pair of R1 and R2″ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and


wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, hydroxy, oxo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R6′ and R7′ are each independently selected from unbranched C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, hydroxy, oxo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6′ and R7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkoxy that R6′ or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6′ or R7′ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6′ and on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R6″ is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, hydroxy, oxo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6″ is optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and


wherein the C1-C6 alkyl or C1-C6 alkoxy that R6″ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6″ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R10 is C1-C6 alkyl;


each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, (C═NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR11R12;


or R8 and R9 taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


R13 is C1-C6 alkyl, C1-C6 haloalkyl, or —(Z1—Z2)a1—Z3; each of R11 and R2 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, and —(Z1—Z2)a1—Z3;


a1 is an integer selected from 0-10 (e.g., 0-5);


each Z1 is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;


each Z2 is independently a bond, NH, N(C1-C6 alkyl), —O—, —S—, or 5-10 membered heteroarylene;


Z3 is independently C6-C10 aryl, C2-C6 alkyenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C alkoxy, oxo, N(C1-C6alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


R3 is selected from hydrogen, cyano, hydroxy, CO2C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, and




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wherein the C1-C2 alkylene group is optionally substituted with oxo;


R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R6;


R15 is —(Z4—Z5)a2—Z6;


a2 is an integer selected from 1-10 (e.g., 1-5 (e.g., 2-5));


each Z4 is independently selected from —O—, —S—, —NH—, and —N(C1-C3 alkyl)-;


provided that the Z4 group directly attached to R1 or R2 is —O— or —S—;


each Z5 is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and


Z6 is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C1-C6 alkoxy), or an optionally substituted group selected from the group consisting of:


C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


or a pharmaceutically acceptable salt thereof.


In another aspect, provided herein is a compound of Formula AA:




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wherein the compound of Formula AA is selected from




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wherein


m=0, 1, or 2;


n=0, 1, or 2;


m′=0, 1, or 2;


n′=0, 1, or 2; wherein the sum of m′ and n′ is 0, 1, or 3;


m″=0, 1, or 2;


n″=0, 1, or 2; wherein the sum of m″ and n″ is 2;


m′″=1;


n′″=1;


o=1 or 2;


p=0, 1, 2, or 3; wherein the sum of o and p is from 1 to 4;


wherein


A′ is selected from:


a 6- to 10-membered heteroaryl,


a C6-C10 aryl,


a 5-membered heteroaryl comprising 2 or more heteroatoms,


a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR1, and


a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety;


A″ is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety;


B is a 6-membered heteroaromatic ring containing 1-3 N atoms, or an N-oxide thereof;


B′ is 2-pyridyl, 3-pyridyl, or an N-oxide thereof;


B″ is 4-pyridyl or an N-oxide thereof;


wherein


at least one R6 is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-2, Formula AA-3, and Formula AA-4;


at least one R6′ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-5;


at least one R6″ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-1;


R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,


wherein the C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);


wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9, or oxo;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, are each optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein:


a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and


b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13 S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and


wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9,


wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R1′ and R2′ are each independently selected from C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, Cl, Br, I, CN, NO2, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NR8R9, C(O)R13, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,


wherein the C2-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, R15, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOG-C10 aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);


wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1′ or R2′ C3-C7 cycloalkyl or of the R1′ or R2′ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C0-C3 alkylene)C6-C10 aryl, halo, NR8R9, or oxo;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R1′ and R2′ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and


wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9,


wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R2″ is F or CH3; or


when the compound of Formula AA is a compound of Formula AA-4, one pair of R1 and R2″ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and


wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R6′ and R7′ are each independently selected from unbranched C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6′ and R7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkoxy that R6′ or R7′ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6′ or R7′ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R6″ is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6″ is optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and


wherein the C1-C6 alkyl or C1-C6 alkoxy that R6″ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6″ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


R10 is C1-C6 alkyl;


each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, (C═NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR11R12;


or R8 and R9 taken together with the nitrogen they are attached to form a 3- to 10-membered monocyclic or bicyclic ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to, wherein the ring is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


R13 is C1-C6 alkyl, C1-C6 haloalkyl, or —(Z1—Z2)a1—Z3; each of R11 and R12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, and —(Z1—Z2)a1—Z3;


al is an integer selected from 0-10 (e.g., 0-5);


each Z1 is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;


each Z2 is independently a bond, NH, N(C1-C6 alkyl), —O—, —S—, or 5-10 membered heteroarylene;


Z3 is independently C6-C10 aryl, C2-C6 alkyenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


R3 is selected from hydrogen, cyano, hydroxy, CO2C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, and




embedded image


wherein the C1-C2 alkylene group is optionally substituted with oxo;


R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R6;


R15 is —(Z4—Z5)a2—Z6;


a2 is an integer selected from 1-10 (e.g., 1-5 (e.g., 2-5));


each Z4 is independently selected from —O—, —S—, —NH—, and —N(C1-C3 alkyl)-;


provided that the Z4 group directly attached to R1 or R2 is —O— or —S—;


each Z5 is independently C1-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and


Z6 is OH, OC1-C6 alkyl, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, NHC(O)(C1-C6 alkyl), NHC(O)(C1-C6 alkoxy), or an optionally substituted group selected from the group consisting of:


C6-C10 aryl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 3- to 10-membered heterocycloalkyl, each of which is optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, oxo, N(C1-C6 alkyl)2, NH2, NH(C1-C6 alkyl), and hydroxy;


or a pharmaceutically acceptable salt thereof.


In another aspect, described herein is a compound of Formula AA




embedded image


wherein the compound of Formula AA is selected from




embedded image


wherein

  • m=0, 1, or 2;
  • n=0, 1, or 2;
  • m′=0, 1, or 2;
  • n′=0, 1, or 2;
  • wherein the sum of m′ and n′ is 0, 1, or 3;
  • m″=0, 1, or 2;
  • n″=0, 1, or 2;
  • wherein the sum of m″ and n″ is 2;
  • m′″=1;
  • n′″=1;
  • o=1 or 2;
  • p=0, 1, 2, or 3;
  • wherein the sum of o and p is from 1 to 4;
  • wherein
  • A′ is selected from:
  • a 6- to 10-membered heteroaryl,
  • a C6-C10 aryl,
  • a 5-membered heteroaryl comprising 2 or more heteroatoms,
  • a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH,
  • and NR1, and
  • a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety;
  • A″ is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety;
  • B is a 6-membered heteroaromatic ring containing 1-3 N atoms, or an N-oxide thereof;
  • B′ is 2-pyridyl, 3-pyridyl, or an N-oxide thereof;
  • B″ is 4-pyridyl or an N-oxide thereof;
  • wherein
  • at least one R6 is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-2, Formula AA-3, and Formula AA-4;
  • at least one R6′ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-5;
  • at least one R6″ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-1;
  • R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH—(C═NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,


wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;

  • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo;
  • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;
  • R1′ and R2′ are each independently selected from C2-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, Cl, Br, I, CN, NO2, COC1-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10- membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C═NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,
  • wherein the C2-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl; wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1′ or R2′ C3-C7 cycloalkyl or of the R1′ or R2′ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1′ and R2′ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;
  • R2″ is F or CH3;
  • or, when the compound of Formula AA is a compound of Formula AA-4, one pair of R1 and R2″ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;
  • R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,
  • wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;
  • R6′ and R7′ are each independently selected from unbranched C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,
  • wherein R6′ and R7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkoxy that R6′ or R7′ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6′ or R7′ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6′ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;
  • R6″ is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6″ is optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6″ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6″ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;

  • R10 is C1-C6 alkyl;
  • each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, (C═NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl or 3- to 7-membered heterocycloalkyl; or R8 and R9 taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to;
  • R13 is C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl;
  • each of R11 and R12 at each occurrence is independently selected from hydrogen and C1-C6 alkyl; and
  • R3 is selected from hydrogen, cyano, hydroxy, CO2C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl, and




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wherein the C1-C2 alkylene group is optionally substituted with oxo; R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R6;

  • or a pharmaceutically acceptable salt thereof.


The Formula AA


In some embodiments, Formula AA is Formula AA-1




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In some embodiments, Formula AA is Formula AA-2




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In some embodiments, Formula AA is Formula AA-3




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In some embodiments, Formula AA is Formula AA-4




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In some embodiments, Formula AA is Formula AA-5




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In some embodiments the variables shown in the formulae herein are as follows:


The variables m, m′, m″, n, n′, and n″


In some embodiments m=0, 1, or 2.


In some embodiments m=0 or 1.


In some embodiments m=1 or 2.


In some embodiments m=0 or 2.


In some embodiments m=0.


In some embodiments m=1.


In some embodiments m=2.


In some embodiments n=0, 1, or 2.


In some embodiments n=0 or 1.


In some embodiments n=1 or 2.


In some embodiments n=0 or 2.


In some embodiments n=0.


In some embodiments n=1.


In some embodiments n=2.


In some embodiments, m=0 and n=0.


In some embodiments, m=1 and n=0.


In some embodiments, m=1 and n=1.


In some embodiments of the compound of Formula AA-1, m=1, and n=0.


In some embodiments of the compound of Formula AA-1, m=1, and n=1.


In some embodiments m′=0, 1, or 2.


In some embodiments m′=0 or 1.


In some embodiments m′=1 or 2.


In some embodiments m′=0 or 2.


In some embodiments m′=0.


In some embodiments m′=1.


In some embodiments m′=2.


In some embodiments n′=0, 1, or 2.


In some embodiments n′=0 or 1.


In some embodiments n′=1 or 2.


In some embodiments n′=0 or 2.


In some embodiments n′=0.


In some embodiments n′=1.


In some embodiments n′=2.


In some embodiments, m′=0 and n′=0.


In some embodiments, m′=1 and n′=0.


In some embodiments, m′=2 and n′=1.


In some embodiments, m′=1 and n′=2.


wherein the sum of m′ and n′ is 0, 1, or 3.


In some embodiments of the compound of Formula AA-2, m′=1 and n′=0.


In some embodiments m″=0, 1, or 2.


In some embodiments m″=0 or 1.


In some embodiments m″=1 or 2.


In some embodiments m″=0 or 2.


In some embodiments m″=0.


In some embodiments m″=1.


In some embodiments m″=2.


In some embodiments n″=0, 1, or 2.


In some embodiments n″=0 or 1.


In some embodiments n″=1 or 2.


In some embodiments n″=0 or 2.


In some embodiments n″=0.


In some embodiments n″=1.


In some embodiments n″=2.


In some embodiments, m″=0 and n″=2.


In some embodiments, m″=2 and n″=0.


In some embodiments, m″=1 and n″=1.


wherein the sum of m″ and n″ is 2.


In some embodiments of the compound of Formula AA-3, m″=1 and n″=1.


The Ring A, A′, and A″ and substitutions on the ring A, A′, and A″


The Ring A


In some embodiments, A is a 5- to 10-membered heteroaryl or a C7-C10 aryl


In some embodiments, A is a 5-membered heteroaryl.


In some embodiments, A is a 6- to 10-membered heteroaryl.


In some embodiments, A is a 6-membered heteroaryl.


In some embodiments, A is a C6-C10 aryl.


In some embodiments, A is a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR1.


In some embodiments, A is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety.


In some embodiments, A is other than a moiety selected from the group consisting of: pyrazolyl, 2-thiophenyl, 2-furanyl, or phenyl monosubstituted with an R1 or R2 at the position ortho to the bond connecting the phenyl to the S(O)(NH) moiety.


In some embodiments, A is selected from the group consisting of: 3-furanyl, 3-thiophenyl, pyrrolyl, imidazoyl, triazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, oxazolyl, pyridyl, pyrimidinyl, triazinyl, benzimidazolyl, benzothiophene, benzofuranyl, indazolyl, benzotriazolyl, quinolinyl, quinazolinyl, and benzotriazinyl.


In some embodiments, A is thiophenyl.


In some embodiments, A is thiazolyl.


In some embodiments, A is pyrazolyl.


In some embodiments, A is imidazolyl.


In some embodiments, A is pyrrolyl.


In some embodiments, A is oxazolyl.


In some embodiments, A is furanyl.


In some embodiments, A is isoxazolyl.


In some embodiments, A is isothiazolyl.


In some embodiments, A is triazolyl (e.g., 1,2,3-triazolyl or 1,2,4-triazolyl).


In some embodiments, A is pyridinyl.


In some embodiments, A is pyridimidinyl.


In some embodiments, A is pyrazinyl.


In some embodiments, A is pyridazinyl.


In some embodiments, A is triazinyl.


In some embodiments, A is phenyl.


In some embodiments, A is phenyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is naphthyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is furanyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 R2.


In some embodiments, A is furanyl optionally substituted with 1 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is thiophenyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is oxazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is thiazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is oxazolyl optionally substituted with 2 R1 or optionally substituted with 2 R2.


In some embodiments, A is thiazolyl optionally substituted with 2 R1 or optionally substituted with 2 R2.


In some embodiments, A is pyrazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is pyrazolyl optionally substituted with 1 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is pyrazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 R2.


In some embodiments, A is pyridyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is indazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is imidazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is pyrrolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is oxazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is furanyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is isoxazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is isothiazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is triazolyl (e.g., 1,2,3-triazolyl or 1,2,4-triazolyl) optionally substituted with 1 R1 and optionally substituted with 1 R2.


In some embodiments, A is pyridinyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is pyridimidinyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is pyrazinyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is pyridazinyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is triazinyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.


In some embodiments, A is phenyl substituted with 1 R1 and optionally substituted with 1 R2.


In some embodiments, A is naphthyl substituted with 1 R1 and optionally substituted with 1 R2.


In some embodiments, A is furanyl substituted with 1 R1 and optionally substituted with 1 R2.


In some embodiments, A is thiophenyl substituted with 1 R1 and optionally substituted with 1 R2.


In some embodiments, A is oxazolyl substituted with 1 R1 and optionally substituted with 1 R2.


In some embodiments, A is thiazolyl substituted with 1 R1 and optionally substituted with 1 R2.


In some embodiments, A is pyrazolyl substituted with 1 R1 and optionally substituted with 1 R2.


In some embodiments, A is pyridyl substituted with 1 R1 and optionally substituted with 1 R2.


In some embodiments, A is indazolyl optionally substituted with 1 R1 and optionally substituted with 1 R2.


In some embodiments, A is phenyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is furanyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is thiophenyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is oxazolyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is thiazolyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is pyrazolyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is pyridyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is imidazolyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is pyrrolyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is oxazolyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is furanyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is isoxazolyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is isothiazolyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is triazolyl (e.g., 1,2,3-triazolyl or 1,2,4-triazolyl) substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is pyridimidinyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is pyrazinyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is pyridazinyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is triazinyl substituted with 1 R1 and substituted with 1 R2.


In some embodiments, A is phenyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A is furanyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A is thiophenyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A is oxazolyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A is thiazolyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A is pyrazolyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A is pyridyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A is indazolyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A is phenyl, m is 0, and n is 0 or 1.


In some embodiments, A is furanyl, m is 0, and n is 0 or 1.


In some embodiments, A is thiophenyl, m is 0, and n is 0 or 1.


In some embodiments, A is oxazolyl, m is 0, and n is 0 or 1.


In some embodiments, A is thiazolyl, m is 0, and n is 0 or 1.


In some embodiments, A is pyrazolyl, m is 0, and n is 0 or 1.


In some embodiments, A is pyridyl, m is 0, and n is 0 or 1.


In some embodiments, A is thiazolyl, m is 1, and n is 1.


In some embodiments, A is pyrazolyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A is imidazolyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A is pyrrolyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A is oxazolyl, m is 1, and n is 1.


In some embodiments, A is furanyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A is isoxazolyl, m is 1, and n is 1.


In some embodiments, A is isothiazolyl, m is 1, and n is 1.


In some embodiments, A is triazolyl (e.g., 1,2,3-triazolyl or 1,2,4-triazolyl), m is 1, and n is 1.


In some embodiments, A is pyridinyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A is pyridimidinyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A is pyrazinyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A is pyridazinyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A is triazinyl, m is 1, and n is 1.


In some embodiments, A is one of the rings disclosed hereinbelow optionally substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line custom-character connects A to the S(O)(NHR3)═N moiety of Formula AA.


In some embodiments, the optionally substituted ring A




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is




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In some embodiments, the optionally substituted ring A is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A is selected from the following:




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In some embodiments of the compound of Formula AA, when ring A is phenyl, then R1 and R2 are each independently selected from C3 alkyl, C5-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C═NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

  • wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
  • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo;
  • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA, when ring A is pyridyl, then R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C═NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,

  • wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
    • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


The Ring A′ when Formula AA is Formula AA-1


In some embodiments, A′ is a 6- to 10-membered (e.g., 6-membered) heteroaryl or a C6-C10 (e.g., C6) monocyclic or bicyclic aryl, such as phenyl.


In some embodiments, A′ is a 6- to 10-membered (e.g., 6-membered) heteroaryl or a C7-C10 (e.g., C6) monocyclic or bicyclic aryl.


In some embodiments, A′ is a 6- to 10-membered (e.g., 6-membered) heteroaryl.


In some embodiments of the compound of Formula AA-1, A′ is a C6-C10 aryl.


In some embodiments, A′ is a 5-membered heteroaryl comprising 2 or more heteroatoms.


In some embodiments, A′ is a 5-membered heteroaryl comprising 1 heteroatom and/or heteroatomic group selected from N, NH, and NR1.


In some embodiments, A′ is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety.


In some embodiments, A′ is a 5-membered heteroaryl containing a sulfur and optionally one or more nitrogens.


In some embodiments, A′ is a C6-C10 aryl.


In some embodiments, A′ is other than pyrazolyl.


In some embodiments, A′ is thiophenyl (e.g., thiophen-3-yl).


In some embodiments, A′ is thiazolyl (e.g., thiazol-2-yl or thiazol-3-yl).


In some embodiments, A′ is pyrazolyl (e.g., pyrazol-2-yl).


In some embodiments, A′ is imidazolyl (e.g., imidazol-2-yl).


In some embodiments, A′ is naphthyl.


In some embodiments, A′ is furanyl.


In some embodiments, A′ is pyridyl.


In some embodiments, A′ is indazolyl.


In some embodiments, A′ is phenyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A′ is furanyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A′ is thiophenyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A′ is thiazolyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A′ is pyrazolyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A′ is pyridyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A′ is indazolyl, m is 0 or 1, and n is 0, 1, or 2.


In some embodiments, A′ is thiazolyl, m is 1, and n is 1.


In some embodiments, A′ is pyrazolyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A′ is imidazolyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A′ is pyrrolyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A′ is oxazolyl, m is 1, and n is 1.


In some embodiments, A′ is furanyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A′ is isoxazolyl, m is 1, and n is 1.


In some embodiments, A′ is isothiazolyl, m is 1, and n is 1.


In some embodiments, A′ is triazolyl (e.g., 1,2,3-triazolyl or 1,2,4-triazolyl), m is 1, and n is 1.


In some embodiments, A′ is pyridinyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A′ is pyridimidinyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A′ is pyrazinyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A′ is pyridazinyl, m is 1 or 2, and n is 1 or 2.


In some embodiments, A′ is triazinyl, m is 1, and n is 1.


In some embodiments, A′ is one of the rings disclosed hereinbelow optionally substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line custom-character connects A to the S(O)(NHR3)═N moiety of Formula AA.


In some embodiments, the optionally substituted ring A′




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In so


In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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me embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is




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In some embodiments, the optionally substituted ring A′ is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A′ is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A′ is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A′ is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A′ is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A′ is selected from the following:




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In some embodiments of the compound of Formula AA-1, when ring A′ is phenyl, then R1 and R2 are each independently selected from C3 alkyl, C5-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C═NR13)NR11R12, CONR8R9, SF5, SC1—C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

  • wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
    • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, when ring A is pyridyl, then R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C═NR13) NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,

  • wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
    • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


The Ring A″ when Formula AA is Formula AA-2


In some embodiments, A″ is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety.


In some embodiments, A″ is thiophen-2-yl.


In some embodiments, A″ is furan-2-yl.


In some embodiments, A″ is one of the rings disclosed hereinbelow optionally substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line custom-character connects A to the S(O)(NHR3)═N moiety of Formula AA.


In some embodiments, the optionally substituted ring A″




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is


The Ring A″ when Formula AA is Formula AA-3


In some embodiments, A″ is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety.


In some embodiments, A″ is thiophen-2-yl.


In some embodiments, A″ is furan-2-yl.


In some embodiments, A″ is furan-2-yl substituted with 2 R1′.


In some embodiments, A″ is furan-2-yl substituted with 2 R2′.


In some embodiments, A″ is furan-2-yl substituted with 1 R1′ and substituted with 1 R2′.


In some embodiments, A″ is thiophen-2-yl substituted with 2 R1′.


In some embodiments, A″ is thiophen-2-yl substituted with 2 R2′.


In some embodiments, A″ is thiophen-2-yl substituted with 1 R1′ and substituted with 1 R2′.


In some embodiments, A″ is one of the rings disclosed hereinbelow optionally substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line custom-character connects A″ to the S(O)(NHR3)═N moiety of Formula AA.


In some embodiments, the optionally substituted ring A




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A is selected from the group consisting of:




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In some embodiments, the optionally substituted ring A is




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The Ring A″ when the compound is a compound of Formula AA-4


In some embodiments, A″ is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety.


In some embodiments, A″ is thiophen-2-yl.


In some embodiments, A″ is furan-2-yl.


In some embodiments, A″ is one of the rings disclosed hereinbelow optionally substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line custom-character connects A to the S(O)(NHR3)═N moiety of Formula AA.


In some embodiments, the optionally substituted ring A




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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In some embodiments, the optionally substituted ring A″ is




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The Ring when Formula AA is Formula AA-5




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In some embodiments,




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In some embodiments,




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In some embodiments,




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In some embodiments,




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In some embodiments,




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In some embodiments,




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In some embodiments,




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The Groups R1′, R2, R2′, and R2″


The Groups R1 and R2


In some embodiments, R′, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.


In some embodiments, R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.


In some embodiments, R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R′, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3 -dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R1, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl. For example, R1 is fluoro.


In some embodiments, R1, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R1 is 2-hydroxy-2-propyl; or R1 is 1,2-dihydroxy-2-propyl).


In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.


In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.


In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3 -dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.


In some embodiments, R2, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy.


In certain of these embodiments, one or more R1 is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR8R9.


In certain of these embodiments, one or more R1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R15.


In certain of these embodiments (e.g., a2=1 or 2), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain of these embodiments (e.g., a2=1), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain embodiments (e.g., a2=1), one or more R1 is independently selected from:




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In certain embodiments (e.g., a2>1), one or more R1 is




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In some embodiments, one or more R1 is independently C1-C6 alkyl substituted with one or more (e.g., one) NR8R9 and further optionally substituted with one or more halo.


In certain of these embodiments, one or more R1 is independently selected from: (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; and dimethylamino(cyclopropyl)methyl (e.g., one or more R1 is dimethylaminomethyl or methylaminomethyl).


In some embodiments, one or more R1 is C1-C6 alkyl that is optionally substituted with one or more halo. In certain of these embodiments, one or more R1 is C2-C6 alkyl that is optionally substituted with one or more halo. As non-limiting examples, R1 is ethyl or difluoromethyl.


In some embodiments, one or more R1 when present is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo and further optionally substituted with one or more C1-C6 alkyl. For example, R1 is 5-methyl-oxazolidin-2-one-5-yl.


In certain of any of the foregoing embodiments of R1, one or more R2 is independently selected from C1-C6 alkyl, C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and halo.


In some embodiments, R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring (e.g., C5 or C6 carbocyclic ring) or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g., methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g., isopropoxyl), OC3-C10 cycloalkyl, NR8R9, ═NR10 CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g., amino, methylamino, or dimethylamino), ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C5-C6 carbocyclic ring optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino; or


R1 and R2 are on adjacent atoms, and taken together, independently form




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each of which is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino; wherein the asterisk represents a point of attachment to a carbon atom; and the custom-character represents a point of attachment to a carbon or a nitrogen atom.


In some embodiments, R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic C4-C12 carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.


In some embodiments, R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.


In some embodiments, R1 and R2 are different.


In some embodiments, R1 and R2 are the same.


In some embodiments, R1 is para or meta to R2.


In some embodiments, R1 is para or ortho to R2.


In some embodiments, R1 is ortho or meta to R2.


In some embodiments, R1 is para to R2.


In some embodiments, R1 is meta to R2.


In some embodiments, R1 is ortho to R2.


The Groups R1 and R2 when Formula AA is Formula AA-1


In some embodiments, R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.


In some embodiments, R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.


In some embodiments, R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3 -dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R1, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R1 is 2-hydroxy-2-propyl; or R1 is 1,2-dihydroxy-2-propyl).


In some embodiments, R1, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl. For example, R1 is fluoro.


In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.


In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.


In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.


In some embodiments, R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.


In some embodiments of the compound of Formula AA-1, R2, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy.


In certain of these embodiments, one or more R1 is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR8R9.


In certain of these embodiments, one or more R1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R15.


In certain of these embodiments (e.g., a2=1 or 2), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain of these embodiments (e.g., a2=1), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain embodiments (e.g., a2=1), one or more R1 is independently selected from:




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In certain embodiments (e.g., a2 >1), one or more R1 is




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In some embodiments, one or more R1 is independently C1-C6 alkyl substituted with one or more (e.g., one) NR8R9 and further optionally substituted with one or more halo.


In certain of these embodiments, one or more R1 is independently selected from: (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; and dimethylamino(cyclopropyl)methyl (e.g., one or more R1 is dimethylaminomethyl or methylaminomethyl).


In some embodiments, one or more R1 is C1-C6 alkyl that is optionally substituted with one or more halo. In certain of these embodiments, one or more R1 is C2-C6 alkyl that is optionally substituted with one or more halo. As non-limiting examples, R1 is ethyl or difluoromethyl.


In some embodiments, one or more R1 when present is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo and further optionally substituted with one or more C1-C6 alkyl. For example, R1 is 5-methyl-oxazolidin-2-one-5-yl.


In certain of any of the foregoing embodiments of R1, one or more R2 is independently selected from C1-C6 alkyl, C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and halo.


In some embodiments of the compound of Formula AA-1, R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring (e.g., C5 or C6 carbocyclic ring) or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g., methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g., isopropoxyl), OC3-C10 cycloalkyl, NR8R9, ═NR10 CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g., amino, methylamino, or dimethylamino), ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C5-C6 carbocyclic ring optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino; or


R1 and R2 are on adjacent atoms, and taken together, independently form




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each of which is optionally substituted with one or more substituents independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino; wherein the asterisk represents a point of attachment to a carbon atom; and the custom-character represents a point of attachment to a carbon or a nitrogen atom.


In some embodiments of the compound of Formula AA-1, R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic C4-C12 carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.


In some embodiments of the compound of Formula AA-1, R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.


The Groups R1 and R2 when Formula AA is Formula AA-2


In some embodiments, R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.


In some embodiments, R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.


In some embodiments, R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.


In some embodiments, R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R1, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl. For example, R1 is fluoro.


In some embodiments, R1, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro. For example, R1, when present, is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R1 is 2-hydroxy-2-propyl; or R1 is 1,2-dihydroxy-2-propyl).


In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.


In some embodiments, R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.


In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3 -dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3 -dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.


In some embodiments, R2, when present, is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy.


In certain of these embodiments, one or more R1 is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR8R9.


In certain of these embodiments, one or more R1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R15.


In certain of these embodiments (e.g., a2=1 or 2), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain of these embodiments (e.g., a2=1), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain embodiments (e.g., a2=1), one or more R1 is independently selected from:




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In certain embodiments (e.g., a2 >1), one or more R1 is




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In some embodiments, one or more R1 is independently C1-C6 alkyl substituted with one or more (e.g., one) NR8R9 and further optionally substituted with one or more halo.


In certain of these embodiments, one or more R1 is independently selected from: (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; and dimethylamino(cyclopropyl)methyl (e.g., one or more R1 is dimethylaminomethyl or methylaminomethyl).


In some embodiments, one or more R1 is C1-C6 alkyl that is optionally substituted with one or more halo. In certain of these embodiments, one or more R1 is C2-C6 alkyl that is optionally substituted with one or more halo. As non-limiting examples, R1 is ethyl or difluoromethyl.


In some embodiments, one or more R1 when present is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo and further optionally substituted with one or more C1-C6 alkyl. For example, R1 is 5-methyl-oxazolidin-2-one-5-yl.


In certain of any of the foregoing embodiments of R1, one or more R2 is independently selected from C1-C6 alkyl, C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and halo.


In some embodiments, one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, when the compound of Formula AA is a compound of Formula AA-2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, NR10 CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


The Groups R1′


and R2′ when Formula AA is Formula AA-3


In some embodiments, R1′, when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted with one or more hydroxy, C2-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; Cl; Br; I; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.


In some embodiments, R1′, when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted with one or more hydroxyl, or NR8R9.


In some embodiments, R1′, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; isopropyl; ethyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12. In certain of these embodiments, R1′ is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl. For example, R1′ is 2-hydroxy-2-propyl. As another example, R1′ is 1,2-dihydroxy-2-propyl.


In some embodiments, R1′, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; isopropyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12. For example, R1′ is 2-hydroxy-2-propyl.


In some embodiments, R2′, when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted with one or more hydroxy, C2-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; Cl; Br; I; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.


In some embodiments, R2′, when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.


In some embodiments, R2′, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; isopropyl; ethyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12. For example, R2′ is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R2′ is 2-hydroxy-2-propyl; or R2′ is 1,2-dihydroxy-2-propyl).


In some embodiments, R2′, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; isopropyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12. For example, R2′ is 2-hydroxy-2-propyl.


In some embodiments, one or more R1′ when present is independently a C2-C6 alkyl substituted with one or more hydroxy.


In certain of these embodiments, one or more R1′ is independently selected from 1-hydroxy-2-methyl prop an-2-yl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.


In some embodiments, one or more R1′ when present is independently a C2-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR8R9.


In certain of these embodiments, one or more R1′ is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.


In some embodiments, one or more R1′ when present is independently a C2-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R15.


In certain of these embodiments (e.g., a2=1 or 2), one or more R1′ is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain of these embodiments (e.g., a2=1), one or more R1′ is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain embodiments (e.g., a2=1), one or more R1′ is independently selected from:




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In certain embodiments (e.g., a2 >1), one or more is




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In some embodiments, one or more R1′ is independently C2-C6 alkyl substituted with one or more (e.g., one) NR8R9 and further optionally substituted with one or more halo.


In certain of these embodiments, one or more R1′ is independently selected from: 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (1-(cyclobutyl)amino-eth-1-yl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; and 1-dimethylamino-2,2,2-trimethyleth-1-yl.


In some embodiments, one or more R1′ is C2-C6 alkyl that is optionally substituted with one or more halo. In certain of these embodiments, one or more R1′ is C2-C6 alkyl that is optionally substituted with one or more halo. As non-limiting examples, R1′ is ethyl or difluoroethyl.


In some embodiments, one or more R1′ when present is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo and further optionally substituted with one or more C1-C6 alkyl. For example, R1′ is 5-methyl-oxazolidin-2-one-5-yl.


In certain of any of the foregoing embodiments of R1′, one or more R2′ is independently selected from C2-C6 alkyl, C2-C6 alkyl optionally substituted with one or more hydroxy, C2-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, Br, Cl, and I.


In some embodiments, one pair of R1′ and R2′ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, R1′ and R2′ are the same.


In some embodiments, R1′ and R2′ are different.


In some embodiments, R1′ is meta to R2′.


In some embodiments, R1′ is ortho to R2′.


R1 and R2″ when Formula AA is Formula AA-4


In some embodiments, R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12, S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.


In some embodiments, R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.


In some embodiments, R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In certain embodiments, R1 is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (methylamino)methyl; (dimethylamino)methyl; and fluoro. As a non-limiting example of the foregoing embodiments, R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R1 is 2-hydroxy-2-propyl; or R1 is 1,2-dihydroxy-2-propyl).


In some embodiments, R1 is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. In some embodiments of the compound of Formula AA-4, R1 is 2-hydroxy-2-propyl. n some embodiments of the compound of Formula AA-4, R1 is fluoro.


In some embodiments, R2″ is fluoro.


In some embodiments, R2″ is methyl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy.


In certain of these embodiments, one or more R1 is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR8R9.


In certain of these embodiments, one or more R1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R15 .


In certain of these embodiments (e.g., a2=1 or 2), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain of these embodiments (e.g., a2=1), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain embodiments (e.g., a2=1), one or more R1 is independently selected from:




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In certain embodiments (e.g., a2>1), one or more R1 is




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In some embodiments, one or more R1 is independently C1-C6 alkyl substituted with one or more (e.g., one) NR8R9 and further optionally substituted with one or more halo.


In certain of these embodiments, one or more R1 is independently selected from: (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; and dimethylamino(cyclopropyl)methyl (e.g., one or more R1 is dimethylaminomethyl or methylaminomethyl).


In some embodiments, one or more R1 is C1-C6 alkyl that is optionally substituted with one or more halo. In certain of these embodiments, one or more R1 is C2-C6 alkyl that is optionally substituted with one or more halo. As non-limiting examples, R1 is ethyl or difluoromethyl.


In some embodiments, one or more R1 when present is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo and further optionally substituted with one or more C1-C6 alkyl. For example, R1 is 5-methyl-oxazolidin-2-one-5-yl.


In some embodiments, one pair of R1 and R2″ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, R1 and R2″ are the same.


In some embodiments, R1 and R2″ are different.


In some embodiments, R1 is meta to R2″.


In some embodiments, R1 is ortho to R2″.


R1 and R2″ when Formula AA is Formula AA-5


In some embodiments, R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.


In some embodiments, R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.


In some embodiments, R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; methyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.


In some embodiments, R1 is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R1 is 2-hydroxy-2-propyl; or R1 is 1,2-dihydroxy-2-propyl).


In some embodiments, R1 is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. For example, R1 is 2-hydroxy-2-propyl. For example, R1 is fluoro.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy.


In certain of these embodiments, one or more R1 is independently selected from 1-hydroxy-2-methylpropan-2-yl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; and 1,2,3-trihydroxy-2-propyl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) NR8R9.


In certain of these embodiments, one or more R1 is independently selected from 1-amino-2-hydroxy-prop-2-yl; 1-acetamido-2-hydroxy-prop-2-yl; and 1-(tert-butoxycarbonyl)amino-2-hydroxy-prop-2-yl.


In some embodiments, one or more R1 when present is independently a C1-C6 alkyl substituted with one or more hydroxy and further substituted with one or more (e.g., one) R15.


In certain of these embodiments (e.g., a2=1 or 2), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl; 1-(2-benzyloxyethoxy)-2-hydroxy-2-propyl; and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain of these embodiments (e.g., a2=1), one or more R1 is independently selected from 1-(2-hydroxyethoxy)-2-hydroxy-2-propyl and 1-(2-methoxyethoxy)-2-hydroxy-2-propyl.


In certain embodiments (e.g., a2=1), one or more R1 is independently selected from:




embedded image


In certain embodiments (e.g., a2>1), one or more R1 is




embedded image


In some embodiments, one or more R1 is independently C1-C6 alkyl substituted with one or more (e.g., one) NR8R9 and further optionally substituted with one or more halo.


In certain of these embodiments, one or more R1 is independently selected from: (methylamino)methyl; (2,2-difluoroeth-1-yl)(methyl)aminomethyl; (2,2,2-trifluoroeth-1-yl)(methyl)aminomethyl; (dimethylamino)methyl; 1-(dimethylamino)ethyl; 2-((methyl)aminomethyl)-prop-2-yl; 2-((methyl)amino)-prop-2-yl; (methyl)(cyclopropylmethyl)aminomethyl; (methyl)(2-(dimethylamino)eth-1-yl)aminomethyl; (cyclobutyl)(methyl)aminomethyl; 1-(cyclobutyl)amino-eth-1-yl; isopropylaminomethyl; (cyclobutyl)aminomethyl; cycloheptylaminomethyl; tetrahydropyranylaminomethyl; sec-butylaminomethyl; ethylaminomethyl; allylaminomethyl; (2,2-difluoroeth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)aminomethyl; (2-methoxy-eth-1-yl)(methyl)aminomethyl; 2-fluoro-1-dimethylamino-eth-1-yl; 1-dimethylamino-2,2-difluoroeth-1-yl; 1-dimethylamino-2,2,2-trifluoroeth-1-yl; 1-dimethylamino-2,2,2-trimethyleth-1-yl; and dimethylamino(cyclopropyl)methyl (e.g., one or more R1 is dimethylaminomethyl or methylaminomethyl).


In some embodiments, one or more R1 is C1-C6 alkyl that is optionally substituted with one or more halo. In certain of these embodiments, one or more R1 is C2-C6 alkyl that is optionally substituted with one or more halo. As non-limiting examples, R1 is ethyl or difluoromethyl.


In some embodiments, one or more R1 when present is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo and further optionally substituted with one or more C1-C6 alkyl. For example, R1 is 5-methyl-oxazolidin-2-one-5-yl.


In certain of any of the foregoing embodiments of one or more R2 is independently selected from C1-C6 alkyl, C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more C1-C6 alkoxy, and halo.


In some embodiments, R2″ is fluoro.


In some embodiments, R2− is methyl.


The variables o and p


In some embodiments, o=1 or 2.


In some embodiments, o=1.


In some embodiments, o=2.


In some embodiments, p=0, 1, 2, or 3.


In some embodiments, p=0.


In some embodiments, p=1.


In some embodiments, p=2.


In some embodiments, o=1 and p=0.


In some embodiments, o=2 and p=0.


In some embodiments, o=1 and p=1.


In some embodiments, o=1 and p=2.


In some embodiments, o=2 and p=1.


In some embodiments, o=2 and p=2.


In some embodiments, o=2 and p=3.


The ring B and substitutions on the ring B


In some embodiments, B is pyridyl or an N-oxide thereof (e.g., 2-pyridyl or an N-oxide thereof, 3-pyridyl or an N-oxide thereof, or 4-pyridyl or an N-oxide thereof).


In some embodiments, B is pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl).


In some embodiments, B is a pyridyl N-oxide (e.g., 2-pyridyl N-oxide, 3-pyridyl N-oxide, or 4-pyridyl N-oxide).


In some embodiments, B is pyrimidinyl or an N-oxide thereof (e.g., 4-pyrimidinyl or an N-oxide thereof, or 5-pyrimidinyl or an N-oxide thereof).


In some embodiments, B is pyridazinyl.


In some embodiments, B is pyrazinyl.


In some embodiments, B is triazinyl.


In some embodiments, B is one of the rings disclosed hereinbelow, substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line custom-character connects B to the NHC(O)group of Formula AA.


In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


embedded image


In some embodiments, the substituted ring B is:




embedded image


In certain of these embodiments, the substituted ring B is:




embedded image


In some embodiments, the substituted ring B is




embedded image


In certain of these embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In certain of these embodiments, the substituted ring B is




embedded image


The Ring B when Formula AA is Formula AA-1


In some embodiments, B is pyridyl or an N-oxide thereof (e.g., 2-pyridyl or an N-oxide thereof, 3-pyridyl or an N-oxide thereof, or 4-pyridyl or an N-oxide thereof).


In some embodiments, B is pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl).


In some embodiments, B is a pyridyl N-oxide (e.g., 2-pyridyl N-oxide, 3-pyridyl N-oxide, or 4-pyridyl N-oxide).


In some embodiments, B is pyrimidinyl or an N-oxide thereof (e.g., 4-pyrimidinyl or an N-oxide thereof, or 5-pyrimidinyl or an N-oxide thereof).


In some embodiments, B is pyridazinyl.


In some embodiments, B is pyrazinyl.


In some embodiments, B is triazinyl.


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B i




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




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In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


embedded image


In some embodiments, the substituted ring B is:




embedded image


In certain of these embodiments, the substituted ring B is:




embedded image


In some embodiments, the substituted ring B is




embedded image


In certain of these embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In certain of these embodiments, the substituted ring B is




embedded image


The Ring B when Formula AA is Formula AA-2


In some embodiments, B is pyridyl or an N-oxide thereof (e.g., 2-pyridyl or an N-oxide thereof, 3-pyridyl or an N-oxide thereof, or 4-pyridyl or an N-oxide thereof).


In some embodiments, B is pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl).


In some embodiments, B is a pyridyl N-oxide (e.g., 2-pyridyl N-oxide, 3-pyridyl N-oxide, or 4-pyridyl N-oxide).


In some embodiments, B is pyrimidinyl or an N-oxide thereof (e.g., 4-pyrimidinyl or an N-oxide thereof, or 5-pyrimidinyl or an N-oxide thereof).


In some embodiments, B is pyridazinyl.


In some embodiments, B is pyrazinyl.


In some embodiments, B is triazinyl.


In some embodiments, B is a 6-membered heteroaryl including from 1-2 optionally substituted nitrogen atoms.


In some embodiments, B is a N-substituted pyridonyl (e.g., N-substituted pyrid-2-on-4-yl).


In some embodiments, B is one of the rings disclosed hereinbelow, substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line custom-character connects B to the NHC(O)group of Formula AA.


In some embodiments, the substituted ring Bis




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is:




embedded image


In some embodiments, the substituted ring B is:




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


embedded image


In some embodiments, the substituted ring B is:




embedded image


In certain of these embodiments, the substituted ring B is:




embedded image


In some embodiments, the substituted ring Bis




embedded image


In certain of these embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In certain of these embodiments, the substituted ring B is




embedded image


The Ring B when Formula AA is Formula AA-3


In some embodiments, B is pyridyl or an N-oxide thereof (e.g., 2-pyridyl or an N-oxide thereof, 3-pyridyl or an N-oxide thereof, or 4-pyridyl or an N-oxide thereof).


In some embodiments, B is pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl).


In some embodiments, B is a pyridyl N-oxide (e.g., 2-pyridyl N-oxide, 3-pyridyl N-oxide, or 4-pyridyl N-oxide).


In some embodiments, B is pyrimidinyl or an N-oxide thereof (e.g., 4-pyrimidinyl or an N-oxide thereof, or 5-pyrimidinyl or an N-oxide thereof).


In some embodiments, B is pyridazinyl.


In some embodiments, B is pyrazinyl.


In some embodiments, B is triazinyl.


In some embodiments, B is one of the rings disclosed hereinbelow, substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line custom-character connects B to the NHC(O)group of Formula AA.


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring Bis




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


In some embodiments, the substituted ring B is selected from the group consisting of:




embedded image


embedded image


The Ring B′ when Formula AA is Formula AA-4


In some embodiments, B′ is 2-pyridyl or 3-pyridyl, or an N-oxide thereof.


In some embodiments, B′ is 2-pyridyl.


In some embodiments, B′ is 3-pyridyl.


In some embodiments, B′ is 2-pyridyl N-oxide.


In some embodiments, B′ is 3-pyridyl N-oxide.


In some embodiments, B′ is one of the rings disclosed hereinbelow, substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line custom-character connects B′ to the NHC(O)group of Formula AA.


In some embodiments, the substituted ring B′ is




embedded image


In some embodiments, the substituted ring B′ is




embedded image


In some embodiments, the substituted ring B′ is




embedded image


In some embodiments, the substituted ring B′ is




embedded image


In some embodiments, the substituted ring B′ is




embedded image


In some embodiments, the substituted ring B′ is




embedded image


In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is:




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In some embodiments, the substituted ring B′ is:




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In some embodiments, the substituted ring B′ is




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In certain of these embodiments, the substituted ring B′ is




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In some embodiments, the substituted ring B′ is




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In certain of these embodiments, the substituted ring B′ is




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The Ring B″


In some embodiments, B″ is 4-pyridyl.


In some embodiments, B″ is 4-pyridyl N-oxide.


In some embodiments, B″ is one of the rings disclosed hereinbelow, substituted as disclosed hereinbelow, wherein in each case the bond that is shown as being broken by the wavy line custom-character connects B″ to the NHC(O)group of Formula AA.


In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is




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In some embodiments, the substituted ring B″ is selected from the group consisting of:




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In some embodiments, the substituted ring B″ is selected from the group consisting of:




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In some embodiments, the substituted ring B″ is selected from the group consisting of:




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In some embodiments, the substituted ring B″ is selected from the group consisting of:




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In some embodiments, the substituted ring B″ is:




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In certain of these embodiments, the substituted ring B″ is:




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The groups R6, R6′, R6″, R7, and R7′


The Groups R6 and R7


In some embodiments, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


In some embodiments, each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments, R6 and R7 are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl; or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, R6 and R7 are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, R6 and R7 are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,

  • wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, R6 and R7 are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,

  • wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.


In some embodiments, each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.


In some embodiments, each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.


In some embodiments, each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl. For example, each R6 is isopropyl.


In some embodiments, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR20, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.


In some embodiments, each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.


In some embodiments, one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In certain embodiments (when one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9),the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted with one or more oxo, CH3, or hydroxy. For example, the C5 carbocyclic ring is substituted with one CH3. For example, the C5 carbocyclic ring is geminally substituted with two CH3.


In certain embodiments (when one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9), the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.


In some embodiments, each of R6 and R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or


one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


The Groups R6″ and R7 when Formula AA is Formula AA-1


In some embodiments of the compound of Formula AA-1, R6″ is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6″ is optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6″ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6″ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;


In some embodiments of the compound of Formula AA-1, each R6″ is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments of the compound of Formula AA-1, each R6″ is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-1, each R6″ is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.


In some embodiments of the compound of Formula AA-1, each R6″ is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl. For example, each R6″ is isopropyl.


In some embodiments of the compound of Formula AA-1, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments of the compound of Formula AA-1, R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


In some embodiments of the compound of Formula AA-1, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-1, each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.


In some embodiments of the compound of Formula AA-1, one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In certain embodiments of the compound of Formula AA-1 (when one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9), the C4-C8 carbocyclic ring is a C8 carbocyclic ring optionally substituted with one or more oxo, CH3, or hydroxy. For example, the C8 carbocyclic ring is substituted with one CH3. For example, the C8 carbocyclic ring is geminally substituted with two CH3.


In certain embodiments of the compound of Formula AA-1 (when one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9), the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.


In some embodiments of the compound of Formula AA-1, R6″ is selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6″ is optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6″ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6″ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


In some embodiments of the compound of Formula AA-1, R6″ is selected from C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,

  • wherein R6″ is optionally substituted with one or more substituents independently selected from hydroxy, Cl, Br, I, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6″ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6″ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • R7 is selected from C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, R6″ is selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,

  • wherein R6″ is optionally substituted with one or more substituents independently selected from hydroxy, Cl, Br, I, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6″ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6″ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • R7 is selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, OOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, each of R6″ and R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or


one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


The Groups R6 and R7 when Formula AA is Formula AA-2


In some embodiments of the compound of Formula AA-2, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,

  • wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-2, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-2, each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments of the compound of Formula AA-2, each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-2, each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-2, each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.


In some embodiments of the compound of Formula AA-2, each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl. For example, each R6 is isopropyl.


In some embodiments of the compound of Formula AA-2, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments of the compound of Formula AA-2, each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-2, each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.


In some embodiments of the compound of Formula AA-2, one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-2, one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In certain embodiments of the compound of Formula AA-2 (when one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.), the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted with one or more oxo, CH3, or hydroxy. For example, the C5 carbocyclic ring is substituted with one CH3. For example, the C5 carbocyclic ring is geminally substituted with two CH3.


In certain embodiments of the compound of Formula AA-2 (when one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9), the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.


In some embodiments, each of R6 and R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


The Groups R6 and R7 when Formula AA is Formula AA-3


In some embodiments of the compound of Formula AA-3, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,

  • wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-3, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-3, each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments of the compound of Formula AA-3, each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-3, each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.


In some embodiments of the compound of Formula AA-3, each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl. For example, each R6 is isopropyl.


In some embodiments of the compound of Formula AA-3, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments of the compound of Formula AA-3, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-3, each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.


In some embodiments of the compound of Formula AA-3, one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-3, one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In certain embodiments of the compound of Formula AA-3 (when one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9), the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted with one or more oxo, CH3, or hydroxy. For example, the C5 carbocyclic ring is substituted with one CH3. For example, the C5 carbocyclic ring is geminally substituted with two CH3.


In certain embodiments of the compound of Formula AA-3 (when one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9)the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.


In some embodiments, each of R6 and R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


The Groups R6 and R7 when Formula AA is Formula AA-4


In some embodiments of the compound of Formula AA-4, R6 and IC are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,

  • wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-4, R6 and R7 are each independently selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-4, each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments of the compound of Formula AA-4, each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-4, each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.


In some embodiments of the compound of Formula AA-4, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments of the compound of Formula AA-4, each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-4, each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.


In some embodiments, each of R6 and R7 is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


The Groups R6′ and R7′ when Formula AA is Formula AA-5


In some embodiments of the compound of Formula AA-5, R6′ and R7′ are each independently selected from unbranched C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6′ and R7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkoxy that R6′ or R7′ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6′ or R7′ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 10-membered heteroaryl, are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;


or one pair of R6′ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOH, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-5, R6′ and R7′ are each independently selected from unbranched C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,

  • wherein R6′ and R7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkoxy that R6′ or R7′ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6′ or R7′ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-5, R6′ and R7′ are each independently selected from unbranched C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6′ and R7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkoxy that R6′ or R7′ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6′ or R7′ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;

    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-5, each R6′ is independently selected from the group consisting of: unbranched C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the unbranched C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments of the compound of Formula AA-5, each R6′ is independently selected from the group consisting of: unbranched C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-5, each R6′ is independently selected from the group consisting of: unbranched C1-C6 alkyl and C3-C7 cycloalkyl.


In some embodiments of the compound of Formula AA-5, each R6′ is independently selected from the group consisting of: methyl, cyclopropyl, fluoro, and phenyl.


In some embodiments of the compound of Formula AA-5, each R7′ is independently selected from the group consisting of: unbranched C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments of the compound of Formula AA-5, each R7 is independently selected from the group consisting of: unbranched C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.


In some embodiments of the compound of Formula AA-5, each R7′ is independently selected from the group consisting of: methyl, cyclopropyl, fluoro, and phenyl.


In some embodiments of the compound of Formula AA-5, one pair of R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-5, one pair of R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In certain embodiments of the compound of Formula AA-5 (when one pair of R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9), the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted with one or more oxo, CH3, or hydroxy. For example, the C5 carbocyclic ring is substituted with one CH3. For example, the C5 carbocyclic ring is geminally substituted with two CH3.


In certain embodiments of the compound of Formula AA-5 (when one pair of R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9), the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.


In some embodiments, each of R6′ and R7′ is independently selected from the group consisting of: C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl; or


one pair of R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


The group R3


In some embodiments, R3 is selected from hydrogen, C1-C6 alkyl, and




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wherein the C1-C2 alkylene group is optionally substituted with oxo.


In some embodiments, R3 is hydrogen.


In some embodiments, R3 is other than hydrogen.


In some embodiments, R3 is cyano.


In some embodiments, R3 is hydroxy.


In some embodiments, R3 is C1-C6 alkoxy.


In some embodiments, R3 is C1-C6 alkyl.


In some embodiments, R3 is methyl.


In some embodiments, R3 is




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wherein the C1-C2 alkylene group is optionally substituted with oxo.


In some embodiments, R3 is —CH2R14.


In some embodiments, R3 is —C(O)R14. In certain of these embodiments, R3 is CHO. In certain other of these embodiments, R3 is C(O)C1-C6 alkyl.


In some embodiments, R3 is —CH2CH2R14.


In some embodiments, R3 is —CHR14CH3.


In some embodiments, R3 is —CH2C(O)R14.


In some embodiments, R3 is —C(O)CH2R14.


In some embodiments, R3 is CO2C1-C6 alkyl (e.g., CO2t-Bu).


The group R14


In some embodiments, R14 is hydrogen, C1-C6 alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R6.


In some embodiments, R14 is hydrogen or C1-C6 alkyl.


In some embodiments, R14 is hydrogen, 5- to 10-membered monocyclic or bicyclic heteroaryl or C6-C10 monocyclic or bicyclic aryl, wherein each C1-C6 alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R6.


In some embodiments, R14 is hydrogen.


In some embodiments, R14 is C1-C6 alkyl.


In some embodiments, R14 is methyl.


In some embodiments, R1′ is 5- to 10-membered monocyclic or bicyclic heteroaryl optionally independently substituted with 1 or 2 R6.


In some embodiments, R1′ is C6-C10 monocyclic or bicyclic aryl optionally independently substituted with 1 or 2 R6.


The moiety S(═O)(NHR3)═N—


In some embodiments, the sulfur in the moiety S(═O)(NHR3)═N— has (S) stereochemistry.


In some embodiments, the sulfur in the moiety S(═O)(NHR3)═N— has (R) stereochemistry.


The group R10


In some embodiments, R10 is C1-C6 alkyl.


In some embodiments, R10 is methyl.


In some embodiments, R10 is ethyl.


The groups R8 and R9


In some embodiments, each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, (C═NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl or 3- to 7-membered heterocycloalkyl; or R8 and R9 taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to.


In some embodiments, each of R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, (C═NR13)NR11R12, S(O2)C1-C6 alkyl, S(O2)NR11R12, COR13, CO2R13 and CONR11R12; wherein the C1-C6 alkyl is optionally substituted with one or more hydroxy, halo, C1-C6 alkoxy, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C7 cycloalkyl or 3- to 7-membered heterocycloalkyl; or R8 and R9 taken together with the nitrogen they are attached to form a 3- to 7-membered ring optionally containing one or more heteroatoms in addition to the nitrogen they are attached to.


In some embodiments, each of R8 and R9 at each occurrence is hydrogen,


In some embodiments, each R8 at each occurrence is hydrogen and each R9 at each occurrence is C1-C6 alkyl.


In some embodiments, each R8 at each occurrence is hydrogen and each R9 at each occurrence is methyl.


In some embodiments, each R8 at each occurrence is hydrogen and each R9 at each occurrence is ethyl.


In some embodiments, each of R8 and R9 at each occurrence is methyl.


In some embodiments, each of R8 and R9 at each occurrence is ethyl.


In some embodiments, R8 and R9 taken together with the nitrogen they are attached to form a 3-membered ring.


In some embodiments, R8 and R9 taken together with the nitrogen they are attached to form a 4-membered ring.


In some embodiments, R8 and R9 taken together with the nitrogen they are attached to form a 5-membered ring.


In some embodiments, R8 and R9 taken together with the nitrogen they are attached to form a 6-membered ring optionally containing one or more oxygen atoms in addition to the nitrogen they are attached to.


In some embodiments, R8 and R9 taken together with the nitrogen they are attached to form a 6-membered ring optionally containing one or more nitrogen atoms in addition to the nitrogen they are attached to.


In some embodiments, R8 and R9 taken together with the nitrogen they are attached to form a 7-membered ring.


In some embodiments, one of R8 and R9 is C(O)R13; R13 is —(Z1—Z2)a1—Z3; and al is 0.


In certain of these embodiments, the other one of R8 and R9 is hydrogen.


As a non-limiting example of the foregoing embodiments, NR8R9 is selected from the group consisting of: NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In some embodiments, one of R8 and R9 is C(O)R13; R13 is C1-C6 alkyl.


In certain embodiments, NR8R9 is selected from the group consisting of: NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, and NH(C═NR13)NR11R12.


In certain embodiments, NR8R9 is selected from the group consisting of: NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, and NHCOOC1-C6 alkyl.


The group R13


In some embodiments, R13 is C1-C6 alkyl.


In some embodiments, R13 is methyl.


In some embodiments, R13 is ethyl.


In some embodiments, R13 is C6-C10 aryl.


In some embodiments, R13 is phenyl.


In some embodiments, R13 is 5- to 10-membered heteroaryl.


In some embodiments, R13 is —(Z1—Z2)a1—Z3.


In certain of these embodiments, a1 is 0. In certain embodiments, Z3 is C6-C10 aryl or 5- to 10-membered heteroaryl.


In some embodiments, R13 is C6-C10 aryl.


In some embodiments, R13 is phenyl.


In some embodiments, R13 is 5- to 10-membered heteroaryl.


In some embodiments, C(O)R13 is selected from COC1-C6 alkyl, CO—C6-C10 aryl, and CO(5- to 10-membered heteroaryl).


The groups R11 and R12


In some embodiments, each of R11 and R12 at each occurrence is independently selected from hydrogen and C1-C6 alkyl.


In some embodiments, each of R11 and R12 at each occurrence is hydrogen,


In some embodiments, each R11 at each occurrence is hydrogen and each R12 at each occurrence is C1-C6 alkyl.


In some embodiments, each R11 at each occurrence is hydrogen and each 102 at each occurrence is methyl.


In some embodiments, each R11 at each occurrence is hydrogen and each R12 at each occurrence is ethyl.


In some embodiments, each of R11 and R12 at each occurrence is methyl.


In some embodiments, each of R11 and R12 at each occurrence is ethyl.


The Group R15


In some embodiments, R15 is —(Z4—Z5)a2—Z6.


In certain embodiments, a2 is 1-5.


In certain embodiments, the Z4 group directly attached to R1 or R2 is —O—.


In certain embodiments, each Z4 is independently —O— or —NH—, provided that the Z4 group directly attached to R1 or R2 is —O—.


In certain embodiments, each Z4 is —O—.


In certain embodiments, each Z5 is independently C2-C6 alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxyl. In certain these embodiments, each Z5 is independently C2-C4 (e.g., C2-C3 (e.g., C2 or C3)) alkylene.


In certain embodiments, Z6 is OH.


In certain embodiments, Z6 is NHC(O)(C1-C6 alkoxy).


In certain embodiments, Z6 is C6-C10 aryl.


In certain embodiments, Z6 is C1-C6 alkoxy.


In certain embodiments of R15, a2=1; and Z4 is 0. In certain of these embodiments, Z5 is C2-C4 (e.g., C2-C3 (e.g., C2 or C3)) alkylene. In certain of the foregoing embodiments, Z6 is selected from OH, NHC(O)(C1-C6 alkoxy), and C1-C6 alkoxy.


As non-limiting examples, R15 is selected from:




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In certain embodiments of R15, a2=1; and each Z4 is O. In certain of these embodiments, Z5 is C2-C4 (e.g., C2-C3 (e.g., C2 or C3)) alkylene. In certain of the foregoing embodiments, Z6 is selected from OH, NHC(O)(C1-C6 alkoxy), and C1-C6 alkoxy. In certain other of the foregoing embodiments, Z6 is C6-C10 aryl (e.g., R15 is




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In certain embodiments of R15, a2≥2 (e.g., a2 is 3 or 4); each Z4 is O; and each Z5 is ethylene. In certain of these embodiments Z6 is OH. In certain other embodiments, Z6 is NHC(O)(C1-C6 alkoxy) (e.g., Boc). As a non-limiting example, R15 is:




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Non-Limiting Combinations

In some embodiments, ring A is a 5-membered heteroaryl containing two or more heteroatoms (e.g., two) each independently selected from N, O, and S (e.g., N and S); m is 1; and n is 0 or 1. In certain of these embodiments, ring A is thiazolyl (e.g., thiazol-5-yl) or pyrazolyl (e.g., pyrazol-3-yl).


In certain embodiments (when ring A is a 5-membered heteroaryl containing two or more heteroatoms each independently selected from N, O, and S (e.g., N and S); m is 1; and n is 0 or 1), R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more substituents each independently selected from hydroxy, NR8R9, and halo (e.g., hydroxy). In certain of these embodiments, n is 1; and R2 is halo (e.g., F). In certain other embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted with one or more hydroxy.


In some embodiments, ring A is a 5-membered heteroaryl containing one ring sulfur atom and optionally one or more ring nitrogen atoms; m is 1; and n is 0 or 1. In certain of these embodiments ring A is thiophenyl or thiazolyl (e.g., thiazolyl (e.g., thiazol-5-yl)).


In certain embodiments (when ring A is a 5-membered heteroaryl containing one ring sulfur atom; m is 1; and n is 0 or 1), R1 is C1-C6 alkyl optionally substituted with one or more substituents each independently selected from hydroxy, NR8R9, and halo (e.g., hydroxy). In certain of these embodiments, n is 1; and R2 is halo (e.g., F). In certain other embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted with one or more hydroxy.


In some embodiments, ring A is thiazolyl (e.g., thiazol-5-yl); m is 1; and n is 0 or 1. In certain of these embodiments, R1 is C1-C6 alkyl optionally substituted with one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is




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In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted with one or more hydroxy. In certain other embodiments, n is 0.


In some embodiments, ring A is pyrazolyl; m is 1; and n is 0 or 1. In certain of these embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more halo (e.g., 0, 1, 2, or 3 (e.g., 0, 2 or 3)). In certain of the foregoing embodiments, R2 is halo (e.g., F).


In some embodiments, A is thiazolyl (e.g., 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); and R2, when present, is C1-C6 alkyl optionally substituted with hydroxyl (e.g., methyl, hydroxymethyl, or hydroxyethyl).


In some embodiments, A is pyrazolyl (e.g., 3-pyrazolyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted with 1-3 halo (e.g., fluoro).


In some embodiments, A is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted with NR8R9 (e.g., dimethylamino); and R2, when present, is halo (e.g., fluoro).


In some embodiments, A is thiophenyl (e.g., 2-thiophenyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., isopropyl, 2-hydroxy-2-propyl, or 1-propanoyl).


In some embodiments of one or more Formulae described herein, the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring. In certain of these embodiments, q is 0; and r is 1 or 2.


For example, the substituted ring B is selected from:




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In some embodiments of one or more Formulae described herein, the substituted ring B is




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R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C6-C10 aryl (e.g., phenyl), and C3-C10 cycloalkyl (e.g., cyclopropyl); p is 0, 1, or 2; q is 0, 1, or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring. In certain of these embodiments, q is 0.


In certain of the foregoing embodiments, the substituted ring B is selected from the group consisting of:




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For example, the substituted ring B is selected from:




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In some embodiments, the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments, the substituted ring B is




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R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C6-C10 aryl (e.g., phenyl), and C3-C10 cycloalkyl (e.g., cyclopropyl); p is 0, 1, or 2; q is 0, 1, or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments, the substituted ring B is




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each R6 is independently selected from C1-C6 alkyl (e.g., isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.


In some embodiments, the substituted ring B is




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each R6 is independently selected from C1-C6 alkyl (e.g., isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.


In some embodiments, A is thiazolyl (e.g., 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); R2, when present, is C1-C6 alkyl optionally substituted with hydroxyl (e.g., methyl, hydroxymethyl, or hydroxyethyl); the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments, A is pyrazolyl (e.g., 3-pyrazolyl); m is 1; n is 0; R1 is C1-C6 alkyl optionally substituted with 1-3 halo (e.g., fluoro); the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments, A is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted with NR8R9 (e.g., dimethylamino); R2, when present, is halo (e.g., fluoro); the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments, the optionally substituted ring A is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR', and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is a pyrazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is an imidazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is a thiophenyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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wherein Rx is selected from the group consisting of H and C1-C6 alkyl (e.g., methyl); Z1 is selected from the group consisting of O, NH, and —CH2— optionally substituted with 1-2 R20; Z2 is selected from the group consisting of NH and —CH2— optionally substituted with 1-2 R20; Z3 is selected from the group consisting of —CH2— optionally substituted with 1-2 R20, —CH2CH2— optionally substituted with 1-2 R20, and —CH2CH2CH2— optionally substituted with 1-2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C1-C6 alkyl (e.g., methyl or ethyl) optionally substituted with one R21, C1-C6 alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R21, NR8R9, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R21, or one pair of R20 on the same atom, taken together with the atom connecting them, independently forms a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O)2Ph; R21 is selected from the group consisting of halo (e.g., fluoro), NR8R9, C2-C6 alkynyl (e.g., ethynyl), and C1-C6 alkoxy (e.g., methoxy); R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl (e.g., methyl or ethyl), COR13, and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (e.g., methyl or t-butyl) and C1-C6 haloalkyl (e.g., trifluoromethyl).


In some embodiments, the optionally substituted ring A is




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wherein Z4 is selected from the group consisting of —CH2—, —C(O)—, and NH; Z5 is selected from the group consisting of O, NH, N—CH3, and —CH2—.


In some embodiments, the substituted ring B is




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R6 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl) and C3-C10 cycloalkyl (e.g., cyclopropyl); R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C1-C6 haloalkyl (e.g., trifluoromethyl) and C3-C10 cycloalkyl (e.g., cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted with one or more C1-C6 alkyl (e.g., methyl); q is 0, 1, or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-1, the substituted ring B is




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R6 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl) and C3-C10 cycloalkyl (e.g., cyclopropyl); R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C1-C6 haloalkyl (e.g., trifluoromethyl) and C3-C10 cycloalkyl (e.g., cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted with one or more C1-C6 alkyl (e.g., methyl); q is 0, 1, or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments, the optionally substituted ring A is




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wherein Rx is selected from the group consisting of H and C1-C6 alkyl (e.g., methyl); Z1 is selected from the group consisting of O, NH, and —CH2— optionally substituted with 1-2 R20; Z2 is selected from the group consisting of NH and —CH2— optionally substituted with 1-2 R20; Z3 is selected from the group consisting of —CH2— optionally substituted with 1-2 R20, —CH2CH2— optionally substituted with 1-2 R20, and —CH2CH2CH2— optionally substituted with 1-2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C1-C6 alkyl (e.g., methyl or ethyl) optionally substituted with one R21, C1-C6 alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R21, NR8R9, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R21, or one pair of R20 on the same atom, taken together with the atom connecting them, independently forms a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O)2Ph; R21 is selected from the group consisting of halo (e.g., fluoro), NR8R9, C2-C6 alkynyl (e.g., ethynyl), and C1-C6 alkoxy (e.g., methoxy); R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl (e.g., methyl or ethyl), COR13, and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (e.g., methyl or t-butyl) and C1-C6 haloalkyl (e.g., trifluoromethyl); and


the substituted ring B is




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R6 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl) and C3-C10 cycloalkyl (e.g., cyclopropyl); R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C1-C6 haloalkyl (e.g., trifluoromethyl) and C3-C10 cycloalkyl (e.g., cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted with one or more C1-C6 alkyl (e.g., methyl); q is 0, 1, or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments, the optionally substituted ring A is selected from the group consisting of:




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and the substituted ring B is selected from the group consisting of:




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In some embodiments, ring A is a 5-membered heteroaryl containing two or more heteroatoms each independently selected from N, O, and S (e.g., N and S (e.g., ring A is pyrazolyl (e.g., pyrazol-3-yl) or thiazolyl (e.g., thiazol-5-yl));


m is 1; n is 0 or 1;


R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more substituents each independently selected from hydroxy and halo;


R2 is halo or C1-C6 alkyl optionally substituted with one or more hydroxy;


the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In certain embodiments of [4A], ring A is thiazolyl (e.g., thiazol-5-yl). In certain of these embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is




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In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted with one or more hydroxy. In certain other embodiments, n is 0.


In certain embodiments of [4A], ring A is pyrazolyl. In certain of these embodiments, R1 is C1-C6 alkyl optionally substituted with one or more halo (e.g., 0, 1, 2, or 3 (e.g., 0, 2 or 3)). In certain of the foregoing embodiments, R2 is halo (e.g., F).


In certain embodiments of [4A], q is 0; and r is 1 or 2.


For example, the substituted ring B is selected from:




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In some embodiments, ring A is a 5-membered heteroaryl containing two or more (e.g., two) heteroatoms each independently selected from N, O, and S (e.g., N and S (e.g., ring A is pyrazolyl (e.g., pyrazol-3-yl) or thiazolyl (e.g., thiazol-5-yl));


m is 1; n is 0 or 1;


R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more substituents each independently selected from hydroxy and halo;


R2 is halo or C1-C6 alkyl optionally substituted with one or more hydroxy; and


the substituted ring B is




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R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C6-C10 aryl (e.g., phenyl), and C3-C10 cycloalkyl (e.g., cyclopropyl); p is 0, 1, or 2; q is 0, 1, or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In certain embodiments of [4B], ring A is thiazolyl (e.g., thiazol-5-yl). In certain of these embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is




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In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted with one or more hydroxy. In certain other embodiments, n is 0.


In certain embodiments of [4B], ring A is pyrazolyl. In certain of these embodiments, R1 is C1-C6 alkyl optionally substituted with one or more halo (e.g., 0, 1, 2, or 3 (e.g., 0, 2, or 3)). In certain of the foregoing embodiments, R2 is halo (e.g., F).


In certain of embodiments of [4B], p is 1 or 2.


In certain of these embodiments, p is 2.


In certain other embodiments, p is 1; and R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), and C3-C10 cycloalkyl (e.g., cyclopropyl)


In certain embodiments of [4B], q is 0.


In certain embodimens of [4B], the substituted ring B is selected from the group consisting of:




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For example, the substituted ring B is selected from:




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In some embodiments of Formula AA-1, ring A′ is a 5-membered heteroaryl containing two or more heteroatoms (e.g., two) each independently selected from N, O, and S (e.g., N and S); m is 1; and n is 0 or 1. In certain of these embodiments, ring A′ is thiazolyl (e.g., thiazol-5-yl) or pyrazolyl (e.g., pyrazol-3-yl).


In certain embodiments (when ring A′ is a 5-membered heteroaryl containing two or more heteroatoms each independently selected from N, O, and S (e.g., N and S); m is 1; and n is 0 or 1), R′ is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more substituents each independently selected from hydroxy, NR8R9, and halo (e.g., hydroxy). In certain of these embodiments, n is 1; and R2 is halo (e.g., F). In certain other embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted with one or more hydroxy.


In some embodiments of Formula AA-1, ring A′ is a 5-membered heteroaryl containing one ring sulfur atom and optionally one or more ring nitrogen atoms; m is 1; and n is 0 or 1. In certain of these embodiments ring A′ is thiophenyl or thiazolyl (e.g., thiazolyl (e.g., thiazol-5-yl)).


In certain embodiments (when ring A′ is a 5-membered heteroaryl containing one ring sulfur atom; m is 1; and n is 0 or 1), R1 is C1-C6 alkyl optionally substituted with one or more substituents each independently selected from hydroxy, NR8R9, and halo (e.g., hydroxy). In certain of these embodiments, n is 1; and R2 is halo (e.g., F). In certain other embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted with one or more hydroxy.


In some embodiments, ring A′ is thiazolyl (e.g., thiazol-5-yl); m is 1; and n is 0 or 1. In certain of these embodiments, R1 is C1-C6 alkyl optionally substituted with one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is




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In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted with one or more hydroxy. In certain other embodiments, n is 0.


In some embodiments, ring A′ is pyrazolyl; m is 1; and n is 0 or 1. In certain of these embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more halo (e.g., 0, 1, 2, or 3 (e.g., 0, 2 or 3)). In certain of the foregoing embodiments, R2 is halo (e.g., F).


In some embodiments of the compound of Formula AA-1, A′ is thiazolyl (e.g., 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); and R2, when present, is C1-C6 alkyl optionally substituted with hydroxyl (e.g., methyl, hydroxymethyl, or hydroxyethyl).


In some embodiments of the compound of Formula AA-1, A′ is pyrazolyl (e.g., 3-pyrazolyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted with 1-3 halo (e.g., fluoro).


In some embodiments of the compound of Formula AA-1, A′ is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted with NR8R9 (e.g., dimethylamino); and R2, when present, is halo (e.g., fluoro).


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is a pyrazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is an imidazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is




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wherein R1 is selected from the group consisting of H and C1-C6 alkyl (e.g., methyl); Z1 is selected from the group consisting of O, NH, and —CH2— optionally substituted with 1-2 R20; Z2 is selected from the group consisting of NH and —CH2— optionally substituted with 1-2 R20; Z3 is selected from the group consisting of —CH2— optionally substituted with 1-2 R20, —CH2CH2— optionally substituted with 1-2 R20, and —CH2CH2CH2— optionally substituted with 1-2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C1-C6 alkyl (e.g., methyl or ethyl) optionally substituted with one R21, C1-C6 alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R21, NR8R9, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R21, or one pair of R20 on the same atom, taken together with the atom connecting them, independently forms a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O)2Ph; R21 is selected from the group consisting of halo (e.g., fluoro), NR8R9, C2-C6 alkynyl (e.g., ethynyl), and C1-C6 alkoxy (e.g., methoxy); R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl (e.g., methyl or ethyl), COR13, and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (e.g., methyl or t-butyl) and C1-C6 haloalkyl (e.g., trifluoromethyl).


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is




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wherein Z4 is selected from the group consisting of —CH2—, —C(O)—, and NH; Z5 is selected from the group consisting of O, NH, N—CH3, and —CH2—.


In some embodiments of the compound of Formula AA-1, the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-1, the substituted ring B is




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R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C6-C10 aryl (e.g., phenyl), and C3-C10 cycloalkyl (e.g., cyclopropyl); p is 0, 1, or 2; q is 0, 1, or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-1, the substituted ring B is




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each R6″ is independently selected from C1-C6 alkyl (e.g., isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.


In some embodiments of the compound of Formula AA-1, the substituted ring B is




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each R6″ is independently selected from C1-C6 alkyl (e.g., isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.


In some embodiments of the compound of Formula AA-1, A′ is thiazolyl (e.g., 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); R2, when present, is C1-C6 alkyl optionally substituted with hydroxyl (e.g., methyl, hydroxymethyl, or hydroxyethyl); the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-1, A′ is pyrazolyl (e.g., 3-pyrazolyl); m is 1; n is 0; R1 is C1-C6 alkyl optionally substituted with 1-3 halo (e.g., fluoro); the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-1, A′ is phenyl; m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted with NR8R9 (e.g., dimethylamino); and R2, when present, is halo (e.g., fluoro) ; the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═N10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is a pyrazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2),wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, NR10 CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is an imidazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is a thiophenyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is




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wherein R1 is selected from the group consisting of H and C1-C6 alkyl (e.g., methyl); Z1 is selected from the group consisting of O, NH, and —CH2— optionally substituted with 1-2 R20; Z2 is selected from the group consisting of NH and —CH2— optionally substituted with 1-2 R20; Z3 is selected from the group consisting of —CH2— optionally substituted with 1-2 R20, —CH2CH2— optionally substituted with 1-2 R20, and —CH2CH2CH2— optionally substituted with 1-2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C1-C6 alkyl (e.g., methyl or ethyl) optionally substituted with one R21, C1-C6 alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R21, NR8R9, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R21, or one pair of R20 on the same atom, taken together with the atom connecting them, independently forms a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O)2Ph; R21 is selected from the group consisting of halo (e.g., fluoro), NR8R9, C2-C6 alkynyl (e.g., ethynyl), and C1-C6 alkoxy (e.g., methoxy); R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl (e.g., methyl or ethyl), COR13, and CO2R13; R13 is selected from the group consisting of: C1-C6 alkyl (e.g., methyl or t-butyl) and C1-C6 haloalkyl (e.g., trifluoromethyl).


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is




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wherein Z4 is selected from the group consisting of —CH2—, —C(O)—, and NH; Z5 is selected from the group consisting of O, NH, N—CH3, and —CH2—.


In some embodiments of the compound of Formula AA-1, the substituted ring B is




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R6 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl) and C3-C10 cycloalkyl (e.g., cyclopropyl); R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C1-C6 haloalkyl (e.g., trifluoromethyl) and C3-C10 cycloalkyl (e.g., cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted with one or more C1-C6 alkyl (e.g., methyl); q is 0, 1, or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is




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wherein R1 is selected from the group consisting of H and C1-C6 alkyl (e.g., methyl); Z1 is selected from the group consisting of O, NH, and —CH2— optionally substituted with 1-2 R20; Z2 is selected from the group consisting of NH and —CH2— optionally substituted with 1-2 R20; Z3 is selected from the group consisting of —CH2— optionally substituted with 1-2 R20, —CH2CH2— optionally substituted with 1-2 R20, and —CH2CH2CH2— optionally substituted with 1-2 R20; R20 is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C1-C6 alkyl (e.g., methyl or ethyl) optionally substituted with one R21, C1-C6 alkoxy (e.g., methoxy, ethoxy, or isopropoxy) optionally substituted with one R21, NR8R9, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or pyrrolidinyl) optionally substituted with one R21, or one pair of R20 on the same atom, taken together with the atom connecting them, independently forms a monocyclic C3-C4 carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 0 atom optionally substituted with OS(O)2Ph; R21 is selected from the group consisting of halo (e.g., fluoro), NR8R9, C2-C6 alkynyl (e.g., ethynyl), and C1-C6 alkoxy (e.g., methoxy); R8 and R9 at each occurrence is independently selected from hydrogen, C1-C6 alkyl (e.g., methyl or ethyl), COR13, and CO2R13; Rn is selected from the group consisting of: C1-C6 alkyl (e.g., methyl or t-butyl) and C1-C6 haloalkyl (e.g., trifluoromethyl); and


the substituted ring B is




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R6 is selected from C1-C6 alkyl (e.g., methyl); R7 is selected from C1-C6 alkyl (e.g., isopropyl) and C3-C10 cycloalkyl (e.g., cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted with one or more C1-C6 alkyl (e.g., methyl); q is 0, 1, or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is selected from the group consisting of:




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and the substituted ring B is selected from the group consisting of:




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In some embodiments, ring A′ is a 5-membered heteroaryl containing two or more heteroatoms each independently selected from N, O, and S (e.g., N and S (e.g., ring A′ is pyrazolyl (e.g., pyrazol-3-yl) or thiazolyl (e.g., thiazol-5-yl));


m is 1; n is 0 or 1;


R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more substituents each independently selected from hydroxy and halo;


R2 is halo or C1-C6 alkyl optionally substituted with one or more hydroxy; the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In certain embodiments of [4C], ring A′ is thiazolyl (e.g., thiazol-5-yl). In certain of these embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is




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In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted with one or more hydroxy. In certain other embodiments, n is 0.


In certain embodiments of [4C], ring A′ is pyrazolyl. In certain of these embodiments, R1 is C1-C6 alkyl optionally substituted with one or more halo (e.g., 0, 1, 2, or 3 (e.g., 0, 2 or 3)). In certain of the foregoing embodiments, R2 is halo (e.g., F).


In certain embodiments of [4C], q is 0; and r is 1 or 2.


For example, the substituted ring B is selected from:




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4D

In some embodiments, ring A′ is a 5-membered heteroaryl containing two or more (e.g., two) heteroatoms each independently selected from N, O, and S (e.g., N and S (e.g., ring A′ is pyrazolyl (e.g., pyrazol-3-yl) or thiazolyl (e.g., thiazol-5-yl));


m is 1; n is 0 or 1;


R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more substituents each independently selected from hydroxy and halo;


R2 is halo or C1-C6 alkyl optionally substituted with one or more hydroxy; and


the substituted ring B is




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R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C6-C10 aryl (e.g., phenyl), and C3-C10 cycloalkyl (e.g., cyclopropyl); p is 0, 1, or 2; q is 0, 1, or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In certain embodiments of [4D], ring A′ is thiazolyl (e.g., thiazol-5-yl). In certain of these embodiments, R1 is C1-C6 (e.g., C2-C4) alkyl optionally substituted with one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R1 is




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In certain of the foregoing embodiments, n is 1; and R2 is C1-C6 alkyl optionally substituted with one or more hydroxy. In certain other embodiments, n is 0.


In certain embodiments of [4D], ring A′ is pyrazolyl. In certain of these embodiments, R1 is C1-C6 alkyl optionally substituted with one or more halo (e.g., 0, 1, 2, or 3 (e.g., 0, 2, or 3)). In certain of the foregoing embodiments, R2 is halo (e.g., F).


In certain embodiments of [4D], p is 1 or 2.


In certain of these embodiments, p is 2.


In certain other embodiments, p is 1; and R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), and C3-C10 cycloalkyl (e.g., cyclopropyl)


In certain embodiments of [4D], q is 0.


In certain embodimens of [4D], the substituted ring B is selected from the group consisting of:




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For example, the substituted ring B is selected from:




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In some embodiments of the compound of Formula AA-2, A″ is thiophenyl (e.g., 2-thiophenyl); m′ is 1; n′ is 0; and R1 is C1-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., isopropyl, 2-hydroxy-2-propyl, or 1-propanoyl).


In some embodiments of the compound of Formula AA-2, the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-2, the substituted ring B is




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R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C6-C10 aryl (e.g., phenyl), and C3-C10 cycloalkyl (e.g., cyclopropyl); p is 0, 1, or 2; q is 0, 1, or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-2, the substituted ring B is




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each R6 is independently selected from C1-C6 alkyl (e.g., isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.


In some embodiments of the compound of Formula AA-2, the substituted ring B is




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each R6 is independently selected from C1-C6 alkyl (e.g., isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.


In some embodiments of the compound of Formula AA-2, A″ is thiophenyl (e.g., 2-thiophenyl); m′ is 1; n′ is 0; R1 is C1-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., isopropyl, 2-hydroxy-2-propyl, or 1-propanoyl); the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-3, A″ is thiophenyl (e.g., 2-thiophenyl); m″ is 1; n″ is 1; R1′ is C2-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., 2-hydroxy-2-propyl); and R2′ is C2-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., 2-hydroxy-2-propyl).


In some embodiments of the compound of Formula AA-3, the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-3, the substituted ring B is




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R7 is selected from C1-C6 alkyl (e.g., methyl, ethyl, or isopropyl), C6-C10 aryl (e.g., phenyl), and C3-C10 cycloalkyl (e.g., cyclopropyl); p is 0, 1, or 2; q is 0, 1, or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-3, the substituted ring B is




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each R6 is independently selected from C1-C6 alkyl (e.g., isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.


In some embodiments of the compound of Formula AA-3, the substituted ring B is




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each R6 is independently selected from C1-C6 alkyl (e.g., isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.


In some embodiments of the compound of Formula AA-3, A″ is thiophenyl (e.g., 2-thiophenyl); m″ is 1; n″ is 1; R1′ is C2-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., 2-hydroxy-2-propyl); R2′ is C2-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., 2-hydroxy-2-propyl); the substituted ring B is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-3, the optionally substituted ring A″ is a thiophenyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-3, the substituted ring B is




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R6 is selected from C1-C6 alkyl (e.g., methyl); R7 is selected from C1-C6 alkyl (e.g., isopropyl) and C3-C10 cycloalkyl (e.g., cyclopropyl or cyclobutyl); or R6 and R7, taken together with the atoms connecting them, independently form a C5 carbocyclic ring optionally substituted with one or more C1-C6 alkyl (e.g., methyl); q is 0, 1, or 2; each Y is independently selected from C1-C6 alkyl (e.g., methyl); or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments, the optionally substituted ring A″ is selected from the group consisting of:




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and


the substituted ring B is selected from the group consisting of:




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In some embodiments of the compound of Formula AA-4, A″ is thiophenyl (e.g., 2-thiophenyl); R1 is C1-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., methyl or 2-hydroxy-2-propyl); and R2″ is methyl.


In some embodiments of the compound of Formula AA-4, the substituted ring B′ is




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each R6 is independently selected from C1-C6 alkyl (e.g., isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.


In some embodiments of the compound of Formula AA-4, A″ is thiophenyl (e.g., 2-thiophenyl); R1 is C1-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., methyl or 2-hydroxy-2-propyl); R2″ is methyl; the substituted ring B′ is




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each R6 is independently selected from C1-C6 alkyl (e.g., isopropyl); each R7 is independently selected from halo (e.g., fluoro); p is 0 or 1.


In some embodiments of the compound of Formula AA-5, the substituted ring B″ is




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q is 0, 1, or 2; r is 0, 1, or 2; wherein each of Y and Z is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or wherein when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring; or wherein when two Z are attached to the same carbon, the two Z are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments of the compound of Formula AA-5, the substituted ring B″ is




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R7′ is selected from unbranched C1-C6 alkyl (e.g., methyl or ethyl), C6-C10 aryl (e.g., phenyl), and C3-C10 cycloalkyl (e.g., cyclopropyl); p is 0, 1, or 2; q is 0, 1, or 2; wherein each Y is independently selected from C1-C6 alkyl (e.g., methyl) and hydroxy; or when two Y are attached to the same carbon, the two Y are taken together with the carbon they are attached to to form a cyclopropyl ring.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the nitrogen atom attached to R1), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, NR10 CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the nitrogen atom attached to R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, NR10 CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the nitrogen attached to R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, NR10 CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one of the adjacent atoms is a nitrogen atom, then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom attached to R1), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9,═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the nitrogen atom attached to R1), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, NR10 CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one of the adjacent atoms is a nitrogen atom, then the heterocyclic ring includes from 0-2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom attached to R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments, the optionally substituted ring A is




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one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the nitrogen atom(s) attached to R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA, when ring A is phenyl, then R1 and R2 are each independently selected from C3-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC1-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C═NR13) NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

  • wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
    • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA, when ring A is pyridyl, then R1 and R2 are each independently selected from C3-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC1-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C═NR13) NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, and 3- to 7-membered heterocycloalkyl,

  • wherein the C3-C6 alkyl, C1-C6 haloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
    • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo;
  • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA, when ring A is phenyl, then R1 and R2 are each independently selected from C3 alkyl, C5-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH—(C═NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

  • wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
    • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo;
  • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9;
  • when ring A is pyridyl, then R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH—(C═NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl,
  • wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
    • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9; and R6 and R7 are each independently selected from a C2-C6 alkyl, C2-C6 haloalkyl, C2-C6 alkoxy, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,
  • wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of the compound of Formula AA-1, when ring A′ is phenyl, then R1 and R2 are each independently selected from C3 alkyl, C5-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, F, I, CN, NO2, COC2-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC2-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH-(C═NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl,

  • wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;



1wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo;

  • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4 or C6-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9; when ring A is pyridyl, then R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO—C6-C10 aryl, CO(5- to 10-membered heteroaryl), CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC2-C6 alkyl, N(C1-C6 alkyl)2, NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, NHCOOC1-C6 alkyl, NH—(C═NR13)NR11R12, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, S(O2)NR11R12, S(O)C1-C6 alkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC2-C6 alkynyl;
    • wherein each C1-C6 alkyl substituent and each C1-C6 alkoxy substituent of the R1 or R2 C3-C7 cycloalkyl or of the R1 or R2 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, halo, NR8R9, or oxo; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2,and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9; R6″ is selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6″ is optionally substituted with one or more substituents independently selected from hydroxy, Cl, Br, I, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6″ is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6″ is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;
    • wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • R7 is selected from C2-C6 alkyl, C2-C6 haloalkyl, C1-C6 haloalkoxy, I, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl, wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC2-C6 alkynyl, C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen; wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl;
  • or one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., one) NR8R9.


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., one) NR8R9.


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl substituted with one or more (e.g., one) NR8R9.


In some embodiments of Formula AA, Ring A is




embedded image


R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl); and R2 is halo.


In some embodiments of Formula AA, Ring A is




embedded image


R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl); and R2 is halo.


In some embodiments of Formula AA, Ring A is




embedded image


R1 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl); and R2 is halo.


In some embodiments of Formula AA, Ring A is




embedded image


R1 is C1-C6 alkyl substituted with one or more (e.g., one) NR8R9; and R2 is halo.


In some embodiments of Formula AA, Ring A is




embedded image


R1 is C1-C6 alkyl substituted with one or more (e.g., one) NR8R9; and R2 is halo.


In some embodiments of Formula AA, Ring A is




embedded image


R1 is C1-C6 alkyl substituted with one or more (e.g., one) NR8R9; and R2 is halo.


In some embodiments of Formula AA, Ring A is




embedded image


and each of R1 and R2 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy.


In some embodiments of Formula AA, Ring A is




embedded image


and each of R1 and R2 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy.


In some embodiments of Formula AA, Ring A is




embedded image


and each of R1 and R2 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy. In certain of these embodiments, R2 is hydroxy methyl.


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl optionally substituted with one or more halo (e.g., ethyl or difluoromethyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 is C1-C6 alkyl optionally substituted with one or more halo (e.g., ethyl or difluoromethyl).


In some embodiments of Formula AA, Ring A is:




embedded image


and and R1 is C1-C6 alkyl optionally substituted with one or more halo (e.g., ethyl or difluoromethyl).


In some embodiments of Formula AA, Ring A is




embedded image


and R1 and R2 taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring (e.g., C5 or C6 carbocyclic ring) or one monocyclic or bicyclic 5- to-12-membered (e.g., 6-membered or 5-membered) heterocyclic ring containing 1-3 (e.g., 1-2, e.g., 1) heteroatoms independently selected from O, N, and S (e.g., N or O), wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g., methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g., methoxy, ethoxy, isopropoxyl), OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g., amino, methylamino, or dimethylamino), ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of Formula AA, Ring A is




embedded image


and each of R1 and R2 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy.


In some embodiments of Formula AA, Ring A is




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and each of R1 and R2 is C1-C6 alkyl substituted with one or more (e.g., from 1-2) hydroxy.


In some embodiments of Formula AA, Ring A is




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and R1 and R2 taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring (e.g., C5 or C6 carbocyclic ring) or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring containing 1-3 (e.g., 1-2, e.g., 1) heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g., methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g., methoxy, ethoxy, isopropoxyl), OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g., amino, methylamino, or dimethylamino), ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.


In some embodiments of Formula AA, the substituted ring B is




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In certain of these embodiments, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is selected from




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and the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR89, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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In certain embodiments (when the substituted ring B is




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one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


In certain embodiments (when the substituted ring B is




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and one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl):


the remaining R6 and R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl.


As non-limiting examples of the foregoing embodiments, B is




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In some embodiments of Formula AA, the substituted ring B is




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In certain of these embodiments, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is




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and the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R8, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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In certain embodiments (when the substituted ring B is




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one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


In certain embodiments (when the substituted ring B is




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and one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl):


the remaining R6 and each R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl.


As non-limiting examples of the foregoing embodiments, B is:




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In some embodiments of Formula AA, the substituted ring B is




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In certain of these embodiments, one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is is




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and one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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(e.g., R7 is cyano or halo (e.g., halo such as F)).


In some embodiments of Formula AA-1, the substituted ring B is




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In certain of these embodiments, the R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is selected from:




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and the R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6″ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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In certain embodiments (when the substituted ring B is




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one R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, one R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6″ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


In certain embodiments (when the substituted ring B is




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and one R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl):


the remaining R6″ and R7 are independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl.


As non-limiting examples of the foregoing embodiments, B is:




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In some embodiments of Formula AA-1, the substituted ring B is




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In certain of these embodiments, the R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is




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and the R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6″ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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In certain embodiments (when the substituted ring B is




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one R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, one R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6″ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


In certain embodiments (when the substituted ring B is




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and one R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl):


the remaining R6″ and each R7 are independently selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl.


As non-limiting examples of the foregoing embodiments, B is:




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In some embodiments of Formula AA-1, the substituted ring B is




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In certain of these embodiments, one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is




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and one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6″ is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6″ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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(e.g., R7 is cyano or halo (e.g., halo such as F)).


In some embodiments of Formula AA-2, the substituted ring B is




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In certain of these embodiments, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is selected from:




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and the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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In certain embodiments (when the substituted ring B




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one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


In certain embodiments (when the substituted ring B is




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and one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl):


the remaining R6 and R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl.


As non-limiting examples of the foregoing embodiments, B is:




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In some embodiments of Formula AA-2, the substituted ring B is




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In certain of these embodiments, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is




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and the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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In certain embodiments (when the substituted ring B is




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one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


In certain embodiments (when the substituted ring B is




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and one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl):


the remaining R6 and each R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl.


As non-limiting examples of the foregoing embodiments, B is:




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In some embodiments of Formula AA-2, the substituted ring B is




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In certain of these embodiments, one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is is




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and one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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(e.g., R7 is cyano or halo (e.g., halo such as F)).


In some embodiments of Formula AA-3, the substituted ring B is




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In certain of these embodiments, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is selected from:




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and the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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In certain embodiments (when the substituted ring B is




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one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


In certain embodiments (when the substituted ring B is




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and one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl):


the remaining R6 and R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl.


As non-limiting examples of the foregoing embodiments, B is:




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In some embodiments of Formula AA-3, the substituted ring B is




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In certain of these embodiments, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B




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and the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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In certain embodiments (when the substituted ring B is




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one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


In certain embodiments (when the substituted ring B is




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and one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl):


the remaining R6 and each R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl.


As non-limiting examples of the foregoing embodiments, B is:




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In some embodiments of Formula AA-3, the substituted ring B is




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In certain of these embodiments, one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B is




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In certain embodiments (when the substituted ring B is is




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and one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:




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(e.g., R7 is cyano or halo (e.g., halo such as F)).




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In some embodiments of Formula AA-4, the substituted ring B′ is


In certain of these embodiments, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B′ is




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In certain embodiments (when the substituted ring B′ is




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and the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B′ is selected from:




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In certain embodiments (when the substituted ring B′ is




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one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


In certain embodiments (when the substituted ring B′ is




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and one R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl):


the remaining R6 and each R7 are independently selected from the group consisting of cyano, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl.


As non-limiting examples of the foregoing embodiments, B is




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In some embodiments of Formula AA-4, the substituted ring B′ is




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In certain of these embodiments, one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B′ is




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In certain embodiments (when the substituted ring B′ is is




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and one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6 is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6 is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B′ is selected from:




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(e.g., R7 is cyano or halo (e.g., halo such as F)).


In some embodiments of Formula AA-5, the substituted ring B″ is




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In certain of these embodiments, the R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9. For example, the R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C5) carbocyclic ring. For example, the substituted ring B″ is




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In certain embodiments (when the substituted ring B″ is selected from:




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and the R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form C4-C7 (e.g., C4 or C5) carbocyclic ring or 5-to-7-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9):


the remaining R6′ is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, the remaining R6′ is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6′ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


As a non-limiting example of the foregoing embodiments, substituted ring B″ is selected from:




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In certain embodiments (when the substituted ring B″ is




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one R6′ is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.


In certain of these embodiments, one R6′ is C6-C10 aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy. For example, R6′ is 5-6 membered heteroaryl (e.g., pyridinyl (e.g., pyridin-4-yl), pyrimidinyl, pyridazinyl, oxazolyl, or thiazolyl) optionally substituted with a substituent selected from halo, CN, C1-C6 alkyl, and C1-C6 alkoxy.


In certain embodiments (when the substituted ring B″ is




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and one R6′ is C6-C10 aryl or 5- to 10-membered heteroaryl, each of which is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl):


the remaining R6′ and R7 are independently selected from the group consisting of CN, halo, unbranched C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl.


As non-limiting examples of the foregoing embodiments, B″ is:




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In some embodiments, the compound of Formula AA is a compound of Formula BB




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wherein


X1 is selected from CH, CR′, CR2, N, NH, NR1, NR2, and S;


X2 is selected from CH, CR′, CR2, N, NH, NR1, NR2, and S;


X3 is selected from CH, CR′, CR2, N, NH, NR1, NR2, and S;


X4 is selected from CH, CR′, CR2, N, NH, NR1, NR2, and S;




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is aromatic and charge neutral;


X1, X2, X3, and X4 collectively comprise from 0-2 R1 and from 0-2 R2, wherein the sum of R1 and R2 is from 0-3;


o is 1 or 2 and p is 1 or 2, wherein the sum of o and p is 3 or 4; and


and wherein R2, R6, and R7 are as defined previously herein.


In some embodiments of Formula BB, X1 is CR1 or CR2.


In some embodiments of Formula BB, X1 is CH.


In some embodiments of Formula BB, X2 is N.


In some embodiments of Formula BB, X2 is CH.


In some embodiments of Formula BB, X2 is CR1 or CR2.


In some embodiments of Formula BB, X3 is CR1 or CR2.


In some embodiments of Formula BB, X3 is NR1 or NR2.


In some embodiments of Formula BB, X4 is N.


In some embodiments of Formula BB, X4 is S.


In some embodiments of Formula BB, X1 is CR1, X2 is CR1, X3 is NR2, and X4 is N.


In some embodiments of Formula BB-1, X1 is CR1X2 is CH, X3 is NR2, and X4 is N.


In some embodiments of Formula BB-1, X1 is CH, X2 is CR1X3 is NR2, and X4 is N.


In some embodiments of Formula BB, X1 is CR1, X2 is N, X3 is CR2, and X4 is S.


In some embodiments of Formula BB, X1 is CH, X2 is N, X3 is CR2, and X4 is S.


In some embodiments of Formula BB, X1 is S, X2 is CR1X3 is CR2, and X4 is CR1.


In some embodiments of Formula BB, X1 is S, X2 is CR1X3 is CH, and X4 is CR2.


In some embodiments of Formula BB, X1 is CR1, X2 is NR2, X3 is N, and X4 is CR1.


In some embodiments of Formula BB, R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and C(O)R13 (e.g., C1-C6 alkyl, C1-C6 haloalkyl, and halo),


wherein the C1-C6 alkyl is optionally substituted with one or more substituents each independently selected from hydroxy or R15 (e.g., hydroxyl);


or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one monocyclic 5- to-12-membered heterocyclic ring wherein:


a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes 1 oxygen atom; and


when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-1 oxygen atoms (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and


rein the heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, and NR8R9.


In some embodiments of Formula BB, R1 and R2 are each independently selected from methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, fluoro, and acetyl (e.g., methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, and fluoro),


one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one monocyclic 6-membered heterocyclic ring wherein:


a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes 1 oxygen atom; and


b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-1 oxygen atoms (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and


wherein the heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, methoxy, and methylamino.


In some embodiments of Formula BB, R1 and R2 are each independently selected from methyl, ethyl, isopropyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, fluoromethyl, difluoromethyl, and fluoro.


In some embodiments of Formula BB, R1 and R2 are each independently selected from ethyl, 1,2-dihydroxy-2-propyl, and fluoro.


In some embodiments of Formula BB, o is 1 and p is 2.


In some embodiments of Formula BB, o is 2 and p is 1.


In some embodiments of Formula BB, o is 2 and p is 2.


In some embodiments of Formula BB, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, CO2C1-C6 alkyl, and C3-C10 cycloalkyl, wherein R6 and R7 are each optionally substituted with one or more sub stituents independently selected from halo and C1-C6 alkyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, oxo, and C1-C6 alkyl.


In some embodiments of Formula BB, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl, and C3-C10 cycloalkyl, wherein R6 and R7 are each optionally substituted with one or more sub stituents independently selected from halo and C1-C6 alkyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, oxo, and C1-C6 alkyl.


In some embodiments of Formula BB, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO2Et, and cyclopropyl,


wherein R6 and R7 are each optionally substituted with one or more sub stituents independently selected from fluoro and methyl;

  • or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, oxo, and methyl.


In some embodiments of Formula BB, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more methyl.


In some embodiments of Formula BB, R6 and R7 are each independently selected from methyl and trifluoromethyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more methyl.


In some embodiments, the compound of Formula AA is a compound of Formula BB-1




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wherein

  • J1 and J2 are each independently selected from the group consisting of —CH2—,




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—CHR—, —C(═O)-, and —CR2—;



  • each R is independently selected from hydroxy and C1-C6 alkyl;

  • o is 0 or 1 and p is 0 or 1, wherein the sum of o and p is 1 or 2;

  • X1 is selected from CH and CR1; and

  • X2, X3, X4, R6, and R7 are as defined previously herein.



In some embodiments of Formula BB-1, X1 is CH.


In some embodiments of Formula BB-1, X1 is CR1.


In some embodiments of Formula BB-1, X2 is N.


In some embodiments of Formula BB-1, X2 is CH.


In some embodiments of Formula BB-1, X2 is CR1 or CR2.


In some embodiments of Formula BB-1, X3 is CR1 or CR2.


In some embodiments of Formula BB-1, X3 is NR1 or NR2.


In some embodiments of Formula BB-1, X4 is N.


In some embodiments of Formula BB-1, X4 is S.


In some embodiments of Formula BB-1, X1 is CR1X2 is CR1, X3 is NR2, and X4 is N.


In some embodiments of Formula BB-1, X1 is CR1X2 is CH, X3 is NR2, and X4 is N.


In some embodiments of Formula BB-1, X1 is CH, X2 is CR1, X3 is NR2, and X4 is N.


In some embodiments of Formula BB, X1 is CR1, X2 is N, X3 is CR2, and X4 is S.


In some embodiments of Formula BB-1, X1 is CH, X2 is N, X3 is CR2, and X4 is S.


In some embodiments of Formula BB-1, X1 is S, X2 is CR1X3 is CR2, and X4 is CR1.


In some embodiments of Formula BB, X1 is S, X2 is CR1, X3 is CH, and X4 is CR2.


In some embodiments of Formula BB-1, X1 is CR1, X2 is NR2, X3 is N, and X4 is CR1.


In some embodiments of Formula BB-1, R1 and R2 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and C(O)R13 (e.g., C1-C6 alkyl, C1-C6 haloalkyl, and halo), wherein the C1-C6 alkyl is optionally substituted with one or more substituents each independently selected from hydroxyl or R15 (e.g., hydroxyl);


or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one monocyclic 5- to-12-membered heterocyclic ring wherein:


a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes 1 oxygen atom; and


b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-1 oxygen atoms (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and


wherein the heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, and NR8R9.


In some embodiments of Formula BB-1, R1 and R2 are each independently selected from methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, fluoro, and acetyl (e.g., methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, and fluoro),


or one pair of R1 and R2 on adjacent atoms, taken together with the atoms connecting them, independently form at least one monocyclic 6-membered heterocyclic ring wherein:


a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes 1 oxygen atom; and


b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-1 oxygen atoms (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and


wherein the heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, methoxy, and methylamino.


In some embodiments of Formula BB-1, R1 and R2 are each independently selected from methyl, ethyl, isopropyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, fluoromethyl, difluoromethyl, and fluoro.


In some embodiments of Formula BB-1, R1 and R2 are each independently selected from ethyl, 1,2-dihydroxy-2-propyl, and fluoro.


In some embodiments of Formula BB-1, o is 1 and p is 0.


In some embodiments of Formula BB-1, o is 0 and p is 1.


In some embodiments of Formula BB-1, o is 1 and p is 1.


In some embodiments of Formula BB-1, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, CO2C1-C6 alkyl, and C3-C10 cycloalkyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from halo and C1-C6 alkyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, oxo, and C1-C6 alkyl.


In some embodiments of Formula BB-1, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl, and C3-C10 cycloalkyl,


wherein R6 and R7 are each optionally substituted with one or more sub stituents independently selected from halo and C1-C6 alkyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, oxo, and C1-C6 alkyl.


In some embodiments of Formula BB-1, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO2Et, and cyclopropyl,


wherein R6 and R7 are each optionally substituted with one or more sub stituents independently selected from fluoro and methyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, oxo, and methyl.


In some embodiments of Formula BB-1, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more methyl.


In some embodiments of Formula BB-1, R6 and R7 are each independently selected from methyl and trifluoromethyl;


or at least one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C5 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more methyl.


In some embodiments of Formula BB-1, J1 is selected from the group consisting of —CH2—,




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—CHR—, —C(═O)—, and —CR2; and J2 is —CH2—. In any of these embodiments, R is C1-C6 alkyl (e.g., methyl).


In some embodiments of Formula BB-1, J1 is selected from the group consisting of —CH2— and —CR2—; and J2 is —CH2—. In any of these embodiments, R is C1-C6 alkyl (e.g., methyl).


In some embodiments of Formula BB-1, R is C1-C6 alkyl (e.g., methyl).


In certain embdoiments, J1 is —CH2—; and J2 is —CH2—.


In some embodiments, the compound of Formula BB is a compound of Formula BB-1a or Formula BB-1b




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  • J1, J2, and J3 are each independently selected from the group consisting of —CH2—,





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—CHR—, —CR2—, and C(═O);



  • each R is independently selected from hydroxy and C1-C6 alkyl;

  • X1 is selected from CH and CR1;

  • X2 is selected from N, CH, CR1and CR2;



R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl.


In some embodiments of Formula BB-1a, X2 is N.


In some embodiments of Formula BB-1a, X2 is CH.


In some embodiments of Formula BB-1a, X2 is CR1 or CR2.


In some embodiments of Formula BB-1b, X1 is selected from CH;


In some embodiments of Formula BB-1b, X1 is selected from CR1;


In some embodiments of Formula BB-1a and/or Formula BB-1b, each R1 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and C(O)R13 (e.g., C1-C6 alkyl, C1-C6 haloalkyl, and halo),


wherein the C1-C6 alkyl is optionally substituted with one or more substituents each independently selected from hydroxyl or R15 (e.g., hydroxyl).


In some embodiments of Formula BB-1a and/or Formula BB-1b, each R1 is independently selected from methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, fluoro, and acetyl (e.g., methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, and fluoro).


In some embodiments of Formula BB-1a and/or Formula BB-1b, each R1 is independently selected from methyl, ethyl, isopropyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, fluoromethyl, difluoromethyl, and fluoro.


In some embodiments of Formula BB-1a and/or Formula BB-1b, each R1 is independently selected fromethyl, 1,2-dihydroxy-2-propyl, and fluoro.


In some embodiments of Formula BB-1a, the R1 connected to carbon is halo; X2 is CH; and the R1 connected to nitrogen is C1-C3 alkyl. For example, the R1 connected to carbon is fluoro; X2 is CH; and the R1 connected to nitrogen is ethyl.


In some embodiments of Formula BB-1b, X1 is CH; and R1 is C1-C3 alkyl optionally substituted with one or more hydroxyl. For example, X1 is CH; and R1 is 1,2-dihydroxy-2-propyl.


In some embodiments of any of the foregoing embodiments, the 1,2-dihydroxy-2-propyl has an (R) configuration at the 2-position. In other embodiments of any of the foregoing embodiments, the 1,2-dihydroxy-2-propyl has an (S) configuration at the 2-position.


In some embodiments of Formula BB-1a and/or Formula BB-1b, each R2 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and C(O)R13 (e.g., C1-C6 alkyl, C1-C6 haloalkyl, and halo),


wherein the C1-C6 alkyl is optionally substituted with one or more substituents each independently selected from hydroxyl or R15 (e.g., hydroxyl).


In some embodiments of Formula BB-1a and/or Formula BB-1b, each R2 is independently selected from methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, fluoro, and acetyl (e.g., methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, and fluoro).


In some embodiments of Formula BB-1a and/or Formula BB-1b, each R2 is independently selected from methyl, ethyl, isopropyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, fluoromethyl, difluoromethyl, and fluoro.


In some embodiments of Formula BB-1a and/or Formula BB-1b, each R2 is independently selected fromethyl, 1,2-dihydroxy-2-propyl, and fluoro.


In some embodiments of Formula BB-1a, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, CO2C1-C6 alkyl, and C3-C10 cycloalkyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from halo and C1-C6 alkyl.


In some embodiments of Formula BB-1a, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl, and C3-C10 cycloalkyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from halo and C1-C6 alkyl.In some embodiments of Formula BB-1a, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO2Et, and cyclopropyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from fluoro and methyl.


In some embodiments of Formula BB-1a, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl.


In some embodiments of Formula BB-1a, R6 and R7 are each independently selected from methyl and trifluoromethyl. For example, R6 is methyl; and R7 is trifluoromethyl.


In some embodiments of Formula BB-1a, J1 and J2 are independently selected from —CH2—, —CHR—, and —CR2—.


In some embodiments of Formula BB-1a, J1 is selected from —CH2—, —CHR—, and —CR2—; and J2 is —CH2—.


In some embodiments of Formula BB-1a, J1 is selected from —CH2— and —CR2—; and J2 is —CH2—.


In some embodiments of Formula BB-1b, J1 and J3 are independently selected from the group consisting of —CH2—,




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—CHR—, —CR2—, and —C(═O)—. In any of these embodiments, R is C1-C6 alkyl (e.g., methyl).


In some embodiments of Formula BB-1b, J1 and J3 are independently selected from the group consisting of —CH2— and —CR2—.


In some embodiments of Formula BB-1b, one or two of J1 and J3 is other than CH2.


In some embodiments of Formula BB-1b, J1 is




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—CHR—, —CR2—, or —C(═O)— (e.g.,



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—CHR—, —CR2—); and J3 is CH2.


In some embodiments of Formula BB-1a and/or Formula BB-1b, R is C1-C6 alkyl (e.g., methyl).


In some embodiments, the compound of Formula BB is a compound of Formula BB-1a.


In some embodiments, the compound of Formula BB is a compound of Formula BB-1b.


In some embodiments, the compound of Formula BB is a compound of Formula BB-1a-i or Formula BB-1b-i




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  • J′ is selected from the group consisting of —CH2—,





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—CHR—, —CR2-, and -C(═O)-; each R is independently selected from hydroxy and C1-C6 alkyl;


R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, NO2, COC1-C6 alkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryl, 5- to 10-membered heteroaryl, NH2, NHC1-C6 alkyl, N(C1-C6 alkyl)2, CONR8R9, SF5, SC1-C6 alkyl, S(O2)C1-C6 alkyl, C3-C10 cycloalkyl and 3- to 10-membered heterocycloalkyl, and C2-C6 alkenyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C6-C10 aryloxy, and S(O2)C1-C6 alkyl; and wherein the C1-C6 alkyl or C1-C6 alkoxy that R6 or R7 is substituted with is optionally substituted with one or more hydroxyl, C6-C10 aryl or NR8R9, or wherein R6 or R7 is optionally fused to a five- to -seven-membered carbocyclic ring or heterocyclic ring containing one or two heteroatoms independently selected from oxygen, sulfur and nitrogen;


wherein the 3- to 7-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl) and NHCO(3- to 7-membered heterocycloalkyl) are optionally substituted with one or more substituents independently selected from halo, C1-C6 alkyl, and OC1-C6 alkyl.


In some embodiments of Formula BB-1a-i and/or Formula BB-1b-i, each R1 is independently selected from C1-C6 alkyl, C1-C6 haloalkyl, halo, and C(O)R13 (e.g., C1-C6 alkyl, C1-C6 haloalkyl, and halo)


wherein the C1-C6 alkyl is optionally substituted with one or more substituents each independently selected from hydroxyl or R15 (e.g., hydroxyl).


In some embodiments of Formula BB-1a-i and/or Formula BB-1b-i, each R1 is independently selected from methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, fluoro, and acetyl (e.g., methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, 2-hydroxyethyl, 1,2,3-trihydroxy-2-propyl, fluoromethyl, difluoromethyl, and fluoro).


In some embodiments of Formula BB-1a-i and/or Formula BB-1b-i, each R1 is independently selected from methyl, ethyl, isopropyl, 1,2-dihydroxy-2-propyl, 2-hydroxy-2-propyl, fluoromethyl, difluoromethyl, and fluoro.


In some embodiments of Formula BB-1a-i and/or Formula BB-1b-i, each R1 is independently selected fromethyl, 1,2-dihydroxy-2-propyl, and fluoro.


In some embodiments of Formula BB-1a-i, the R1 connected to carbon is halo; and the le connected to nitrogen is C1-C3 alkyl.


In some embodiments of Formula BB-1b-i, R1 is C1-C3 alkyl optionally substituted with one or more hydroxyl.


In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, CO2C1-C6 alkyl, and C3-C10 cycloalkyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from halo and C1-C6 alkyl.


In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl, and C3-C10 cycloalkyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from halo and C1-C6 alkyl.


In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO2Et, and cyclopropyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from fluoro and methyl.


In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl,


wherein R6 and R7 are each optionally substituted with one or more substituents independently selected from fluoro and methyl.


In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl.


In some embodiments of Formula BB-1a-i, R6 and R7 are each independently selected from methyl and trifluoromethyl.


In some embodiments of Formula BB-1b, Pis selected from the group consisting of




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—CHR—, and —CR2—.

In some embodiments of Formula BB-1b, Pis selected from the group consisting of —CHR— and —CR2—.


In some embodiments, the compound of Formula BB is a compound of Formula BB-1a-i.


In some embodiments, the compound of Formula BB is a compound of Formula BB-1b-i.


Additional Features of the Embodiments Herein

In some embodiments of the compound of Formula AA (e.g., Formula AA-1, Formula AA-2, Formula AA-3, Formula AA-4, or Formula AA-5), R6 is not CN.


In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of:




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In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of:




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In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of:




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In some embodiments, the compound of Formula AA is not a compound selected from the group consisting of:




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In some embodiments the compound of any of the formulae herein is not a compound disclosed in U.S. Provisional 62/536,271, filed on Jul. 24, 2017; and U.S. Provisional 62/573,894, filed on Oct. 18, 2017, each of which is incorporated herein by reference in its entirety.


In some embodiments the compound of any of the formulae herein is not a compound disclosed in EP 0173498, which is incorporated herein by reference in its entirety.


In some embodiments the compound of any of the formulae herein is not a compound disclosed in U.S. Pat. No. 4,666,506, which is incorporated herein by reference in its entirety.


In one embodiment, provided herein is a combination of a compound of any preceding embodiemnt, for use in the treatment or the prevention of a condition mediated by TNF-α, in a patient in need thereof, wherein the compound is administered to said patient at a therapeutically effective amount. Preferably, the subject is resistant to treatment with an anti-TNFα agent. Preferably, the condition is a gut disease or disorder.


In one embodiment, provided herein is a pharmaceutical composition of comprising a compound of any preceding embodiment, and an anti-TNFα agent disclosed herein. Preferably wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNFα agent is Adalimumab.


In one embodiment, provided herein is a pharmaceutical combination of a compound of any preceding embodiment, and an anti-TNFα agent Preferably wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNFα agent is Adalimumab.


In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment or the prevention of a condition mediated by TNF-α, in particular a gut disease or disorder, in a patient in need thereof, wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.


In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment or the prevention of a condition, in particular a gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.


In one embodiment, the present invention relates to an NLRP3 antagonist for use in the treatment, stabilization or lessening the severity or progression of gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.


In one embodiment, the present invention relates to an NLRP3 antagonist for use in the slowing, arresting, or reducing the development of a gut disease or disorder, in a patient in need thereof wherein the NLRP3 antagonist is administered to said patient at a therapeutically effective amount.


In one embodiment, the present invention relates to an NLRP3 antagonist for use according to above listed embodiments wherein the NLRP3 antagonist is a gut-targeted NLRP3 antagonist.


In one embodiment, the present invention relates ton NLRP3 antagonist for use according to any of the above embodiments, wherein the gut disease is IBD.


In one embodiment, the present invention relates to an NLRP3 antagonist for use according to any of the above embodiments, wherein the gut disease is US or CD.


In one embodiment, the present invention relates to a method for the treatment or the prevention of a condition mediated by TNF-a, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.


In one embodiment, the present invention relates to a method for the treatment or the prevention of a condition, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.


In one embodiment, the present invention relates to a method for the treatment, stabilization or lessening the severity or progression of gut disease or disorder, in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.


In one embodiment, the present invention relates to a method for slowing, arresting, or reducing the development of a gut disease or disorder, in a patient in need thereof comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.


In one embodiment, the present invention relates to a method according to any of the above embodiments, wherein the gut disease is IBD.


In one embodiment, the present invention relates to a method according to any of the above embodiments x to xx, wherein the gut disease is UC or CD.


In one embodiment, the present invention relates to a method for the treatment or the prevention of a condition mediated by TNF-a, in particular a gut disease or disorder, in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a gut-targeted NLRP3 antagonist.


Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.


It is understood that the combination of variables in the formulae herein is such that the compounds are stable.


In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1A:












TABLE 1A





Compound #
Structure
Compound #
Structure


















101


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141ba


embedded image







101a


embedded image


141bb


embedded image







101b


embedded image


142


embedded image







102


embedded image


142a


embedded image







102a


embedded image


142b


embedded image







102b


embedded image


143


embedded image







103


embedded image


143a


embedded image







103aa


embedded image


143b


embedded image







103ab


embedded image


144


embedded image







103ba


embedded image


145


embedded image







103bb


embedded image


145a


embedded image







104


embedded image


145b


embedded image







104a


embedded image


146


embedded image







104b


embedded image


147


embedded image







105


embedded image


147a


embedded image







105a


embedded image


147b


embedded image







105b


embedded image


148


embedded image







106


embedded image


148a


embedded image







106a


embedded image


148b


embedded image







106b


embedded image


149


embedded image







107


embedded image


149a


embedded image







107a


embedded image


149b


embedded image







107b


embedded image


150


embedded image







110


embedded image


150


embedded image







111


embedded image


150b


embedded image







112


embedded image


151


embedded image







113


embedded image


152


embedded image







114


embedded image


153


embedded image







114a


embedded image


153a


embedded image







114b


embedded image


153b


embedded image







115


embedded image


154


embedded image







116


embedded image


154a


embedded image







116a


embedded image


154b


embedded image







116b


embedded image


155


embedded image







117


embedded image


155a


embedded image







117a


embedded image


155b


embedded image







117b


embedded image


156


embedded image







118


embedded image


156a


embedded image







118a


embedded image


156b


embedded image







118b


embedded image


157


embedded image







119


embedded image


157a


embedded image







119a


embedded image


157b


embedded image







119b


embedded image


158


embedded image







120


embedded image


158a


embedded image







120a


embedded image


158b


embedded image







120b


embedded image


159


embedded image







121


embedded image


159a


embedded image







121a


embedded image


159b


embedded image







121b


embedded image


160


embedded image







122


embedded image


160a


embedded image







122a


embedded image


160b


embedded image







122b


embedded image


161


embedded image







123


embedded image


161a


embedded image







124


embedded image


161b


embedded image







124a


embedded image


162


embedded image







124b


embedded image


162aa


embedded image







125


embedded image


162ab


embedded image







125a


embedded image


162ba


embedded image







125b


embedded image


162bb


embedded image







126


embedded image


163


embedded image







126a


embedded image


163a


embedded image







126b


embedded image


163b


embedded image







127


embedded image


164


embedded image







127a


embedded image


164a


embedded image







127b


embedded image


164b


embedded image







128


embedded image


165


embedded image







128a


embedded image


165a


embedded image







128b


embedded image


165b


embedded image







129


embedded image


166


embedded image







129aa


embedded image


167


embedded image







129ab


embedded image


167a


embedded image







129ba


embedded image


167b


embedded image







129bb


embedded image


168


embedded image







130


embedded image


168a


embedded image







130a


embedded image


168aa


embedded image







130b


embedded image


168ab


embedded image







131


embedded image


168b


embedded image







131a


embedded image


168ba


embedded image







131aab


embedded image


168bb


embedded image







131b


embedded image


169a


embedded image







131c


embedded image


169b


embedded image







131d


embedded image


170


embedded image







131e


embedded image


171


embedded image







131f


embedded image


172


embedded image







131g


embedded image


172a


embedded image







132


embedded image


172b


embedded image







132a


embedded image


173


embedded image







132b


embedded image


173a


embedded image







133


embedded image


173b


embedded image







133a


embedded image


174


embedded image







133b


embedded image


174a


embedded image







134


embedded image


174b


embedded image







134aa


embedded image


175


embedded image







134ab


embedded image


175a


embedded image







134ba


embedded image


175b


embedded image







134bb


embedded image


176


embedded image







135


embedded image


177


embedded image







136


embedded image


178


embedded image







136a


embedded image


179


embedded image







136b


embedded image


180


embedded image







137


embedded image


180a


embedded image







137a


embedded image


180b


embedded image







137b


embedded image


181


embedded image







138


embedded image


182


embedded image







139


embedded image


183


embedded image







140


embedded image


183a


embedded image







140a


embedded image


183b


embedded image







140aa


embedded image


183c


embedded image







140ab


embedded image


183d


embedded image







140b


embedded image


184a


embedded image







140ba


embedded image


184b


embedded image







140bb


embedded image


184c


embedded image







141


embedded image


184d


embedded image







141a


embedded image


201


embedded image







141aa


embedded image


201a


embedded image







141ab


embedded image









141b


embedded image









141ba


embedded image











and pharmaceutically acceptable salts thereof.


In some embodiments, provided herein is a compound that is selected from the following:

















185b


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185


embedded image







185a


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and pharmaceutically acceptable salts thereof.


In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1B:












TABLE 1B







301


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421


embedded image







302


embedded image


422


embedded image







303


embedded image


423


embedded image







304


embedded image


424


embedded image







305


embedded image


425


embedded image







306


embedded image


426


embedded image







307


embedded image


427


embedded image







308


embedded image


428


embedded image







309


embedded image


429


embedded image







311


embedded image


430


embedded image







312


embedded image


431


embedded image







313


embedded image


432


embedded image







314


embedded image


433


embedded image







315


embedded image


434


embedded image







316


embedded image


435


embedded image







317


embedded image


436


embedded image







318


embedded image


437


embedded image







319


embedded image


438


embedded image







320


embedded image


439


embedded image







321


embedded image


440


embedded image







322


embedded image


441


embedded image







323


embedded image


442


embedded image







324


embedded image


443


embedded image







325


embedded image


444


embedded image







326


embedded image


445


embedded image







327


embedded image


446


embedded image







328


embedded image


447


embedded image







330


embedded image


449


embedded image







331


embedded image


450


embedded image







332


embedded image


451


embedded image







333


embedded image


452


embedded image







334


embedded image


453


embedded image







335


embedded image


454


embedded image







336


embedded image


455


embedded image







337


embedded image


456


embedded image







338


embedded image


457


embedded image







339


embedded image


458


embedded image







340


embedded image


459


embedded image







341


embedded image


460


embedded image







342


embedded image


461


embedded image







343


embedded image


462


embedded image







344


embedded image


463


embedded image







345


embedded image


464


embedded image







346


embedded image


465


embedded image







347


embedded image


466


embedded image







348


embedded image


467


embedded image







349


embedded image


468


embedded image







350


embedded image


469


embedded image







351


embedded image


470


embedded image







352


embedded image


471


embedded image







353


embedded image


472


embedded image







354


embedded image


473


embedded image







355


embedded image


474


embedded image







356


embedded image


475


embedded image







357


embedded image


476


embedded image







358


embedded image


477


embedded image







359


embedded image


478


embedded image







360


embedded image


479


embedded image







361


embedded image


480


embedded image







362


embedded image


481


embedded image







363


embedded image


482


embedded image







364


embedded image


483


embedded image







365


embedded image


484


embedded image







366


embedded image


485


embedded image







367


embedded image


486


embedded image







368


embedded image


487


embedded image







369


embedded image


488


embedded image







370


embedded image


489


embedded image







371


embedded image


490


embedded image







372


embedded image


491


embedded image







373


embedded image


492


embedded image







374


embedded image


493


embedded image







375


embedded image


494


embedded image







376


embedded image


495


embedded image







377


embedded image


496


embedded image







378


embedded image


497


embedded image







379


embedded image


498


embedded image







380


embedded image


499


embedded image







381


embedded image


500


embedded image







382


embedded image


501


embedded image







383


embedded image


502


embedded image







384


embedded image


503


embedded image







385


embedded image


504


embedded image







386


embedded image


505


embedded image







387


embedded image


506


embedded image







388


embedded image


507


embedded image







389


embedded image


508


embedded image







390


embedded image


509


embedded image







391


embedded image


510


embedded image







392


embedded image


511


embedded image







393


embedded image


512


embedded image







394


embedded image


513


embedded image







395


embedded image


514


embedded image







396


embedded image


515


embedded image







397


embedded image


516


embedded image







398


embedded image


517


embedded image







399


embedded image


518


embedded image







400


embedded image


519


embedded image







401


embedded image


520


embedded image







402


embedded image


521


embedded image







403


embedded image


522


embedded image







404


embedded image


523


embedded image







405


embedded image


524


embedded image







406


embedded image


525


embedded image







407


embedded image


526


embedded image







408


embedded image


527


embedded image







409


embedded image


528


embedded image







410


embedded image


529


embedded image







411


embedded image


530


embedded image







412


embedded image


531


embedded image







413


embedded image


532


embedded image







414


embedded image


533


embedded image







415


embedded image


534


embedded image







416


embedded image


535


embedded image







417


embedded image


536


embedded image







418


embedded image


537


embedded image







419


embedded image


538


embedded image







420


embedded image


539


embedded image









540


embedded image











and pharmaceutically acceptable salts thereof.


In some embodiments, provided herein is a compound that is selected from the group consisting of the compounds in Table 1C:










TABLE 1C









embedded image


115a







embedded image


115b







embedded image


140c







embedded image


170a







embedded image


170b







embedded image


171a







embedded image


171b







embedded image


171c







embedded image


171d







embedded image


176a







embedded image


176b







embedded image


181a







embedded image


181b







embedded image


182a







embedded image


182b







embedded image


201b







embedded image


201c







embedded image


201d







embedded image


201e







embedded image


201f







embedded image


304a







embedded image


304b







embedded image


306a







embedded image


306b







embedded image


601







embedded image


601a







embedded image


601b







embedded image


602







embedded image


602a







embedded image


602b







embedded image


603







embedded image


604







embedded image


604a







embedded image


604b







embedded image


605







embedded image


605a







embedded image


605b







embedded image


605c







embedded image


605d







embedded image


605e







embedded image


605f







embedded image


605g







embedded image


605h







embedded image


607







embedded image


607a







embedded image


607b







embedded image


608







embedded image


608a







embedded image


608b







embedded image


608c







embedded image


608d







embedded image


609







embedded image


610







embedded image


610a







embedded image


610b







embedded image


611







embedded image


611a







embedded image


611b







embedded image


612







embedded image


612a







embedded image


612b







embedded image


613







embedded image


613a







embedded image


613b







embedded image


614







embedded image


614a







embedded image


614b







embedded image


615







embedded image


615a







embedded image


615b







embedded image


616







embedded image


616a







embedded image


616b







embedded image


617







embedded image


617a







embedded image


617b







embedded image


618







embedded image


618a







embedded image


618b







embedded image


619







embedded image


620







embedded image


620a







embedded image


620b







embedded image


621







embedded image


621a







embedded image


621b







embedded image


622







embedded image


622a







embedded image


622b







embedded image


623







embedded image


623a







embedded image


623b







embedded image


624







embedded image


624a







embedded image


624b







embedded image


625







embedded image


625a







embedded image


625b







embedded image


626







embedded image


626a







embedded image


626b







embedded image


627







embedded image


628







embedded image


628a







embedded image


628b







embedded image


629







embedded image


630







embedded image


630a







embedded image


630b







embedded image


631







embedded image


631a







embedded image


631b







embedded image


632







embedded image


632a







embedded image


632b







embedded image


633







embedded image


633a







embedded image


633b







embedded image


634







embedded image


634a







embedded image


634b







embedded image


635







embedded image


636a







embedded image


636b







embedded image


636c







embedded image


637







embedded image


637a







embedded image


637b







embedded image


638







embedded image


638a







embedded image


638b







embedded image


639







embedded image


639a







embedded image


639b







embedded image


640







embedded image


640a







embedded image


640b







embedded image


640c







embedded image


641







embedded image


642







embedded image


642a







embedded image


642b







embedded image


643







embedded image


643a







embedded image


643b







embedded image


644







embedded image


644a







embedded image


644b







embedded image


645







embedded image


645a







embedded image


645b







embedded image


646a







embedded image


647







embedded image


647a







embedded image


647b







embedded image


648







embedded image


648a







embedded image


648b







embedded image


649







embedded image


649a







embedded image


649b







embedded image


650







embedded image


650a







embedded image


650b







embedded image


651







embedded image


651a







embedded image


651b







embedded image


652







embedded image


652a







embedded image


652b







embedded image


653







embedded image


653a







embedded image


653b







embedded image


654







embedded image


654a







embedded image


654b







embedded image


655







embedded image


655a







embedded image


655b







embedded image


656







embedded image


656a







embedded image


656b







embedded image


656c







embedded image


656d







embedded image


657







embedded image


657a







embedded image


657b







embedded image


658







embedded image


658a







embedded image


658b







embedded image


659







embedded image


659a







embedded image


659b







embedded image


660







embedded image


660a







embedded image


660b







embedded image


660c







embedded image


660d







embedded image


661







embedded image


661a







embedded image


661b







embedded image


662







embedded image


662a







embedded image


662b







embedded image


662c







embedded image


662d







embedded image


662e







embedded image


663







embedded image


663a







embedded image


663b







embedded image


664







embedded image


664a







embedded image


664b







embedded image


665







embedded image


667







embedded image


667a







embedded image


667b







embedded image


668







embedded image


668a







embedded image


668b







embedded image


668c







embedded image


668d







embedded image


669







embedded image


669a







embedded image


669b







embedded image


670







embedded image


670a







embedded image


670b







embedded image


671







embedded image


671a







embedded image


671b







embedded image


671c







embedded image


671d







embedded image


672







embedded image


673







embedded image


673a







embedded image


673b







embedded image


674







embedded image


674a







embedded image


674b







embedded image


675







embedded image


675a







embedded image


675b







embedded image


676







embedded image


676a







embedded image


676b







embedded image


677







embedded image


678







embedded image


678a







embedded image


678b







embedded image


679







embedded image


680







embedded image


680a







embedded image


680b







embedded image


681







embedded image


681a







embedded image


681b







embedded image


682







embedded image


682a







embedded image


682b







embedded image


683







embedded image


683a







embedded image


683b







embedded image


684







embedded image


684a







embedded image


684b







embedded image


685







embedded image


685a







embedded image


685b







embedded image


686







embedded image


686a







embedded image


686b







embedded image


687







embedded image


687a







embedded image


687b







embedded image


688







embedded image


688a







embedded image


688b







embedded image


689







embedded image


689a







embedded image


689b







embedded image


690







embedded image


690a







embedded image


690b







embedded image


691







embedded image


691a







embedded image


691b







embedded image


692







embedded image


692a







embedded image


692b







embedded image


693







embedded image


694







embedded image


694a







embedded image


694b







embedded image


695







embedded image


695a







embedded image


695b







embedded image


696







embedded image


697a







embedded image


697b







embedded image


698a







embedded image


698b







embedded image


699a







embedded image


699b







embedded image


699c







embedded image


700a







embedded image


700b







embedded image


701a







embedded image


701b







embedded image


702







embedded image


703







embedded image


704







embedded image


705a







embedded image


705b







embedded image


706







embedded image


707







embedded image


708







embedded image


709







embedded image


710







embedded image


711







embedded image


712







embedded image


713







embedded image


716a







embedded image


716b







embedded image


717







embedded image


718a







embedded image


719







embedded image


720a







embedded image


720b







embedded image


720c







embedded image


721a







embedded image


721b







embedded image


721c







embedded image


722







embedded image


723a







embedded image


723b







embedded image


723c







embedded image


724







embedded image


725a







embedded image


726







embedded image


726a







embedded image


726b







embedded image


727







embedded image


727a







embedded image


727b







embedded image


728







embedded image


728a







embedded image


728b







embedded image


729







embedded image


729a







embedded image


729b







embedded image


730







embedded image


730a







embedded image


730b







embedded image


731







embedded image


731a







embedded image


731b







embedded image


732a







embedded image


733







embedded image


734







embedded image


735







embedded image


736







embedded image


737







embedded image


738







embedded image


739







embedded image


739a







embedded image


739b







embedded image


739c







embedded image


739d







embedded image


740







embedded image


740a







embedded image


740b







embedded image


741







embedded image


741a







embedded image


741b







embedded image


742







embedded image


742a







embedded image


742b







embedded image


743







embedded image


743a







embedded image


743b







embedded image


743c







embedded image


743d







embedded image


744







embedded image


744a







embedded image


744b







embedded image


744c







embedded image


744d







text missing or illegible when filed








and pharmaceutically acceptable salts thereof.


In some embodiments, the compound is selected from the group consisting of compounds in Table 1D below










TABLE 1D





Cmpd



#
Structure







801


embedded image







801a


embedded image







801b


embedded image







802


embedded image







802a


embedded image







802b


embedded image







802c


embedded image







802d


embedded image







803


embedded image







803a


embedded image







803b


embedded image







804


embedded image







804a


embedded image







804b


embedded image







805


embedded image







805a


embedded image







805b


embedded image







806


embedded image







806a


embedded image







806b


embedded image







807


embedded image







807a


embedded image







807b


embedded image







808


embedded image







808a


embedded image







808b


embedded image







809


embedded image







809a


embedded image







809b


embedded image







810


embedded image







811a


embedded image







811b


embedded image







811


embedded image







811a


embedded image







811b


embedded image







812


embedded image







812a


embedded image







812b


embedded image







813


embedded image







813a


embedded image







813b


embedded image







814


embedded image







814a


embedded image







814b


embedded image







814c


embedded image







814d


embedded image







815


embedded image







815a


embedded image







815d


embedded image







816


embedded image







816a


embedded image







816b


embedded image







816c


embedded image







816d


embedded image







817


embedded image







817a


embedded image







817b


embedded image







817c


embedded image







817d


embedded image







818


embedded image







818a


embedded image







818b


embedded image







819


embedded image







819a


embedded image







819b


embedded image







820


embedded image







820a


embedded image







820b


embedded image







820c


embedded image







820d


embedded image







821


embedded image







821a


embedded image







821b


embedded image







822


embedded image







822a


embedded image







822b


embedded image







823


embedded image







823a


embedded image







823b


embedded image







824


embedded image







824a


embedded image







824b


embedded image







825


embedded image







825a


embedded image







825b


embedded image







826


embedded image







826a


embedded image







826b


embedded image







827


embedded image







827a


embedded image







827b


embedded image







828


embedded image







828a


embedded image







828b


embedded image







828c


embedded image







828d


embedded image







829


embedded image







829a


embedded image







829b


embedded image







829c


embedded image







829d


embedded image







830


embedded image







830a


embedded image







830b


embedded image







831


embedded image







831a


embedded image







831b


embedded image







832


embedded image







832a


embedded image







832b


embedded image







833


embedded image







833a


embedded image







833b


embedded image







834


embedded image







834a


embedded image







834b


embedded image







835


embedded image







835a


embedded image







835b


embedded image







836


embedded image







836a


embedded image







836b


embedded image







837


embedded image







837a


embedded image







837b


embedded image







838


embedded image







838a


embedded image







838b


embedded image







839


embedded image







839a


embedded image







839b


embedded image







840


embedded image







840a


embedded image







840b


embedded image







841


embedded image







841a


embedded image







841b


embedded image







842


embedded image







842a


embedded image







842b


embedded image







843


embedded image







843a


embedded image







843b


embedded image











and pharmaceutically acceptable salts thereof.


In some embodiments, the compound is selected from the group consisting of compounds in Table 1E below










TABLE 1E





Cmpd #
Structure







 901


embedded image







 901a


embedded image







 901b


embedded image







 902


embedded image







 902a


embedded image







 902b


embedded image







 903


embedded image







 903a


embedded image







 903b


embedded image







 904


embedded image







 904a


embedded image







 904b


embedded image







 905


embedded image







 905a


embedded image







 905b


embedded image







 906


embedded image







 907


embedded image







 907a


embedded image







 907b


embedded image







 908


embedded image







 908a


embedded image







 909


embedded image







 910


embedded image







 911


embedded image







 911a


embedded image







 911b


embedded image







 912


embedded image







 912a


embedded image







 912b


embedded image







 913


embedded image







 914


embedded image







 914a


embedded image







 914b


embedded image







 915


embedded image







 915a


embedded image







 915b


embedded image







 916


embedded image







 916a


embedded image







 916b


embedded image







 917


embedded image







 917a


embedded image







 917b


embedded image







 918


embedded image







 918a


embedded image







 918b


embedded image







 919


embedded image







 920


embedded image







 920a


embedded image







 920b


embedded image







 921


embedded image







 921a


embedded image







 921b


embedded image







 922


embedded image







 922a


embedded image







 922b


embedded image







 923


embedded image







 923a


embedded image







 923b


embedded image







 924


embedded image







 924a


embedded image







 924b


embedded image







 925


embedded image







 926


embedded image







 926a


embedded image







 926b


embedded image







 927


embedded image







 928


embedded image







 929


embedded image







 930


embedded image







 931


embedded image







 932


embedded image







 933a


embedded image







 934a


embedded image







 934b


embedded image







 935a


embedded image







 935b


embedded image







 935c


embedded image







 935d


embedded image







 935e


embedded image







 936a


embedded image







 936b


embedded image







 936c


embedded image







 937a


embedded image







 937b


embedded image







 937c


embedded image







 937d


embedded image







 937e


embedded image







 937f


embedded image







 938a


embedded image







 938b


embedded image







 938c


embedded image







 939a


embedded image







 939b


embedded image







 940a


embedded image







 940b


embedded image







 941a


embedded image







 941b


embedded image







 941c


embedded image







 941d


embedded image







 942a


embedded image







 942b


embedded image







 942c


embedded image







 943a


embedded image







 943b


embedded image







 944a


embedded image







 944b


embedded image







 945a


embedded image







 945b


embedded image







 946a


embedded image







 946b


embedded image







 947a


embedded image







 947b


embedded image







 948a


embedded image







 948b


embedded image







 949a


embedded image







 950a


embedded image







 951a


embedded image







 952a


embedded image







 953a


embedded image







 954a


embedded image







 955a


embedded image







 956a


embedded image







 957a


embedded image







 958a


embedded image







 959a


embedded image







 960a


embedded image







 961a


embedded image







 962a


embedded image







 963a


embedded image







 964a


embedded image







 965a


embedded image







 966a


embedded image







 967a


embedded image







1041a


embedded image







 967b


embedded image







 968


embedded image







 969


embedded image







 969a


embedded image







 969b


embedded image







 970


embedded image







 970a


embedded image







 970b


embedded image







 971


embedded image







 971a


embedded image







 971b


embedded image







 972


embedded image







 973


embedded image







 974


embedded image







 974a


embedded image







 974b


embedded image







 975


embedded image







 975a


embedded image







 975b


embedded image







 976


embedded image







 976a


embedded image







 976b


embedded image







 977


embedded image







 977a


embedded image







 977b


embedded image







 978


embedded image







 978a


embedded image







 978b


embedded image







 979


embedded image







 979a


embedded image







 979b


embedded image







 980


embedded image







 980a


embedded image







 980b


embedded image







 981a


embedded image







 981b


embedded image







 981c


embedded image







 982a


embedded image







 983


embedded image







 983a


embedded image







 983b


embedded image







 984


embedded image







 984a


embedded image







 984b


embedded image







 985


embedded image







 985a


embedded image







 985b


embedded image







 986


embedded image







 987


embedded image







 987a


embedded image







 987b


embedded image







 988


embedded image







 989


embedded image







 990


embedded image







 991


embedded image







 992


embedded image







 992a


embedded image







 993


embedded image







 994


embedded image







 994a


embedded image







 995


embedded image







 996


embedded image







 997


embedded image







 998


embedded image







 998a


embedded image







 999


embedded image







 999a


embedded image







1000


embedded image







1000a


embedded image







1001


embedded image







1001a


embedded image







1002


embedded image







1002a


embedded image







1003


embedded image







1003a


embedded image







1004


embedded image







1004a


embedded image







1005


embedded image







1005a


embedded image







1006


embedded image







1006a


embedded image







1007


embedded image







1007a


embedded image







1008


embedded image







1008a


embedded image







1009


embedded image







1009a


embedded image







1010


embedded image







1010a


embedded image







1011


embedded image







1011a


embedded image







1012


embedded image







1013


embedded image







1013a


embedded image







1014


embedded image







1014a


embedded image







1015


embedded image







1015a


embedded image







1016


embedded image







1016a


embedded image







1017


embedded image







1017a


embedded image







1018


embedded image







1018a


embedded image







1019


embedded image







1019a


embedded image







1020


embedded image







1020a


embedded image







1021


embedded image







1022


embedded image







1022a


embedded image







1023


embedded image







1024


embedded image







1025


embedded image







1025a


embedded image







1026


embedded image







1026a


embedded image







1027


embedded image







1028


embedded image







1029


embedded image







1029a


embedded image







1030


embedded image







1031


embedded image







1032


embedded image







1033


embedded image







1034


embedded image







1034a


embedded image







1035


embedded image







1036


embedded image







1037


embedded image







1038


embedded image







1039


embedded image







1040


embedded image







1041


embedded image











and pharmaceutically acceptable salts thereof.


In some embodiments, the compound is selected from the group consisting of compounds in Table 1F below












TABLE 1F





Cpd

Cpd



#
Structure
#
Structure







1100


embedded image


1101


embedded image







1100a


embedded image


1101a


embedded image







1100b


embedded image


1101b


embedded image







1100c


embedded image


1101c


embedded image







1100d


embedded image


1101d


embedded image









1101e


embedded image







1102


embedded image


1103


embedded image







1102a


embedded image


1103a


embedded image







1102b


embedded image


1103b


embedded image







1104


embedded image


1105


embedded image







1104a


embedded image


1105a


embedded image







1104b


embedded image


1105b


embedded image







1106


embedded image


1107


embedded image







1106a


embedded image


1107a


embedded image







1106b


embedded image


1107b


embedded image







1108


embedded image


1109


embedded image







1108a


embedded image


1109a


embedded image







1108b


embedded image


1109b


embedded image







1110


embedded image


1111


embedded image







1110a


embedded image


1110b


embedded image







1112


embedded image


1113


embedded image







1113a


embedded image


1113b


embedded image







1114


embedded image


1115a


embedded image







1115b


embedded image


1116a


embedded image







1116b


embedded image


1117a


embedded image







1117b


embedded image


1118


embedded image







1119


embedded image


1004b


embedded image







1007b


embedded image











In one embodiment, provided herein is a pharmaceutical composition comprising any NLRP3 antagonist species defined here (for example, a compound or example of Tables 1A, 1E, 1F, B1, B2, B3, and B4; for example any one of examples 1 to 794) and an anti-TNFα agent disclosed herein. Preferably wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNFα agent is Adalimumab.


In one embodiment, provided herein is a pharmaceutical combination of any NLRP3 antagonist species defined here (for example, a compound or example of Tables 1A, 1E, 1F, B1, B2, B3, and B4; for example any one of examples 1 to 794), and an anti-TNFα agent Preferably wherein the anti-TNFα agent is Infliximab, Etanercept, Certolizumab pegol, Golimumab or Adalimumab, more preferably wherein the anti-TNFα agent is Adalimumab.


Anti-TNFα Agents

The term “anti-TNFα agent” refers to an agent which directly or indirectly blocks, down-regulates, impairs, inhibits, impairs, or reduces TNFα activity and/or expression. In some embodiments, an anti-TNFα agent is an antibody or an antigen-binding fragment thereof, a fusion protein, a soluble TNFα receptor (a soluble tumor necrosis factor receptor superfamily member 1A (TNFR1) or a soluble tumor necrosis factor receptor superfamily 1B (TNFR2)), an inhibitory nucleic acid, or a small molecule TNFα antagonist. In some embodiments, the inhibitory nucleic acid is a ribozyme, small hairpin RNA, a small interfering RNA, an antisense nucleic acid, or an aptamer.


Exemplary anti-TNFα agents that directly block, down-regulate, impair, inhibit, or reduce TNFα activity and/or expression can, e.g., inhibit or decrease the expression level of TNFα or a receptor of TNFα (TNFR1 or TNFR2) in a cell (e.g., a cell obtained from a subject, a mammalian cell), or inhibit or reduce binding of TNFα to its receptor (TNFR1 and/or TNFR2) and/or. Non-limiting examples of anti-TNFα agents that directly block, down-regulate, impair, inhibit, or reduce TNFα activity and/or expression include an antibody or fragment thereof, a fusion protein, a soluble TNFα receptor (e.g., a soluble TNFR1 or soluble TNFR2), inhibitory nucleic acids (e.g., any of the examples of inhibitory nucleic acids described herein), and a small molecule TNFα antagonist.


Exemplary anti-TNFα agents that can indirectly block, down-regulate, impair, inhibitreduce TNFα activity and/or expression can, e.g., inhibit or decrease the level of downstream signaling of a TNFα receptor (e.g., TNFR1 or TNFR2) in a mammalian cell (e.g., decrease the level and/or activity of one or more of the following signaling proteins: AP-1, mitogen-activated protein kinase kinase kinase 5 (ASK1), inhibitor of nuclear factor kappa B (IKK), mitogen-activated protein kinase 8 (JNK), mitogen-activated protein kinase (MAPK), MEKK 1/4, MEKK 4/7, MEKK 3/6, nuclear factor kappa B (NF-KB), mitogen-activated protein kinase kinase kinase 14 (NIK), receptor interacting serine/threonine kinase 1 (RIP), TNFRSF1A associated via death domain (TRADD), and TNF receptor associated factor 2 (TRAF2), in a cell), and/or decrease the level of TNFα-induced gene expression in a mammalian cell (e.g., decrease the transcription of genes regulated by, e.g., one or more transcription factors selected from the group of activating transcription factor 2 (ATF2), c-Jun, and NF-κB). A description of downstream signaling of a TNFα receptor is provided in Waj ant et al., Cell Death Differentiation 10:45-65, 2003 (incorporated herein by reference). For example, such indirect anti-TNFα agents can be an inhibitory nucleic acid that targets (decreases the expression) a signaling component downstream of a TNFα-induced gene (e.g., any TNFα-induced gene known in the art), a TNFα receptor (e.g., any one or more of the signaling components downstream of a TNFα receptor described herein or known in the art), or a transcription factor selected from the group of NF-κB, c-Jun, and ATF2.


In other examples, such indirect anti-TNFα agents can be a small molecule inhibitor of a protein encoded by a TNFα-induced gene (e.g., any protein encoded by a TNFα-induced gene known in the art), a small molecule inhibitor of a signaling component downstream of a TNFα receptor (e.g., any of the signaling components downstream of a TNFα receptor described herein or known in the art), and a small molecule inhibitor of a transcription factor selected from the group of ATF2, c-Jun, and NF-κB.


In other embodiments, anti-TNFα agents that can indirectly block, down-regulate, impair, or reduce one or more components in a cell (e.g., acell obtained from a subject, a mammalian cell) that are involved in the signaling pathway that results in TNFα mRNA transcription, TNFα mRNA stabilization, and TNFα mRNA translation (e.g., one or more components selected from the group of CD14, c-Jun, ERK1/2, IKK, IκB, interleukin 1 receptor associated kinase 1 (IRAK), JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-κB, NIK, PKR, p38, AKT serine/threonine kinase 1 (rac), raf kinase (raf), ras, TRAF6, TTP). For example, such indirect anti-TNFα agents can be an inhibitory nucleic acid that targets (decreases the expression) of a component in a mammalian cell that is involved in the signaling pathway that results in TNFα mRNA transcription, TNFα mRNA stabilization, and TNFα mRNA translation (e.g., a component selected from the group of CD14, c-Jun, ERK1/2, IKK, IκB, IRAK, JNK, LBP, MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-κB, NIK, IRAK, lipopolysaccharide binding protein (LBP), PKR, p38, rac, raf, ras, TRAF6, TTP). In other examples, an indirect anti-TNFα agents is a small molecule inhibitor of a component in a mammalian cell that is involved in the signaling pathway that results in TNFα mRNA transcription, TNFα mRNA stabilization, and TNFα mRNA translation (e.g., a component selected from the group of CD14, c-Jun, ERK1/2, IKK, IκB, IRAK, JNK, lipopolysaccharide binding protein (LBP), MEK1/2, MEK3/6, MEK4/7, MK2, MyD88, NF-κB, NIK, IRAK, lipopolysaccharide binding protein (LBP), PKR, p38, rac, raf, ras, TRAF6, TTP).


Antibodies

In some embodiments, the anti-TNFα agent is an antibody or an antigen-binding fragment thereof (e.g., a Fab or a scFv). In some embodiments, an antibody or antigen-binding fragment of an antibody described herein can bind specifically to TNFα. In some embodiments, an antibody or antigen-binding fragment described herein binds specifically to any one of TNFα, TNFR1, or TNFR2. In some embodiments, an antibody or antigen-binding fragment of an antibody described herein can bind specifically to a TNFα receptor (TNFR1 or TNFR2).


In some embodiments, the antibody can be a humanized antibody, a chimeric antibody, a multivalent antibody, or a fragment thereof. In some embodiments, an antibody can be a scFv-Fc, a VHH domain, a VNAR domain, a (scFv)2, a minibody, or a BiTE.


In some embodiments, an antibody can be a crossmab, a diabody, a scDiabody, a scDiabody-CH3, a Diabody-CH3, a DutaMab, a DT-IgG, a diabody-Fc, a scDiabody-HAS, a charge pair antibody, a Fab-arm exchange antibody, a SEEDbody, a Triomab, a LUZ-Y, a Fcab, a kλ-body, an orthogonal Fab, a DVD-IgG, an IgG(H)-scFv, a scFv-(H)IgG, an IgG(L)-scFv, a scFv-(L)-IgG, an IgG (L,H)-Fc, an IgG(H)-V, a V(H)-IgG, an IgG(L)-V, a V(L)-IgG, an KIH IgG-scFab, a 2scFv-IgG, an IgG-2scFv, a scFv4-Ig, a Zybody, a DVI-IgG, a nanobody, a nanobody-HSA, a DVD-Ig, a dual-affinity re-targeting antibody (DART), a triomab, a kih IgG with a common LC, an ortho-Fab IgG, a 2-in-1-IgG, IgG-ScFv, scFv2-Fc, a bi-nanobody, tanden antibody, a DART-Fc, a scFv-HAS-scFv, a DAF (two-in-one or four-in-one), a DNL-Fab3, knobs-in-holes common LC, knobs-in-holes assembly, a TandAb, a Triple Body, a miniantibody, a minibody, a TriBi minibody, a scFv-CH3 KIH, a Fab-scFv, a scFv-CH-CL-scFv, a F(ab′)2-scFV2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a tandem scFv-Fc, an intrabody, a dock and lock bispecific antibody, an ImmTAC, a HSAbody, a tandem scFv, an IgG-IgG, a Cov-X-Body, and a scFv1-PEG-scFv2.


Non-limiting examples of an antigen-binding fragment of an antibody include an Fv fragment, a Fab fragment, a F(ab′)2 fragment, and a Fab′ fragment. Additional examples of an antigen-binding fragment of an antibody is an antigen-binding fragment of an antigen-binding fragment of an IgA (e.g., an antigen-binding fragment of IgA1 or IgA2) (e.g., an antigen-binding fragment of a human or humanized IgA, e.g., a human or humanized IgA1 or IgA2); an antigen-binding fragment of an IgD (e.g., an antigen-binding fragment of a human or humanized IgD); an antigen-binding fragment of an IgE (e.g., an antigen-binding fragment of a human or humanized IgE); an IgG (e.g., an antigen-binding fragment of IgG1, IgG2, IgG3, or IgG4) (e.g., an antigen-binding fragment of a human or humanized IgG, e.g., human or humanized IgG1, IgG2, IgG3, or IgG4); or an antigen-binding fragment of an IgM (e.g., an antigen-binding fragment of a human or humanized IgM).


Non-limiting examples of anti-TNFα agents that are antibodies that specifically bind to TNFα are described in Ben-Horin et al., Autoimmunity Rev. 13(1):24-30, 2014; Bongartz et al., JAMA 295(19):2275-2285, 2006; Butler et al., Eur. Cytokine Network 6(4):225-230, 1994; Cohen et al., Canadian J. Gastroenterol. Hepatol. 15(6):376-384, 2001; Elliott et al., Lancet 1994; 344: 1125-1127, 1994; Feldmann et al., Ann. Rev. Immunol. 19(1):163-196, 2001; Rankin et al., Br. J Rheumatol. 2:334-342, 1995; Knight et al., Molecular Immunol. 30(16):1443-1453, 1993; Lorenz et al., J. Immunol. 156(4):1646-1653, 1996; Hinshaw et al., Circulatory Shock 30(3):279-292, 1990; Ordas et al., Clin. Pharmacol. Therapeutics 91(4):635-646, 2012; Feldman, Nature Reviews Immunol. 2(5):364-371, 2002; Taylor et al., Nature Reviews Rheumatol. 5(10):578-582, 2009; Garces et al., Annals Rheumatic Dis. 72(12):1947-1955, 2013; Palladino et al., Nature Rev. Drug Discovery 2(9):736-746, 2003; Sandborn et al., Inflammatory Bowel Diseases 5(2):119-133, 1999; Atzeni et al., Autoimmunity Reviews 12(7):703-708, 2013; Maini et al., Immunol. Rev. 144(1):195-223, 1995; Wanner et al., Shock 11(6):391-395, 1999; and U.S. Pat. Nos. 6,090,382; 6,258,562; and 6,509,015).


In certain embodiments, the anti-TNFα agent can include or is golimumab (golimumab™), adalimumab (Humira™), infliximab (Remicade™), CDP571, CDP 870, or certolizumab pegol (Cimzia™). In certain embodiments, the anti-TNFα agent can be a TNFα inhibitor biosimilar. Examples of approved and late-phase TNFα inhibitor biosimilars include, but are not limited to, infliximab biosimilars such as Flixabi™ (SB2) from Samsung Bioepis, Inflectra® (CT-P13) from Celltrion/Pfizer, GS071 from Aprogen, Remsima™, PF-06438179 from Pfizer/Sandoz, NI-071 from Nichi-Iko Pharmaceutical Co., and ABP 710 from Amgen; adalimumab biosimilars such as Amgevita® (ABP 501) from Amgen and Exemptia™ from Zydus Cadila, BMO-2 or MYL-1401-A from Biocon/Mylan, CHS-1420 from Coherus, FKB327 from Kyowa Kirin, and BI 695501 from Boehringer Ingelheim;Solymbic®, SB5 from Samsung Bioepis, GP-2017 from Sandoz, ONS-3010 from Oncobiologics, M923 from Momenta, PF-06410293 from Pfizer, and etanercept biosimilars such as Erelzi™ from Sandoz/Novartis, Brenzys™ (SB4) from Samsung Bioepis, GP2015 from Sandoz, TuNEX® from Mycenax, LBEC0101 from LG Life, and CHS-0214 from Coherus.


In some embodiments of any of the methods described herein, the anti-TNFα agent is selected from the group consisting of: adalimumab, certolizumab, etanercept, golimumab, infliximabm, CDP571, and CDP 870.


In some embodiments, any of the antibodies or antigen-binding fragments described herein has a dissociation constant (KD) of less than 1×10−5 M (e.g., less than 0.5×10−5 M, less than 1×10−6 M, less than 0.5×10−6 M, less than 1×10−7 M, less than 0.5×10−7M, less than 1×10−8 M, less than 0.5×10−8 M, less than 1×10−9 M, less than 0.5×10−9 M, less than 1×10−10 M, less than 0.5×10−11 M, less than 1×10−1 1M, less than 0.5×10−11 M, or less than 1×10−12 M), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).


In some embodiments, any of the antibodies or antigen-binding fragments described herein has a KD of about 1×10−12 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, about 0.5×10−6 M, about 1×10−7 M, about 0.5×10−7 M, about 1×10−8 M, about 0.5×10−8 M, about 1×10−9 M, about 0.5×10−9 M, about 1×10−10 M, about 0.5×10−10 M, about 1×10−11 M, or about 0.5×10−11 M (inclusive); about 0.5×10−11 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, about 0.5×10−6 M, about 1×10−7 M, about 0.5×10−7 M, about 1×10−8 M, about 0.5×10−8 M, about 1×10−9 M, about 0.5×10−9 M, about 1×10−10 M, about 0.5×10−10 M, or about 1×10−11 M (inclusive); about 1×10−11 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, about 0.5×10−6 M, about 1×10−7 M, about 0.5×10−7 M, about 1×10−8 M, about 0.5×10−8 M, about 1×10−9 M, about 0.5×10−9 M, about 1×10−10 M, or about 0.5×10−10 M (inclusive); about 0.5×10−10 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, about 0.5×10−6 M, about 1×10−7 M, about 0.5×10−7 M, about 1×10−8 M, about 0.5×10−8 M, about 1×10−9 M, about 0.5×10−9 M, or about 1×10−10 M (inclusive); about 1×10−10 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, about 0.5×10−6 M, about 1×10−7 M, about 0.5×10−7 M, about 1×10−8 M, about 0.5×10−8 M, about 1×10−9 M, or about 0.5×10−9 M (inclusive); about 0.5×10−9 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, about 0.5×10−6 M, about 1×10−7 M, about 0.5×10−6 M, about 1×10−8 M, about 0.5×10−8 M, or about 1×10−9 M (inclusive); about 1×10−9 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, about 0.5×10−6 M, about 1×10−7 M, about 0.5×10−7 M, about 1×10−8 M, or about 0.5×10−8 M (inclusive); about 0.5×10−8 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, about 0.5×10−6 M, about 1×10−7 M, about 0.5×10−7 M, or about 1×10−8 M (inclusive); about 1×10−8 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, about 0.5×10−6 M, about 1×10−7 M, or about 0.5×10−7 M (inclusive); about 0.5×10−7 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, about 0.5×10−6 M, or about 1×10−7 M (inclusive); about 1×10−7 M to about 1×10−5 M, about 0.5×10−5 M, about 1×10−6 M, or about 0.5×10−6 M (inclusive); about 0.5×10−6 M to about 1×10−5 M, about 0.5×10−5 M, or about 1×10−6 M (inclusive); about 1×10−6 M to about 1×10−5 M or about 0.5×10−5 M (inclusive); or about 0.5×10−5 M to about 1×10−5 M (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).


In some embodiments, any of the antibodies or antigen-binding fragments described herein has a Koff of about 1×10−6 s−1 to about 1×10−3 s−1, about 0.5×10−3 s−1, about 1×10−4 s−1, about 0.5×10−4 s−1, about 1×10−5 s−1, or about 0.5×10−5 s−1 (inclusive); about 0.5×10−5 s−1 to about 1×10−3 s−1, about 0.5×10−3 s−1, about 1×10−4 s−1, about 0.5×10−4 s−1, or about 1×10−5 s−1 (inclusive); about 1×10−5 s−1 to about 1×10−3 s−1, about 0.5×10−3 s−1, about 1×10−4 s−1, or about 0.5×10−4 s−1 (inclusive); about 0.5×10−4 s−1 to about 1×10−3 s−1, about 0.5×10−3 s−1, or about 1×10−4 s−1 (inclusive); about 1×10-4 s−1 to about 1×10−3 s−1, or about 0.5×10−3 s−1 (inclusive); or about 0.5×10−5 s−1 to about 1×10−3 s−1 (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).


In some embodiments, any of the antibodies or antigen-binding fragments described herein has a Kon of about 1×102 M−1s−1 to about 1×106 M−1s−1, about 0.5×106 M−1s−1, about 1×105 M−1s−1, about 0.5×105 M−1s−1, about 1×104 M−1s−1, about 0.5×104 M−1s−1, about 1×103 M−1s−1, or about 0.5×103 M−1s−1 (inclusive); about 0.5×103 M−1s−1 to about 1×106 M−1s−1, about 0.5×106 M−1 s−1, about 1×105 M−1s−1, about 0.5×105 M−1s−1, about 1×104 M−1s−1, about 0.5×104 M−1s−1, or about 1×103 M−1s−1 (inclusive); about 1×103 M−1s−1to about 1×106 M−1s−1, about 0.5×106 M−1s−1, about 1×105 M−1s−1, about 0.5×105 M−1s−1, about 1×104 M−1s−1, or about 0.5×104 M−1s−1 (inclusive); about 0.5×104 M−1s−1 to about 1×106 M−1s−1, about 0.5×106 M−1s−1, about 1×105 M−1s−1, about 0.5×105 M−1s−1, or about 1×104 M−1s−1 (inclusive); about 1×104 M−1s−1 to about 1×106 M−1s−1, about 0.5×106 M−1s−1, about 1×105 M−1s−1, or about 0.5×105 M−1s−1 (inclusive); about 0.5×105 M−1s−1 to about 1×106 M−1s−1, about 0.5×106 M−1s−1, or about 1×105 M−1s−1 (inclusive); about 1×105 M−1s−1 to about 1×106 M−1s−1, or about 0.5×106 M−1s−1 (inclusive); or about 0.5×106 M−1s−1 to about 1×106 M−1s−1 (inclusive), e.g., as measured in phosphate buffered saline using surface plasmon resonance (SPR).


Fusion Proteins

In some embodiments, the anti-TNFα agent is a fusion protein (e.g., an extracellular domain of a TNFR fused to a partner peptide, e.g., an Fc region of an immunoglobulin, e.g., human IgG) (see, e.g., Deeg et al., Leukemia 16(2):162, 2002; Peppel et al., J. Exp. Med. 174(6):1483-1489, 1991) or a soluble TNFR (e.g., TNFR1 or TNFR2) that binds specifically to TNFα. In some embodiments, the anti-TNFα agent includes or is a soluble TNFα receptor (e.g., Bjornberg et al., Lymphokine Cytokine Res. 13(3):203-211, 1994; Kozak et al., Am. J. Physiol. Reg. Integrative Comparative Physiol. 269(1):R23-R29, 1995; Tsao et al., Eur Respir J. 14(3):490-495, 1999; Watt et al., J Leukoc Biol. 66(6):1005-1013, 1999; Mohler et al., J. Immunol. 151(3):1548-1561, 1993; Nophar et al., EMBO J 9(10):3269, 1990; Piguet et al., Eur. Respiratory J. 7(3):515-518, 1994; and Gray et al., Proc. Natl. Acad. Sci. U.S.A. 87(19):7380-7384, 1990). In some embodiments, the anti-TNFα agent includes or is etanercept (Enbrel™) (see, e.g., WO 91/03553 and WO 09/406,476, incorporated by reference herein). In some embodiments, the anti-TNFα agent inhibitor includes or is r-TBP-I (e.g., Gradstein et al., J. Acquir. Immune Defic. Syndr. 26(2): 111-117, 2001).


Inhibitory Nucleic Acids

Inhibitory nucleic acids that can decrease the expression of AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA expression in a mammalian cell include antisense nucleic acid molecules, i.e., nucleic acid molecules whose nucleotide sequence is fully or partially complementary to all or part of a AP-1, ASK1, CD14, c-jun, ERK1/2, IKB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (e.g., fully or partially complementary to all or a part of any one of the sequences presented in Table E).










TABLE E






mRNA GenBank


Human gene
accession number(s)







Tumor necrosis factor (TNF, a.k.a. TNF-
NM_000594


alpha)


TNF receptor superfamily member 1A
NM_001065


(TNFRSF1A) (a.k.a. TNFR1)
NM_001346091



NM_001346092


TNF receptor superfamily member 1B
NM_001066


(TNFRSF1B) (a.k.a. TNFR2)
XM_011542060



XM_011542063



XM_017002214



XM_017002215



XM_017002211


TNFRSF1A associated via death domain
NM_003789


(TRADD)
NM_001323552



XM_005256213



XM_017023815


TNF receptor associated factor 2 (TRAF2)
NM_021138



XM_011518976



XM_011518977



XM_011518974


JunD proto-oncogene, AP-1 transcription
NM_001286968


factor subunit (JUND)
NM_005354


Mitogen-activated protein kinase kinase
NM_005923


kinase 5 (MAP3K5) (a.k.a. ASK1)
XM_017010875



XM_017010872



XM_017010873



XM_017010877



XM_017010874



XM_017010871



XM_017010870



XM_017010876



XM_011535839


CD14
NM_000591



NM_001040021



NM_001174104



NM_001174105


Mitogen-activated protein kinase 3
NM_001040056


(MAPK3) (a.k.a. ERK1)
NM_001109891



NM_002746


Mitogen-activated protein kinase 1
NM_002745


(MAPK1) (a.k.a. ERK2)
NM_138957


Inhibitor of nuclear factor kappa B kinase
NM_001190720


subunit beta (IKBKB)
NM_001242778



NM_001556



XM_005273491



XM_005273496



XM_005273493



XM_005273498



XM_011544518



XM_005273492



XM_005273490



XM_005273494



12XM_017013396



XM_011544521



XM_011544522



XM_005273495



XM_011544517



XM_011544520



XM_011544519


NFKB inhibitor alpha (NFKBIA)
NM_020529


Interleukin 1 receptor associated kinase 1
NM_001025242


(IRAK1)
NM_001025243



NM_001569



XM_005274668


Mitogen-activated protein kinase 8
NM_001278547


(MAPK8) (a.k.a. JNK)
NM_001278548



NM_001323302



NM_001323320



NM_001323321



NM_001323322



NM_001323323



NM_001323324



NM_001323325



NM_001323326



NM_001323327



NM_001323328



NM_001323329



NM_001323330



NM_001323331



NM_139046



NM_139049



XM_024448079



XM_024448080


Lipopolysaccharide binding protein (LBP)
NM_004139


Mitogen-activated protein kinase kinase 1
NM_002755


(MAP2K1) (a.k.a. MEK1)
XM_017022411



XM_011521783



XM_017022412



XM_017022413


Mitogen-activated protein kinase kinase 2
NM_030662


(MAP2K2) (a.k.a. MEK2)
XM_006722799



XM_017026990



XM_017026989



XM_017026991


Mitogen-activated protein kinase kinase 3
NM_001316332


(MAP2K3) (a.k.a. MEK3)
NM_002756



NM_145109



XM_017024859



XM_005256723



XM_017024857



XM_011523959



XM_017024858



XM_011523958


Mitogen-activated protein kinase kinase 6
NM_001330450


(MAP2K6) (a.k.a. MEK6)
NM_002758



XM_005257516



XM_011525027



XM_011525026



XM_006721975


Mitogen-activated protein kinase kinase
NM_005921


kinase 1 (MAP3K1) (a.k.a. MEKK1)
XM_017009485



XM_017009484


Mitogen-activated protein kinase kinase
NM_001330431


kinase 3 (MAP3K3) (a.k.a. MEKK3)
NM_001363768



NM_002401



NM_203351



XM_005257378


Mitogen-activated protein kinase kinase
NM_001291958


kinase 4 (MAP3K4) (a.k.a. MEKK4)
NM_001301072



NM_001363582



NM_005922



NM_006724



XM_017010869


Mitogen-activated protein kinase kinase
NM_001297609


kinase 6 (MAP3K6) (a.k.a. MEKK6)
NM_004672



XM_017002771



XM_017002772


Mitogen-activated protein kinase kinase
NM_003188


kinase 7 (MAP3K7) (a.k.a. MEKK7)
NM_145331



NM_145332



NM_145333



XM_006715553



XM_017011226


MAPK activated protein kinase 2
NM_004759


(MAPKAPK2) (a.k.a. MK2)
NM_032960



XM_005273353



XM_017002810


MYD88, innate immune signal transduction
NM_001172566


adaptor (MYD88)
NM_001172567



NM_001172568



NM_001172569



NM_001365876



NM_001365877



NM_002468


Nuclear factor kappa B subunit 1 (NFKB1)
NM_001165412



NM_001319226



NM_003998



XM_024454069



XM_024454067



XM_011532006



XM_024454068


Mitogen-activated protein kinase kinase
NM_003954


kinase 14 (MAP3K14) (a.k.a. NIK)
XM_011525441


Mitogen-activated protein kinase 14
NM_001315


(MAPK14) (a.k.a. p38)
NM_139012



NM_139013



NM_139014



XM_011514310



XM_017010300



XM_017010299



XM_017010301



XM_017010304



XM_017010303



XM_017010302



XM_006714998


Eukaryotic translation initiation factor 2
NM_001135651


alpha kinase 2 (EIF2AK2) (a.k.a. PKR)
NM_001135652



NM_002759



XM_011532987



XM_017004503


AKT serine/threonine kinase 1 (AKT1)
NM_001014431


(a.k.a. RAC)
NM_001014432



NM_005163


Zinc fingers and homeoboxes 2 (ZHX2)
NM_001362797


(a.k.a. RAF)
NM_014943



XM_011516932



XM_005250836


KRAS proto-oncogene, GTPase (KRAS)
NM_001369786



NM_001369787



NM_004985



NM_033360


NRAS proto-oncogene, GTPase (NRAS)
NM_002524


Receptor interacting serine/threonine kinase
NM_001317061


1 (RIPK1) (a.k.a. RIP)
NM_001354930



NM_001354931



NM_001354932



NM_001354933



NM_001354934



NM_003804



XM_017011405



XM_006715237



XM_017011403



XM_017011404


TNF receptor associated factor 6 (TRAF6)
NM_004620



NM_145803



XM_017018220


ZFP36 ring finger protein (ZFP36) (a.k.a.
NM_003407


TTP)









An antisense nucleic acid molecule can be fully or partially complementary to all or part of a non-coding region of the coding strand of a nucleotide sequence encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein. Non-coding regions (5′ and 3′ untranslated regions) are the 5′ and 3′ sequences that flank the coding region in a gene and are not translated into amino acids.


Based upon the sequences disclosed herein, one of skill in the art can easily choose and synthesize any of a number of appropriate antisense nucleic acids to target a nucleic acid encoding an AP-1, ASK 1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein described herein. Antisense nucleic acids targeting a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein can be designed using the software available at the Integrated DNA Technologies website.


An antisense nucleic acid can be, for example, about 5, 10, 15, 18, 20, 22, 24, 25, 26, 28, 30, 32, 35, 36, 38, 40, 42, 44, 45, 46, 48, or 50 nucleotides or more in length. An antisense oligonucleotide can be constructed using enzymatic ligation reactions and chemical synthesis using procedures known in the art. For example, an antisense nucleic acid can be chemically synthesized using variously modified nucleotides or naturally occurring nucleotides designed to increase the physical stability of the duplex formed between the antisense and sense nucleic acids, e.g., phosphorothioate derivatives and acridine substituted nucleotides or to increase the biological stability of the molecules.


Examples of modified nucleotides which can be used to generate an antisense nucleic acid include 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine, 2-methylthio-N6-i sopentenyladenine, uracil-5-oxyacetic acid (v), wybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl) uracil, 5-carboxymethylaminomethyl-2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrouracil, beta-D-galactosylqueosine, inosine, N6-i sopentenyladenine, 5-methylcytosine, N6-adenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarboxymethyluracil, 5-methoxyuracil, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid (v), 5-methyl-2-thiouracil, 3-(3-amino-3-N-2-carboxypropyl) uracil, (acp3)w, and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector into which a nucleic acid has been subcloned in an antisense orientation (i.e., RNA transcribed from the inserted nucleic acid will be of an antisense orientation to a target nucleic acid of interest).


The antisense nucleic acid molecules described herein can be prepared in vitro and administered to a subject, e.g., a human subject. Alternatively, they can be generated in situ such that they hybridize with or bind to cellular mRNA and/or genomic DNA encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP protein to thereby inhibit expression, e.g., by inhibiting transcription and/or translation. The hybridization can be by conventional nucleotide complementarities to form a stable duplex, or, for example, in the case of an antisense nucleic acid molecule that binds to DNA duplexes, through specific interactions in the major groove of the double helix. The antisense nucleic acid molecules can be delivered to a mammalian cell using a vector (e.g., an adenovirus vector, a lentivirus, or a retrovirus).


An antisense nucleic acid can be an α-anomeric nucleic acid molecule. An α-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in which, contrary to the usual, β-units, the strands run parallel to each other (Gaultier et al., Nucleic Acids Res. 15:6625-6641, 1987). The antisense nucleic acid can also comprise a chimeric RNA-DNA analog (Inoue et al., FEBS Lett. 215:327-330, 1987) or a 2′-O-methylribonucleotide (Inoue et al., Nucleic Acids Res. 15:6131-6148, 1987).


Another example of an inhibitory nucleic acid is a ribozyme that has specificity for a nucleic acid encoding an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA, e.g., specificity for any one of the sequences presented in Table E). Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a single-stranded nucleic acid, such as an mRNA, to which they have a complementary region. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff and Gerlach, Nature 334:585-591, 1988)) can be used to catalytically cleave mRNA transcripts to thereby inhibit translation of the protein encoded by the mRNA. An AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be used to select a catalytic RNA having a specific ribonuclease activity from a pool of RNA molecules. See, e.g., Bartel et al., Science 261:1411-1418, 1993.


Alternatively, a ribozyme having specificity for an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA can be designed based upon the nucleotide sequence of any of the AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA sequences disclosed herein (e.g., in Table E). For example, a derivative of a Tetrahymena L-19 IVS RNA can be constructed in which the nucleotide sequence of the active site is complementary to the nucleotide sequence to be cleaved in an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP mRNA (see, e.g., U.S. Pat. Nos. 4,987,071 and 5,116,742).


An inhibitory nucleic acid can also be a nucleic acid molecule that forms triple helical structures. For example, expression of an AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide can be inhibited by targeting nucleotide sequences complementary to the regulatory region of the gene encoding the AP-1, ASK1, CD14, c-jun, ERK1/2, IκB, IKK, IRAK, JNK, LBP, MAPK, MEK1/2, MEKK1/4, MEKK4/7, MEKK 3/6, MK2, MyD88, NF-κB, NIK, p38, PKR, rac, ras, raf, RIP, TNFα, TNFR1, TNFR2, TRADD, TRAF2, TRAF6, or TTP polypeptide (e.g., the promoter and/or enhancer, e.g., a sequence that is at least 1 kb, 2 kb, 3 kb, 4 kb, or 5 kb upstream of the transcription initiation start state) to form triple helical structures that prevent transcription of the gene in target cells. See generally Maher, Bioassays 14(12):807-15, 1992; Helene, Anticancer Drug Des. 6(6):569-84, 1991; and Helene, Ann. N.Y. Acad. Sci. 660:27-36, 1992.


In various embodiments, inhibitory nucleic acids can be modified at the sugar moiety, the base moiety, or phosphate backbone to improve, e.g., the solubility, stability, or hybridization, of the molecule. For example, the deoxyribose phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see, e.g., Hyrup et al., Bioorganic Medicinal Chem. 4(1):5-23, 1996). Peptide nucleic acids (PNAs) are nucleic acid mimics, e.g., DNA mimics, in which the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. The neutral backbone of PNAs allows for specific hybridization to RNA and DNA under conditions of low ionic strength. PNA oligomers can be synthesized using standard solid phase peptide synthesis protocols (see, e.g., Perry-O'Keefe et al., Proc. Natl. Acad. Sci. U.S.A. 93:14670-675, 1996). PNAs can be used as antisense or antigene agents for sequence-specific modulation of gene expression by, e.g., inducing transcription or translation arrest or inhibiting replication.


Small Molecules

In some embodiments, the anti-TNFα agent is a small molecule. In some embodiments, the small molecule is a tumor necrosis factor-converting enzyme (TACE) inhibitor (e.g., Moss et al., Nature Clinical Practice Rheumatology 4: 300-309, 2008). In some embodiments, the anti-TNFα agent is C87 (Ma et al., J. Biol. Chem. 289(18):12457-66, 2014). In some embodiments, the small molecule is LMP-420 (e.g., Haraguchi et al., AIDS Res. Ther. 3:8, 2006). In some embodiments, the TACE inhibitor is TMI-005 and BMS-561392. Additional examples of small molecule inhibitors are described in, e.g., He et al., Science 310(5750):1022-1025, 2005.


In some examples, the anti-TNFα agent is a small molecule that inhibits the activity of one of AP-1, ASK1, IKK, JNK, MAPK, MEKK 1/4, MEKK4/7, MEKK 3/6, NIK, TRADD, RIP, NF-κB, and TRADD in a cell (e.g., in a cell obtained from a subject, a mammalian cell).


In some examples, the anti-TNFα agent is a small molecule that inhibits the activity of one of CD14, MyD88 (see, e.g., Olson et al., Scientific Reports 5:14246, 2015), ras (e.g., Baker et al., Nature 497:577-578, 2013), raf (e.g., vemurafenib (PLX4032, RG7204), sorafenib tosylate, PLX-4720, dabrafenib (GSK2118436), GDC-0879, RAF265 (CHIR-265), AZ 628, NVP-BHG712, SB590885, ZM 336372, sorafenib, GW5074, TAK-632, CEP-32496, encorafenib (LGX818), CCT196969, LY3009120, RO5126766 (CH5126766), PLX7904, and MLN2480).


In some examples, the anti-TNFα agent TNFα inhibitor is a small molecule that inhibits the activity of one of MK2 (PF 3644022 and PHA 767491), JNK (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 1S, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), c-jun (e.g., AEG 3482, BI 78D3, CEP 1347, c-JUN peptide, IQ 15, JIP-1 (153-163), SP600125, SU 3327, and TCS JNK6o), MEK3/6 (e.g., Akinleye et al., J. Hematol. Oncol. 6:27, 2013), p38 (e.g., AL 8697, AMG 548, BIRB 796, CMPD-1, DBM 1285 dihydrochloride, EO 1428, JX 401, ML 3403, Org 48762-0, PH 797804, RWJ 67657, SB 202190, SB 203580, SB 239063, SB 706504, SCIO 469, SKF 86002, SX 011, TA 01, TA 02, TAK 715, VX 702, and VX 745), PKR (e.g., 2-aminopurine or CAS 608512-97-6), TTP (e.g., CAS 329907-28-0), MEK1/2 (e.g., Facciorusso et al., Expert Review Gastroentrol. Hepatol. 9:993-1003, 2015), ERK1/2 (e.g., Mandal et al., Oncogene 35:2547-2561, 2016), NIK (e.g., Mortier et al., Bioorg. Med. Chem. Lett. 20:4515-4520, 2010), IKK (e.g., Reilly et al., Nature Med. 19:313-321, 2013), IκB (e.g., Suzuki et al., Expert. Opin. Invest. Drugs 20:395-405, 2011), NF-κB (e.g., Gupta et al., Biochim. Biophys. Acta 1799(10-12):775-787, 2010), rac (e.g., U.S. Pat. No. 9,278,956), MEK4/7, IRAK (Chaudhary et al., J. Med. Chem. 58(1):96-110, 2015), LBP (see, e.g., U.S. Pat. No. 5,705,398), and TRAF6 (e.g., 3-[(2,5-Dimethylphenyl)amino]-1-phenyl-2-propen-1-one).


In some embodiments of any of the methods described herein, the inhibitory nucleic acid can be about 10 nucleotides to about 50 nucleotides (e.g., about 10 nucleotides to about 45 nucleotides, about 10 nucleotides to about 40 nucleotides, about 10 nucleotides to about 35 nucleotides, about 10 nucleotides to about 30 nucleotides, about 10 nucleotides to about 28 nucleotides, about 10 nucleotides to about 26 nucleotides, about 10 nucleotides to about 25 nucleotides, about 10 nucleotides to about 24 nucleotides, about 10 nucleotides to about 22 nucleotides, about 10 nucleotides to about 20 nucleotides, about 10 nucleotides to about 18 nucleotides, about 10 nucleotides to about 16 nucleotides, about 10 nucleotides to about 14 nucleotides, about 10 nucleotides to about 12 nucleotides, about 12 nucleotides to about 50 nucleotides, about 12 nucleotides to about 45 nucleotides, about 12 nucleotides to about 40 nucleotides, about 12 nucleotides to about 35 nucleotides, about 12 nucleotides to about 30 nucleotides, about 12 nucleotides to about 28 nucleotides, about 12 nucleotides to about 26 nucleotides, about 12 nucleotides to about 25 nucleotides, about 12 nucleotides to about 24 nucleotides, about 12 nucleotides to about 22 nucleotides, about 12 nucleotides to about 20 nucleotides, about 12 nucleotides to about 18 nucleotides, about 12 nucleotides to about 16 nucleotides, about 12 nucleotides to about 14 nucleotides, about 15 nucleotides to about 50 nucleotides, about 15nucleotides to about 45 nucleotides, about 15nucleotides to about 40 nucleotides, about 15nucleotides to about 35 nucleotides, about 15 nucleotides to about 30 nucleotides, about 15nucleotides to about 28 nucleotides, about 15nucleotides to about 26 nucleotides, about 15nucleotides to about 25 nucleotides, about 15nucleotides to about 24 nucleotides, about 15nucleotides to about 22 nucleotides, about 15nucleotides to about 20 nucleotides, about 15nucleotides to about 18 nucleotides, about 15nucleotides to about 16 nucleotides, about 16 nucleotides to about 50 nucleotides, about 16 nucleotides to about 45 nucleotides, about 16 nucleotides to about 40 nucleotides, about 16 nucleotides to about 35 nucleotides, about 16 nucleotides to about 30 nucleotides, about 16 nucleotides to about 28 nucleotides, about 16 nucleotides to about 26 nucleotides, about 16 nucleotides to about 25 nucleotides, about 16 nucleotides to about 24 nucleotides, about 16 nucleotides to about 22 nucleotides, about 16 nucleotides to about 20 nucleotides, about 16 nucleotides to about 18 nucleotides, about 18 nucleotides to about 20 nucleotides, about 20 nucleotides to about 50 nucleotides, about 20 nucleotides to about 45 nucleotides, about 20 nucleotides to about 40 nucleotides, about 20 nucleotides to about 35 nucleotides, about 20 nucleotides to about 30 nucleotides, about 20 nucleotides to about 28 nucleotides, about 20 nucleotides to about 26 nucleotides, about 20 nucleotides to about 25 nucleotides, about 20 nucleotides to about 24 nucleotides, about 20 nucleotides to about 22 nucleotides, about 24 nucleotides to about 50 nucleotides, about 24 nucleotides to about 45 nucleotides, about 24 nucleotides to about 40 nucleotides, about 24 nucleotides to about 35 nucleotides, about 24 nucleotides to about 30 nucleotides, about 24 nucleotides to about 28 nucleotides, about 24 nucleotides to about 26 nucleotides, about 24 nucleotides to about 25 nucleotides, about 26 nucleotides to about 50 nucleotides, about 26 nucleotides to about 45 nucleotides, about 26 nucleotides to about 40 nucleotides, about 26 nucleotides to about 35 nucleotides, about 26 nucleotides to about 30 nucleotides, about 26 nucleotides to about 28 nucleotides, about 28 nucleotides to about 50 nucleotides, about 28 nucleotides to about 45 nucleotides, about 28 nucleotides to about 40 nucleotides, about 28 nucleotides to about 35 nucleotides, about 28 nucleotides to about 30 nucleotides, about 30 nucleotides to about 50 nucleotides, about 30 nucleotides to about 45 nucleotides, about 30 nucleotides to about 40 nucleotides, about 30 nucleotides to about 38 nucleotides, about 30 nucleotides to about 36 nucleotides, about 30 nucleotides to about 34 nucleotides, about 30 nucleotides to about 32 nucleotides, about 32 nucleotides to about 50 nucleotides, about 32 nucleotides to about 45 nucleotides, about 32 nucleotides to about 40 nucleotides, about 32 nucleotides to about 35 nucleotides, about 35 nucleotides to about 50 nucleotides, about 35 nucleotides to about 45 nucleotides, about 35 nucleotides to about 40 nucleotides, about 40 nucleotides to about 50 nucleotides, about 40 nucleotides to about 45 nucleotides, about 42 nucleotides to about 50 nucleotides, about 42 nucleotides to about 45 nucleotides, or about 45 nucleotides to about 50 nucleotides) in length. One skilled in the art will appreciate that inhibitory nucleic acids may comprises at least one modified nucleic acid at either the 5′ or 3′ end of DNA or RNA.


In some embodiments, the inhibitory nucleic acid can be formulated in a liposome, a micelle (e.g., a mixed micelle), a nanoemulsion, or a microemulsion, a solid nanoparticle, or a nanoparticle (e.g., a nanoparticle including one or more synthetic polymers). Additional exemplary structural features of inhibitory nucleic acids and formulations of inhibitory nucleic acids are described in US 2016/0090598.


In some embodiments, the inhibitory nucleic acid (e.g., any of the inhibitory nucleic acid described herein) can include a sterile saline solution (e.g., phosphate-buffered saline (PBS)). In some embodiments, the inhibitory nucleic acid (e.g., any of the inhibitory nucleic acid described herein) can include a tissue-specific delivery molecule (e.g., a tissue-specific antibody).


Pharmaceutical Compositions and Administration


General


In some embodiments, a chemical entity (e.g., a compound that modulates (e.g., antagonizes) NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.


In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-a-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium tri silicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22nd Edition (Pharmaceutical Press, London, UK. 2012).


In some embodiments, an NLRP3 antagonist and/or an anti-TNFα agent disclosed herein is administered as a pharmaceutical composition that includes the NLRP3 antagonist and/or anti-TNFα agent and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein. Preferably the pharmaceutical composition that includes an NLRP3 antagonist and an anti-TNFα agent.


Preferably the above pharmaceutical composition embodiments comprise an NLRP3 antagonist disclosed herein. More preferably the above pharmaceutical composition embodiments comprise an NLRP3 antagonist and an anti-TNFα agent disclosed herein.


Routes of Administration and Composition Components


In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intraci sternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).


Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.


The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.


The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.


Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.


Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788-795.


In certain embodiments, the chemical entities described herein or a pharmaceutical composition thereof are suitable for local, topical administration to the digestive or GI tract, e.g., rectal administration. Rectal compositions include, without limitation, enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, and enemas (e.g., retention enemas).


Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.


In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.


In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.).


Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.


In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.


Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.


In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.


In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K. J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.


Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.


Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.


Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).


Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.


In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.


Enema Formulations


In some embodiments, enema formulations containing the chemical entities described herein are provided in “ready-to-use” form.


In some embodiments, enema formulations containing the chemical entities described herein are provided in one or more kits or packs. In certain embodiments, the kit or pack includes two or more separately contained/packaged components, e.g. two components, which when mixed together, provide the desired formulation (e.g., as a suspension). In certain of these embodiments, the two component system includes a first component and a second component, in which: (i) the first component (e.g., contained in a sachet) includes the chemical entity (as described anywhere herein) and optionally one or more pharmaceutically acceptable excipients (e.g., together formulated as a solid preparation, e.g., together formulated as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and optionally one or more other pharmaceutically acceptable excipients together forming a liquid carrier. Prior to use (e.g., immediately prior to use), the contents of (i) and (ii) are combined to form the desired enema formulation, e.g., as a suspension. In other embodiments, each of component (i) and (ii) is provided in its own separate kit or pack.


In some embodiments, each of the one or more liquids is water, or a physiologically acceptable solvent, or a mixture of water and one or more physiologically acceptable solvents. Typical such solvents include, without limitation, glycerol, ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol. In certain embodiments, each of the one or more liquids is water. In other embodiments, each of the one or more liquids is an oil, e.g. natural and/or synthetic oils that are commonly used in pharmaceutical preparations.


Further pharmaceutical excipients and carriers that may be used in the pharmaceutical products herein described are listed in various handbooks (e.g. D. E. Bugay and W. P. Findlay (Eds) Pharmaceutical excipients (Marcel Dekker, New York, 1999), E-M Hoepfner, A. Reng and P. C. Schmidt (Eds) Fiedler Encyclopedia of Excipients for Pharmaceuticals, Cosmetics and Related Areas (Edition Cantor, Munich, 2002) and H. P. Fielder (Ed) Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik and angrenzende Gebiete (Edition Cantor Aulendorf, 1989)).


In some embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, penetration enhanceers, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, fillers, solubilizing agents, pH modifying agents, preservatives, stabilizing agents, anti-oxidants, wetting or emulsifying agents, suspending agents, pigments, colorants, isotonic agents, chelating agents, emulsifiers, and diagnostic agents.


In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from thickeners, viscosity enhancing agents, mucoadhesive agents, buffers, preservatives, diluents, binders, lubricants, glidants, disintegrants, and fillers.


In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from thickeners, viscosity enhancing agents, bulking agents, mucoadhesive agents, buffers, preservatives, and fillers.


In certain embodiments, each of the one or more pharmaceutically acceptable excipients can be independently selelcted from diluents, binders, lubricants, glidants, and disintegrants.


Examples of thickeners, viscosity enhancing agents, and mucoadhesive agents include without limitation: gums, e.g. xanthan gum, guar gum, locust bean gum, tragacanth gums, karaya gum, ghatti gum, cholla gum, psyllium seed gum and gum arabic; poly(carboxylic acid-containing) based polymers, such as poly (acrylic, maleic, itaconic, citraconic, hydroxyethyl methacrylic or methacrylic) acid which have strong hydrogen-bonding groups, or derivatives thereof such as salts and esters; cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof clays such as manomorillonite clays, e.g. Veegun, attapulgite clay; polysaccharides such as dextran, pectin, amylopectin, agar, mannan or polygalactonic acid or starches such as hydroxypropyl starch or carboxymethyl starch; polypeptides such as casein, gluten, gelatin, fibrin glue; chitosan, e.g. lactate or glutamate or carboxymethyl chitin; glycosaminoglycans such as hyaluronic acid; metals or water soluble salts of alginic acid such as sodium alginate or magnesium alginate; schleroglucan; adhesives containing bismuth oxide or aluminium oxide; atherocollagen; polyvinyl polymers such as carboxyvinyl polymers; polyvinylpyrrolidone (povidone); polyvinyl alcohol; polyvinyl acetates, polyvinylmethyl ethers, polyvinyl chlorides, polyvinylidenes, and/or the like; polycarboxylated vinyl polymers such as polyacrylic acid as mentioned above; polysiloxanes; polyethers; polyethylene oxides and glycols; polyalkoxys and polyacrylamides and derivatives and salts thereof. Preferred examples can include cellulose derivatives, such as methyl cellulose, ethyl cellulose, methylethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl ethyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone).


Examples of preservatives include without limitation: benzalkonium chloride, benzoxonium chloride, benzethonium chloride, cetrimide, sepazonium chloride, cetylpyridinium chloride, domiphen bromide (Bradosol®), thiomersal, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric borate, methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenyl ethyl alcohol, chlorohexidine, polyhexamethylene biguanide, sodium perborate, imidazolidinyl urea, sorbic acid, Purite®), Polyquart®), and sodium perborate tetrahydrate and the like.


In certain embodiments, the preservative is a paraben, or a pharmaceutically acceptable salt thereof. In some embodiments, the paraben is an alkyl substituted 4-hydroxybenzoate, or a pharmaceutically acceptable salt or ester thereof. In certain embodiments, the alkyl is a C1-C4 alkyl. In certain embodiments, the preservative is methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof.


Examples of buffers include without limitation: phosphate buffer system (sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate, bibasic sodium phosphate, anhydrous monobasic sodium phosphate), bicarbonate buffer system, and bisulfate buffer system.


Examples of disintegrants include, without limitation: carmellose calcium, low substituted hydroxypropyl cellulose (L-HPC), carmellose, croscarmellose sodium, partially pregelatinized starch, dry starch, carboxymethyl starch sodium, crospovidone, polysorbate 80 (polyoxyethylenesorbitan oleate), starch, sodium starch glycolate, hydroxypropyl cellulose pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross-linked PVP (Polyplasdone XL from GAF Chemical Corp). In certain embodiments, the disintegrant is crospovidone.


Examples of glidants and lubricants (aggregation inhibitors) include without limitation: talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, aqueous silicon dioxide, synthetic magnesium silicate, fine granulated silicon oxide, starch, sodium laurylsulfate, boric acid, magnesium oxide, waxes, hydrogenated oil, polyethylene glycol, sodium benzoate, stearic acid glycerol behenate, polyethylene glycol, and mineral oil. In certain embodiments, the glidant/lubricant is magnesium stearate, talc, and/or colloidal silica; e.g., magnesium stearate and/or talc.


Examples of diluents, also referred to as “fillers” or “bulking agents” include without limitation: dicalcium phosphate dihydrate, calcium sulfate, lactose (e.g., lactose monohydrate), sucrose, mannitol, sorbitol, cellulose, microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powdered sugar. In certain embodiments, the diluent is lactose (e.g., lactose monohydrate).


Examples of binders include without limitation: starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dxtrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia tragacanth, sodium alginate cellulose, including hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone (povidone). In certain embodiments, the binder is polyvinylpyrrolidone (povidone).


In some embodiments, enema formulations containing the chemical entities described herein include water and one or more (e.g., all) of the following excipients:

    • One or more (e.g., one, two, or three) thickeners, viscosity enhancing agents, binders, and/or mucoadhesive agents (e.g., cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone);
    • One or more (e.g., one or two; e.g., two) preservatives, such as a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof;
    • One or more (e.g., one or two; e.g., two) buffers, such as phosphate buffer system (e.g., sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate);
    • One or more (e.g., one or two, e.g., two) glidants and/or lubricants, such as magnesium stearate and/or talc;
    • One or more (e.g., one or two; e.g., one) disintegrants, such as crospovidone; and
    • One or more (e.g., one or two; e.g., one) diluents, such as lactose (e.g., lactose monohydrate).


In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof.


In certain embodiments, enema formulations containing the chemical entities described herein include water, methyl cellulose, povidone, methylparaben, propylparaben, sodium dihydrogen phospahate dehydrate, disodium phosphate dodecahydrate, crospovidone, lactose monohydrate, magnesium stearate, and talc. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof.


In certain embodiments, enema formulations containing the chemical entities described herein are provided in one or more kits or packs. In certain embodiments, the kit or pack includes two separately contained/packaged components, which when mixed together, provide the desired formulation (e.g., as a suspension). In certain of these embodiments, the two component system includes a first component and a second component, in which: (i) the first component (e.g., contained in a sachet) includes the chemical entity (as described anywhere herein) and one or more pharmaceutically acceptable excipients (e.g., together formulated as a solid preparation, e.g., together formulated as a wet granulated solid preparation); and (ii) the second component (e.g., contained in a vial or bottle) includes one or more liquids and one or more one or more other pharmaceutically acceptable excipients together forming a liquid carrier. In other embodiments, each of component (i) and (ii) is provided in its own separate kit or pack.


In certain of these embodiments, component (i) includes the chemical entitiy (e.g., a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof; e.g., a compound of Formula AA) and one or more (e.g., all) of the following excipients:

    • (a) One or more (e.g., one) binders (e.g., a polyvinyl polymer, such as polyvinylpyrrolidone (povidone);
    • (b) One or more (e.g., one or two, e.g., two) glidants and/or lubricants, such as magnesium stearate and/or talc;
    • (c) One or more (e.g., one or two; e.g., one) disintegrants, such as crospovidone; and
    • (d) One or more (e.g., one or two; e.g., one) diluents, such as lactose (e.g., lactose monohydrate).


In certain embodiments, component (i) includes from about 40 weight percent to about 80 weight percent (e.g., from about 50 weight percent to about 70 weight percent, from about 55 weight percent to about 70 weight percent; from about 60 weight percent to about 65 weight percent; e.g., about 62.1 weight percent) of the chemical entity (e.g., a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof).


In certain embodiments, component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 1.5 weight percent to about 4.5 weight percent, from about 2 weight percent to about 3.5 weight percent; e.g., about 2.76 weight percent) of the binder (e.g., povidone).


In certain embodiments, component (i) includes from about 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; about 2 weight percent e.g., about 1.9 weight percent) of the di sintegrant (e.g., crospovidone).


In certain embodiments, component (i) includes from about 10 weight percent to about 50 weight percent (e.g., from about 20 weight percent to about 40 weight percent, from about 25 weight percent to about 35 weight percent; e.g., about 31.03 weight percent) of the diluent (e.g., lactose, e.g., lactose monohydrate).


In certain embodiments, component (i) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent) of the glidants and/or lubricants.


In certain embodiments (e.g., when component (i) includes one or more lubricants, such as magnesium stearate), component (i) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 1 weight percent; from about 0.1 weight percent to about 1 weight percent; from about 0.1 weight percent to about 0.5 weight percent; e.g., about 0.27 weight percent) of the lubricant (e.g., magnesium stearate).


In certain embodiments (when component (i) includes one or more lubricants, such as talc), component (i) includesfrom about 0.5 weight percent to about 5 weight percent (e.g., from about 0.5 weight percent to about 3 weight percent, from about 1 weight percent to about 3 weight percent; from about 1.5 weight percent to about 2.5 weight percent; from about 1.8 weight percent to about 2.2 weight percent; about 1.93 weight percent) of the lubricant (e.g., talc).


In certain of these embodiments, each of (a), (b), (c), and (d) above is present.


In certain embodiments, component (i) includes the ingredients and amounts as shown in Table A.










TABLE A





Ingredient
Weight Percent







A compound of Formula
40 weight percent to about 80 weight


AA
percent (e.g., from about 50 weight percent



to about 70 weight percent, from about 55



weight percent to about 70 weight percent;



from about 60 weight percent to about 65



weight percent; e.g., about 62.1 weight



percent)


Crospovidone (Kollidon
0.5 weight percent to about 5 weight


CL)
percent (e.g., from about 0.5 weight



percent to about 3 weight percent, from



about 1 weight percent to about 3 weight



percent; about 1.93 weight percent


lactose monohydrate
about 10 weight percent to about 50 weight


(Pharmatose 200M)
percent (e.g., from about 20 weight percent



to about 40 weight percent, from about 25



weight percent to about 35 weight percent;



e.g., about 31.03 weight percent


Povidone (Kollidon K30)
about 0.5 weight percent to about 5 weight



percent (e.g., from about 1.5 weight



percent to about 4.5 weight percent, from



about 2 weight percent to about 3.5 weight



percent; e.g., about 2.76 weight percent


talc
0.5 weight percent to about 5 weight



percent (e.g., from about 0.5 weight



percent to about 3 weight percent, from



about 1 weight percent to about 3 weight



percent; from about 1.5 weight percent to



about 2.5 weight percent; from about 1.8



weight percent to about 2.2 weight



percent; e.g., about 1.93 weight percent


Magnesium stearate
about 0.05 weight percent to about 1



weight percent (e.g., from about 0.05



weight percent to about 1 weight percent;



from about 0.1 weight percent to about 1



weight percent; from about 0.1 weight



percent to about 0.5 weight percent; e.g.,



about 0.27 weight percent









In certain embodiments, component (i) includes the ingredients and amounts as shown in Table B.












TABLE B







Ingredient
Weight Percent









A compound of Formula
About 62.1 weight percent)



AA



Crospovidone (Kollidon
About 1.93 weight percent



CL)



lactose monohydrate
About 31.03 weight percent



(Pharmatose 200M)



Povidone (Kollidon K30)
About 2.76 weight percent



talc
About 1.93 weight percent



Magnesium stearate
About 0.27 weight percent










In certain embodiments, component (i) is formulated as a wet granulated solid preparation. In certain of these embodiments an internal phase of ingredients (the chemical entity, disintegrant, and diluent) are combined and mixed in a high-shear granulator. A binder (e.g., povidone) is dissolved in water to form a granulating solution. This solution is added to the Inner Phase mixture resulting in the development of granules. While not wishing to be bound by theory, granule development is believed to be facilitated by the interaction of the polymeric binder with the materials of the internal phase. Once the granulation is formed and dried, an external phase (e.g., one or more lubricants—not an intrinsic component of the dried granulation), is added to the dry granulation. It is believed that lubrication of the granulation is important to the flowability of the granulation, in particular for packaging.


In certain of the foregoing embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients:

    • (a′) One or more (e.g., one, two; e.g., two) thickeners, viscosity enhancing agents, binders, and/or mucoadhesive agents (e.g., cellulose or cellulose esters or ethers or derivatives or salts thereof (e.g., methyl cellulose); and polyvinyl polymers such as polyvinylpyrrolidone (povidone);
    • (b′) One or more (e.g., one or two; e.g., two) preservatives, such as a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof, propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof, or a combination thereof; and
    • (c′) One or more (e.g., one or two; e.g., two) buffers, such as phosphate buffer system (e.g., sodium dihydrogen phospahate dihydrate, disodium phosphate dodecahydrate);


In certain of the foregoing embodiments, component (ii) includes water and one or more (e.g., all) of the following excipients:

    • (a″) a first thickener, viscosity enhancing agent, binder, and/or mucoadhesive agent (e.g., a cellulose or cellulose ester or ether or derivative or salt thereof (e.g., methyl cellulose));
    • (a′″) a second thickener, viscosity enhancing agent, binder, and/or mucoadhesive agent (e.g., a polyvinyl polymer, such as polyvinylpyrrolidone (povidone));
    • (b″) a first preservative, such as a paraben, e.g., propyl 4-hydroxybenzoate (propylparaben), or a pharmaceutically acceptable salt or ester thereof;



1(b″) a second preservative, such as a paraben, e.g., methyl 4-hydroxybenzoate (methylparaben), or a pharmaceutically acceptable salt or ester thereof,

    • (c″) a first buffer, such as phosphate buffer system (e.g., disodium phosphate dodecahydrate);
    • (c′″) a second buffer, such as phosphate buffer system (e.g., sodium dihydrogen phospahate dehydrate),


In certain embodiments, component (ii) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 3 weight percent; e.g., about 1.4 weight percent) of (a″).


In certain embodiments, component (ii) includes from about 0.05 weight percent to about 5 weight percent (e.g., from about 0.05 weight percent to about 3 weight percent, from about 0.1 weight percent to about 2 weight percent; e.g., about 1.0 weight percent) of (a′″).


In certain embodiments, component (ii) includes from about 0.005 weight percent to about 0.1 weight percent (e.g., from about 0.005 weight percent to about 0.05 weight percent; e.g., about 0.02 weight percent) of (b″).


In certain embodiments, component (ii) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.20 weight percent) of (b′″).


In certain embodiments, component (ii) includes from about 0.05 weight percent to about 1 weight percent (e.g., from about 0.05 weight percent to about 0.5 weight percent; e.g., about 0.15 weight percent) of (c″).


In certain embodiments, component (ii) includes from about 0.005 weight percent to about 0.5 weight percent (e.g., from about 0.005 weight percent to about 0.3 weight percent; e.g., about 0.15 weight percent) of (c′″).


In certain of these embodiments, each of (a″)-(c′″) is present.


In certain embodiments, component (ii) includes water (up to 100%) and the ingredients and amounts as shown in Table C.










TABLE C





Ingredient
Weight Percent







methyl cellulose (Methocel
0.05 weight percent to about 5 weight


A15C premium)
percent (e.g., from about 0.05 weight



percent to about 3 weight percent, from



about 0.1 weight percent to about 3 weight



percent; e.g., about 1.4 weight percent


Povidone (Kollidon K30)
0.05 weight percent to about 5 weight



percent (e.g., from about 0.05 weight



percent to about 3 weight percent, from



about 0.1 weight percent to about 2 weight



percent; e.g., about 1.0 weight percent


propyl 4-hydroxybenzoate
about 0.005 weight percent to about 0.1



weight percent (e.g., from about 0.005



weight percent to about 0.05 weight



percent; e.g., about 0.02 weight percent)


methyl 4-hydroxybenzoate
about 0.05 weight percent to about 1



weight percent (e.g., from about 0.05



weight percent to about 0.5 weight percent;



e.g., about 0.20 weight percent)


disodium phosphate
about 0.05 weight percent to about 1


dodecahydrate
weight percent (e.g., from about 0.05



weight percent to about 0.5 weight percent;



e.g., about 0.15 weight percent)


sodium dihydrogen
about 0.005 weight percent to about 0.5


phospahate dihydrate
weight percent (e.g., from about 0.005



weight percent to about 0.3 weight percent;



e.g., about 0.15 weight percent)









In certain embodiments, component (ii) includes water (up to 100%) and the ingredients and amounts as shown in Table D.












TABLE D







Ingredient
Weight Percent









methyl cellulose (Methocel
about 1.4 weight percent



A15C premium)



Povidone (Kollidon K30)
about 1.0 weight percent



propyl 4-hydroxybenzoate
about 0.02 weight percent



methyl 4-hydroxybenzoate
about 0.20 weight percent



disodium phosphate
about 0.15 weight percent



dodecahydrate



sodium dihydrogen
about 0.15 weight percent



phospahate dihydrate










Ready-to-use” enemas are generally be provided in a “single-use” sealed disposable container of plastic or glass. Those formed of a polymeric material preferably have sufficient flexibility for ease of use by an unassisted patient. Typical plastic containers can be made of polyethylene. These containers may comprise a tip for direct introduction into the rectum. Such containers may also comprise a tube between the container and the tip. The tip is preferably provided with a protective shield which is removed before use. Optionally the tip has a lubricant to improve patient compliance.


In some embodiments, the enema formulation (e.g., suspension) is poured into a bottle for delivery after it has been prepared in a separate container. In certain embodiments, the bottle is a plastic bottle (e.g., flexible to allow for delivery by squeezing the bottle), which can be a polyethylene bottle (e.g., white in color). In some embodiments, the bottle is a single chamber bottle, which contains the suspension or solution. In other embodiments, the bottle is a multichamber bottle, where each chamber contains a separate mixture or solution. In still other embodiments, the bottle can further include a tip or rectal cannula for direct introduction into the rectum.


Dosages


The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.


In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0. 1 mg/Kg to about 200 mg/Kg; from about 0. 1 mg/Kg to about 150 mg/Kg; from about 0. 1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50 mg/Kg; from about 0. 1 mg/Kg to about 10 mg/Kg; from about 0. 1 mg/Kg to about 5 mg/Kg; from about 0. 1 mg/Kg to about 1 mg/Kg; from about 0. 1 mg/Kg to about 0.5 mg/Kg).


In some embodiments, enema formulations include from about 0.5 mg to about 2500 mg (e.g., from about 0.5 mg to about 2000 mg, from about 0.5 mg to about 1000 mg, from about 0.5 mg to about 750 mg, from about 0.5 mg to about 600 mg, from about 0.5 mg to about 500 mg, from about 0.5 mg to about 400 mg, from about 0.5 mg to about 300 mg, from about 0.5 mg to about 200 mg; e.g., from about 5 mg to about 2500 mg, from about 5 mg to about 2000 mg, from about 5 mg to about 1000 mg; from about 5 mg to about 750 mg; from about 5 mg to about 600 mg; from about 5 mg to about 500 mg; from about 5 mg to about 400 mg; from about 5 mg to about 300 mg; from about 5 mg to about 200 mg; e.g., from about 50 mg to about 2000 mg, from about 50 mg to about 1000 mg, from about 50 mg to about 750 mg, from about 50 mg to about 600 mg, from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 50 mg to about 200 mg; e.g., from about 100 mg to about 2500 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 750 mg, from about 100 mg to about 700 mg, from about 100 mg to about 600 mg, from about 100 mg to about 500 mg, from about 100 mg to about 400 mg, from about 100 mg to about 300 mg, from about 100 mg to about 200 mg; e.g., from about 150 mg to about 2500 mg, from about 150 mg to about 2000 mg, from about 150 mg to about 1000 mg, from about 150 mg to about 750 mg, from about 150 mg to about 700 mg, from about 150 mg to about 600 mg, from about 150 mg to about 500 mg, from about 150 mg to about 400 mg, from about 150 mg to about 300 mg, from about 150 mg to about 200 mg; e.g., from about 150 mg to about 500 mg; e.g., from about 300 mg to about 2500 mg, from about 300 mg to about 2000 mg, from about 300 mg to about 1000 mg, from about 300 mg to about 750 mg, from about 300 mg to about 700 mg, from about 300 mg to about 600 mg; e.g., from about 400 mg to about 2500 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1000 mg, from about 400 mg to about 750 mg, from about 400 mg to about 700 mg, from about 400 mg to about 600 from about 400 mg to about 500 mg; e.g., 150 mg or 450 mg) of the chemical entity in from about 1 mL to about 3000 mL (e.g., from about 1 mL to about 2000 mL, from about 1 mL to about 1000 mL, from about 1 mL to about 500 mL, from about 1 mL to about 250 mL, from about 1 mL to about 100 mL, from about 10 mL to about 1000 mL, from about 10 mL to about 500 mL, from about 10 mL to about 250 mL, from about 10 mL to about 100 mL, from about 30 mL to about 90 mL, from about 40 mL to about 80 mL; from about 50 mL to about 70 mL; e.g., about 1 mL, about 5 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL,about 50 mL, about 55 mL, about 60 mL, about 65 mL, about 70 mL, about 75 mL, about 100 mL, about 250 mL, or about 500 mL, or about 1000 mL, or about 2000mL, or about 3000 mL; e.g., 60 mL) of liquid carrier.


In certain embodiments, enema formulations include from about 50 mg to about 250 mg (e.g., from about 100 mg to about 200; e.g., about 150 mg) of the chemical entity in from about 10 mL to about 100 mL (e.g., from about 20 mL to about 100 mL, from about 30 mL to about 90 mL, from about 40 mL to about 80 mL; from about 50 mL to about 70 mL) of liquid carrier. In certain embodiments, enema formulations include about 150 mg of the chemical entity in about 60 mL of the liquid carrier. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 150 mg of a compound of Formula AA in about 60 mL of the liquid carrier.


In certain embodiments, enema formulations include from about 350 mg to about 550 mg (e.g., from about 400 mg to about 500; e.g., about 450 mg) of the chemical entity in from about 10 mL to about 100 mL (e.g., from about 20 mL to about 100 mL, from about 30 mL to about 90 mL, from about 40 mL to about 80 mL; from about 50 mL to about 70 mL) of liquid carrier. In certain embodiments, enema formulations include about 450 mg of the chemical entity in about 60 mL of the liquid carrier. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 450 mg of a compound of Formula AA in about 60 mL of the liquid carrier.


In some embodiments, enema formulations include from about from about 0.01 mg/mL to about 50 mg/mL (e.g., from about 0.01 mg/mL to about 25 mg/mL; from about 0.01 mg/mL to about 10 mg/mL; from about 0.01 mg/mL to about 5 mg/mL; from about 0.1 mg/mL to about 50 mg/mL; from about 0.01 mg/mL to about 25 mg/mL; from about 0.1 mg/mL to about 10 mg/mL; from about 0.1 mg/mL to about 5 mg/mL; from about 1 mg/mL to about 10 mg/mL; from about 1 mg/mL to about 5 mg/mL; from about 5 mg/mL to about 10 mg/mL; e.g., about 2.5 mg/mL or about 7.5 mg/mL) of the chemical entity in liquid carrier. In certain of these embodiments, the chemical entity is a compound of Formula AA, or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof. For example, enema formulations can include about 2.5 mg/mL or about 7.5 mg/mL of a compound of Formula AA in liquid carrier.


Regimens


The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).


In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 1 1 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 1 1 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.


Methods of Treatment


In some embodiments, methods for treating a subject having condition, disease or disorder in which a decrease or increase in NLRP3 activity (e.g., an increase, e.g., NLRP3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder are provided, comprising administering to a subject an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).


Indications


In some embodiments, the condition, disease or disorder is selected from: inappropriate host responses to infectious diseases where active infection exists at any body site, such as septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis, immune-based diseases such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis. For example, the condition, disease or disorder may be an inflammatory disorder such as rheumatoid arthritis, osteoarthritis, septic shock, COPD and periodontal disease.


In some embodiments, the condition, disease or disorder is an autoimmune diseases. Non-limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).


In some embodiments, the condition, disease or disorder is selected from major adverse cardiovascular events such as carbiovascular death, non-fatal myocardial infarction and non-fatal stroke in patients with a prior hear attack and inflammatory atherosclerosis (see for example, NCT01327846).


In some embodiments, the condition, disease or disorder is selected from metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn's disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as Osteoarthritis , osteoporosis and osteopetrosis disorders eye disease, such as glaucoma and macular degeneration, diseased caused by viral infection such as HIV and AIDS, autoimmune disease such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis, Addison's disease, pernicious anemia, cancer and aging.


In some embodiments, the condition, disease or disorder is a cardiovascular indication. In some embodiments, the condition, disease or disorder is myocardial infraction. In some embodiments, the condition, disease or disorder is stroke.


In some embodiments, the condition, disease or disorder is obesity.


In some embodiments, the condition, disease or disorder is Type 2 Diabetes.


In some embodiments, the condition, disease or disorder is NASH.


In some embodiments, the condition, disease or disorder is Alzheimer's disease.


In some embodiments, the condition, disease or disorder is gout.


In some embodiments, the condition, disease or disorder is SLE.


In some embodiments, the condition, disease or disorder is rheumatoid arthritis.


In some embodiments, the condition, disease or disorder is IBD.


In some embodiments, the condition, disease or disorder is multiple sclerosis.


In some embodiments, the condition, disease or disorder is COPD.


In some embodiments, the condition, disease or disorder is asthma.


In some embodiments, the condition, disease or disorder is scleroderma.


In some embodiments, the condition, disease or disorder is pulmonary fibrosis.


In some embodiments, the condition, disease or disorder is age related macular degeneration (AMD).


In some embodiments, the condition, disease or disorder is cystic fibrosis.


In some embodiments, the condition, disease or disorder is Muckle Wells syndrome.


In some embodiments, the condition, disease or disorder is familial cold autoinflammatory syndrome (FCAS).


In some embodiments, the condition, disease or disorder is chronic neurologic cutaneous and articular syndrome.


In some embodiments, the condition, disease or disorder is selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan's cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML) chronic myeloid leukemia (CML); gastric cancer; and lung cancer metastasis.


In some embodiments, the condition, disease or disorder is selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan's cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; gastric cancer; and lung cancer metastasis.


In some embodiments, the indication is MDS.


In some embodiments, the indication is non-small lung cancer in patients carrying mutation or overexpression of NLRP3.


In some embodiments, the indication is ALL in patients resistant to glucocorticoids treatment.


In some embodiments, the indication is LCH.


In some embodiments, the indication is multiple myeloma.


In some embodiments, the indication is promyelocytic leukemia.


In some embodiments, the indication is gastric cancer.


In some embodiments, the indication is lung cancer metastasis.


Combination Therapy


This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.


In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the compounds described herein.


In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).


In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity. By way of example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.


In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).


Patient Selection


In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 polymorphism.


In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 where polymorphism is a gain of function


In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 polymorphism found in CAPS syndromes.


In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related NLRP3 polymorphism where the polymorphism is VAR_014104 (R262W)


In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related NLRP3 polymorphism where the polymorphism is a natural variant reported in http://www.uniprot.org/uniprot/Q96P20.


In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to point mutation of NLRP3 signaling.


Compound Preparation and Biological Assays


As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof.


PREPARATIVE EXAMPLES

The following abbreviations have the indicated meanings:

  • ACN=acetonitrile
  • Ac=acetyl
  • (BnS)2=1,2-dibenzyldisulfane
  • BTC=trichloromethyl chloroformate
  • Boc=t-butyloxy carbonyl
  • Burgess reagent=I -Methoxy-N-triethylarnmoniosulfonyl-methanimidate
  • CDI=N,N′-carbonyldiimidazole
  • m-CPBA=3-chloroperbenzoic acid
  • DAST=diethylaminosulfurtrifluoride
  • DCM=dichloromethane
  • DEA=diethylamine
  • DMAP=N,N-dimethylpyridin-4-amine
  • DME=1,2-dimethoxyethane
  • DMF=N,N-dimethylformamide
  • DMSO=dimethyl sulfoxide
  • DIEA=N,N-diisopropylethylamine
  • DPPA=diphenylphosphoryl azide
  • EtOH=ethanol
  • EtOAc=ethyl acetate
  • HATU=2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium
  • hexafluorophosphate(V)
  • Hex=hexane
  • HPLC=high performance liquid chromatography
  • KHMDS=potassium bis(trimethylsilyl)amide
  • LC-MS=liquid chromatography-mass spectrometry
  • LiHMDS=lithium bis(trimethylsilyl)amide
  • LDA=lithium diisopropylamide
  • Me=methyl
  • MeOH=methanol
  • MSA=methanesulfonic acid
  • Mts-S, R, R-Aux=(2R,3aS,8aR)-3-(mesitylsulfonyl)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole 2-oxide
  • NBS =N-bromosuccinimide
  • NCS=N-chlorosuccinimide
  • NMP=1-methylpyrrolidin-2-one
  • NMR=nuclear magnetic resonance
  • Pd(dppf)Cl2=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium
  • Pd(dtbpf)Cl2=[1,1′-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)
  • PE=petroleum ether
  • Ph=phenyl
  • PPh3Cl2=dichlorotriphenylphosphorane
  • Py=pyridine
  • RT=room temperature
  • Rt=retention time
  • RuPhos=2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl
  • Sat.=saturated
  • SEM-Cl=(2-(chloromethoxy)ethyl)trimethylsilane
  • TBAF=tetrabutylammonium fluoride
  • TBS=tert-butyldimethylsilyl
  • TBSCl=tert-butyldimethylsilyl chloride
  • TBDPSCl=tert-butyldiphenylsilyl chloride
  • t-BuOK=potassium 2-methylpropan-2-olate
  • t-BuOLi=lithium 2-methylpropan-2-olate
  • TCCA=trichloroisocyanuric acid
  • TEA=triethylamine
  • TFA=trifluoroacetic acid
  • THF=tetrahydrofuran
  • TLC=thin layer chromatography
  • TMAD=(E)-N 1,N1,N2, N2-tetramethyldiazene-1,2-dicarboxamide
  • TsOH=4-methylbenzenesulfonic acid
  • UV=ultraviolet
  • Xphos Pd G2=chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)
  • DMA=dimethylacetamide
  • Davephos=2 Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl
  • KHMDS=potassium bis(trimethylsilyl)amide
  • KF=Kart Fischer
  • NMO=4-Methylmorpholine N-oxide
  • Pd(dtbpf)Cl2=1,1′-Bis(di-t-butylphosphino)ferrocene palladium dichloride
  • Sphos=2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl
  • TLC=thin-layer chromatography
  • T3P=2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide


General


The progress of reactions was often monitored by TLC or LC-MS. The identity of the products was often confirmed by LC-MS. The LC-MS was recorded using one of the following methods.


Method A: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5-100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), 2-minute total run time.


Method B: Kinetex EVO, C18, 3×50 mm, 2.2 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95% (1.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH4HCO3), 2 minute total run time.


Method C: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5-100% (2.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), 3 minute total run time.


Method D: Kinetex EVO, C18, 3×50 mm, 2.2 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95% (2.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH4HCO3), 3 minute total run time.


Method F: Phenomenex, CHO-7644, Onyx Monolithic C18, 50×4.6 mm, 10.0 uL injection, 1.5 mL/min flow rate, 100-1500 amu scan range, 220 and 254 nm UV detection, 5% with ACN (0.1% TFA) to 100% water (0.1% TFA) over 9.5 min, with a stay at 100% (ACN, 0.1% TFA) for 1 min, then equilibration to 5% (ACN, 0.1% TFA) over 1.5 min.


The final targets were purified by Prep-HPLC. The Prep-HPLC was carried out using the following method.


Method E: Prep-HPLC: Column,)(Bridge Shield RP18 OBD (19×250 mm, 10 um); mobile phase, Water (10 mM NH4HCO3) and ACN, UV detection 254/210 nm.


Method G: Prep-HPLC: Higgins Analytical Proto 200, C18 Column, 250×20 mm, 10 um; mobile phase, Water (0.1% TFA) and ACN (0.1% TFA), UV detection 254/210 nm.


NMR was recorded on BRUKER NMR 300.03 MHz, DUL-C-H, ULTRASHIELD™300, AVANCE II 300 B-ACS™120 or BRUKER NMR 400.13 MHz, BBFO, ULTRASHIELD™400, AVANCE III 400, B-ACS™120


Scheme for final targets: Schemes 1-7 below illustrate several conditions used for coupling of sulfonimidamide and isocyanate to afford aminocarbonyl sulfonimidamide.




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Scheme for final targets: Schemes IX-XVI below illustrate several conditions used for coupling of sulfonimidamide and isocyanate to afford aminocarbonyl sulfonimidamide.




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Scheme for the preparation of Sulfonamides Intermediates: Schemes 8A-28 below illustrate the preparation of sulfonamide intermediates.




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Intermediate 1



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N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
Step 1: 1-(Thiazol-2-yl)ethanol

Into a 500-mL round-bottom flask was placed 1-(thiazol-2-yl)ethanone (20 g, 157 mmol) in EtOH (200 mL). This was followed by the addition of NaBH4 (3.0 g, 81.3 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT and then was quenched by the addition of 10 mL of NH4Cl (sat.). The resulting solution was diluted with 200 mL of water and extracted with 2×200 mL of DCM. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. This resulted in 20 g (98%) of the title compound as light yellow oil. MS-ESI: 130 (M+1).


Step 2: 2-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole

Into a 500-mL round-bottom flask was placed 1-(thiazol-2-yl)ethanol (20 g, 155 mmol) in DMF (150 mL). To the stirred solution was added 1H-imidazole (20.5 g, 301 mmol). This was followed by the addition of TBDPSCl (46 g, 167 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT and then was diluted with 300 mL of water. The resulting solution was extracted with 3×200 mL of DCM. The organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:100 to 1:80). This resulted in 55 g (97%) of the title compound as colorless oil. MS-ESI: 368.1 (M+1).


Step 3: 2-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonyl chloride

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole (30 g, 81.6 mmol) in THF (200 mL). This was followed by the addition of n-BuLi (2.5 M in THF, 35.2 mL) dropwise with stirring at −78° C. The resulting solution was stirred for 0.5 h at −78° C., and then SO2 was introduced into the above reaction mixture. The reaction was slowly warmed to RT, and then NCS (12.8 g, 95.9 mmol) was added. The resulting solution was stirred for 1 h at RT. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 30 g (crude, 79%) of the title compound as brown oil. The crude product was used in the next step.


Step 4: N-tert-butyl-2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placed 2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonyl chloride (crude, 30 g, 64.4 mmol) in DCM (200 mL). To the stirred solution was added TEA (13 g, 128 mmol) dropwise. This was followed by the addition of 2-methylpropan-2-amine (5.6 g, 76.6 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:30 to 1:20). This resulted in 25 g (61% over two steps) of the title compound as brown oil. MS-ESI: 503.2 (M+1).


Step 5: N-tert-butyl-2-(1-hydroxyethyl)thiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placed N-tert-butyl-2-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-5-sulfonamide (25 g, 49.7 mmol) in THF (200 mL). To this stirred solution was added TBAF (30 g, 99.7 mmol) in portions. The resulting solution was stirred for 2 h at RT and then diluted with 200 mL of water. The resulting solution was extracted with 3×200 mL of DCM. The organic layers were combined and concentrated under vacuum. The residue was eluted from a silica gel with a gradient of EtOAc/PE (1:20 to 1:10). This resulted in 12 g (91%) of the title compound as light yellow oil. MS-ESI: 265.1 (M+1).


Step 6: 2-Acetyl-N-tert-butylthiazole-5-sulfonamide

Into a 500-mL round-bottom flask was placed N-tert-butyl-2-(1-hydroxyethyl)thiazole-5-sulfonamide (12 g, 45.4 mmol) in DCM (200 mL). To this solution was added Dess-Martin reagent (20 g, 47.2 mmol) in portions with stirring at RT. The resulting solution was stirred for 2 h at RT and then concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:20 to 1:10). This resulted in 9.0 g (76%) of the title compound as a light yellow solid. MS-ESI: 263.0 (M+1).


Step 7: 2-Acetylthiazole-5-sulfonamide

Into a 100-mL round-bottom flask was placed 2-acetyl-N-tert-butylthiazole-5-sulfonamide (7.0 g, 26.7 mmol) in TFA (20 mL). The resulting solution was stirred for 14 h at 70° C. and then concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:5 to 1:3). This resulted in 5.0 g (91%) of the title compound as a yellow solid. MS-ESI: 207.0 (M+1).


Step 8: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonamide

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed 2-acetylthiazole-5-sulfonamide (5.0 g, 24.3 mmol) in THF (100 mL). This was followed by the addition of MeMgBr (3 M in THF, 8.1 mL, 24.3 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at RT and then was quenched by the addition of 100 mL of NH4Cl (sat.). The resulting solution was extracted with 2×150 mL of DCM. The organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:5 to 1:3). This resulted in 2.9 g (54%) of the title compound as a light yellow solid. MS-ESI: 223.0 (M+1).


Step 9: N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide

Into a 250-mL round-bottom flask purged with and maintained under nitrogen was placed 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (1.0 g, 4.5 mmol) in DCM (100 mL). To the stirred solution was added 1H-imidazole (613 mg, 9.01 mmol) and TBSCl (3.4 g, 22.5 mmol). The resulting solution was stirred for 14 h at RT and then diluted with 100 mL of water. The resulting mixture was extracted with 3×50 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:10 to 1:3). This resulted in 1.4 g (93%) of the title compound as a white solid. MS-ESI: 337 (M+1).


Step 10: N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed PPH3Cl2 (3.0 g, 10.2 mmol) in CHCl3 (100 mL). This was followed by the addition of TEA (2.06 g, 20.4 mmol) dropwise with stirring at RT. After stirring at 0° C. for 10 min, a solution of N-(tert-butyldimethyl silyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (2.3 g, 6.8 mmol) in CHCl3 (10 mL) was dropwise to the above with stirring at 0° C. The resulting solution was allowed to react for 30 min at 0° C. To the mixture was added a saturated solution of ammonia in DCM (10 mL) at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×50 mL of DCM and the organic layers combined and concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:10 to 1:3). This resulted in 1.2 g (53%) of the title compound as a light yellow solid. MS-ESI: 336 (M+1).




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Intermediate 1



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N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
Step 1: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole

Into a 500-mL round-bottom flask, was placed a solution of 1-(thiazol-2-yl)ethanone (20 g, 157 mmol) in toluene (300 mL) and ethane-1,2-diol (19.5 g, 314 mmol). To the solution was added TsOH (2.7 g, 15.7 mmol). The resulting solution was refluxed overnight, and water was separated from the solution during the reflux. The resulting solution was diluted with 200 mL of water and extracted with 2×100 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. This resulted in 26.6 g (99%) of the title compound as light yellow oil. MS-ESI: 172.0 (M+1).


Step 2: 2-(2-Methyl-1,3-dioxolan-2-yl)thiazole-5-sulfonamide

Into a 500-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(2-methyl-1,3-dioxolan-2-yl)thiazole (14 g, 81.6 mmol) in THF (200 mL). This was followed by the addition of n-BuLi (2.5 M in THF, 35.2 mL, 88 mmol) dropwise with stirring at −78° C. The resulting solution was stirred for 0.5 h at −78° C. and then SO2 was introduced into the above reaction mixture. The reaction was slowly warmed to RT and then NCS (12.8 g, 95.9 mmol) was added. The resulting solution was stirred for 1 h at RT. The solids were filtered out. The resulting filtrate was concentrated under vacuum and then was diluted in DCM (160 mL). To the above was added a saturated solution of ammonia in DCM (300 mL). The resulting solution was stirred for 3 h at RT and then was concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:20 to 1:5). This resulted in 12.5 g (61%) of the title compound as a yellow solid. MS-ESI: 251.0 (M+1).


Step 3: 2-Acetylthiazole-5-sulfonamide

Into a 250-mL round-bottom flask was placed a solution of 2-(2-methyl-1,3-dioxolan-2-yl)thiazole-5- sulfonamide (12.5 g, 50 mmol) in THF (125 mL). To the above was added aq. HCl (4 N, 50.0 mL). The resulting solution was stirred for 6 h at 70° C. The resulting solution was diluted with 100 mL of water and extracted with 2×200 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:2 to 1:1). This resulted in 9.3 g (90%) of the title compound as a yellow solid. MS-ESI: 207.0 (M+1).


Step 4: 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide

Into a 500-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-acetylthiazole-5-sulfonamide (15 g, 72.8 mmol) in THF (150 mL). This was followed by the addition of MeMgBr (3 M in THF, 97 mL, 291mmo1) dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at RT and then was quenched by the addition of 100 mL of NH4Cl (sat.). The resulting solution was extracted with 3×150 mL of DCM and the organic layers combined and dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5 to 1:3). This resulted in 11.5 g (78%) of the title compound as a white solid. MS-ESI: 223 (M+1).


Step 5: N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (5.0 g, 22.5 mmol) in THF (100 mL). Then to the above was added NaH (60% wt. oil dispersion, 1.8 g, 45 mmol) in portions in an ice/water bath. After stirring for 20 minutes in a water/ice bath, this was followed by the addition of a solution of TBSCl (4.1 g, 27.2 mmol) in THF (10 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 4 h at RT. The reaction was quenched with sat. NH4Cl (100 mL). The resulting solution was extracted with 3×100 mL of EtOAc and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude solid was washed with EtOAc/hexane (1:5) (2×100 mL). This resulted in 6.81 g (90%) of the title compound as a yellow solid. MS-ESI: 337 (M+1).


Step 6 used the same procedures for converting compound 20 to Intermediate 1 shown in Scheme 8A to afford Intermediate 1 from compound 25. MS-ESI: 336.1 (M+1).



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Intermediate 2



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N′-(tert-butoxycarbonyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
Step 1: 2-(Thiazol-2-yl)propan-2-ol

Into a 10-L 4-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 1-(thiazol-2-yl)ethanone (200 g, 1.6 mol) in THF (4 L). This was followed by the addition of MeMgBr (3 M in THF, 942 mL) dropwise with stirring at 0° C. The mixture was stirred at 0° C. for 2 h. After warming the mixture to RT, the solution was stirred for an additional 16 h. Then the reaction was quenched by the addition of 3.0 L of NH4Cl (sat.). The resulting solution was extracted with 3×1 L of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:3 to 1:1). This resulted in 210 g (93%) of the title compound as a brown oil. MS-ESI: 144.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J'3.2 Hz, 1H), 7.54 (d, J=3.2 Hz, 1H), 5.94 (s, 1H), 1.51 (s, 6H).


Step 2: Lithium 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate

Into a 10-L 4-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-(thiazol-2-yl)propan-2-ol (50 g, 349 mmol) in THF (1.5 L). This was followed by the addition of n-BuLi (2.5 M in hexane, 350 mL) dropwise with stirring at −78° C. The mixture was stirred at −78° C. for 1 h. Then SO2 was bubbled into the mixture for 15 min below −30° C. The mixture was stirred for an additional 1 h at RT and then was concentrated under vacuum. This resulted in 87 g title compound as a light yellow solid (crude). The crude product was used directly in the next step.


Step 3: Methyl 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate

Into a 2-L 3-necked round-bottom flask, lithium 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate (87 g, crude) was dissolved in anhydrous methanol (500 mL). Then SOCl2 (43 g, 360 mmol) was added to the mixture dropwise with stirring at 0° C. The mixture was stirred overnight at RT and was then concentrated under vacuum. The residue was diluted with 500 mL of EtOAc. The resulting solution was washed with 2×200 mL of water and 2×200 mL of brine. The solution was dried over anhydrous Na2SO4, and then concentrated under vacuum. This resulted in 72 g crude title compound as light yellow oil. The crude product was used directly in the next step. MS-ESI: 222 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 6.32 (s, 1H), 3.65 (s, 3H), 1.53 (d, J=2.0 Hz, 6H).


Step 4: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfinamide

Into a 10-L 4-necked round-bottom flask purged with and maintained under nitrogen, was placed a solution of methyl 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate (72 g, 326 mmol) in THF (500 mL). Then to the above NH3 (0.5 M in THF, 2.0 L) was added. After cooling to −78° C., LiHMDS (1 M in THF, 2.0 L) was added to the mixture dropwise with stirring. Then the mixture was stirred at −78° C. for 2 h. The reaction was quenched by the addition of 500 mL of NH4Cl (sat.). The resulting solution was extracted with 3×300 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. This resulted in 32 g crude title compound as brown oil. The crude product was used directly in the next step. MS-ESI: 207 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 6.73 (s, 2H), 6.17 (s, 1H), 1.51 (d, J=1.4 Hz, 6H).


Step 5: Tert-butyl 2-(2-hydroxypropan-2-yl)thiazol-5-ylsulfinylcarbamate

Into a 1-L 3-necked round-bottom flask purged with and maintained under nitrogen, was placed a solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinamide (32 g, crude) in THF (300 mL). This was followed by the addition of LDA (2 M in THF, 116 mL) dropwise with string at 0° C. The mixture was stirred at 0° C. for 1 h, then (Boc)2O (33.8 g, 155 mmol) was added in portions at 0° C. The mixture was warmed to RT and stirred for an additional 2 h. The reaction was quenched with 200 mL of ice-water (200 mL), and the pH value of the solution was adjusted to 6 with HCO2H. The resulting solution was extracted with 3×200 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:2 to 1:1). This resulted in 19 g (18%, 4 steps) of the title compound as a white solid. MS-ESI: 307 (M+1).


Step 6: N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 1-L 3-necked round-bottom flask purged with and maintained under nitrogen, tert-butyl 2-(2-hydroxypropan-2-yl)thiazol-5-ylsulfinylcarbamate (19 g, 62 mmol) was dissolved in fresh distilled ACN (200 mL). Then to the above solution was added NCS (9.8 g, 74 mmol) in portions. The mixture was stirred for 1 h at RT and then NH3 was bubbled in the mixture for 15 min. The mixture was stirred at RT for 2 h and then concentrated under vacuum. The residue was applied onto silica gel and eluted with a gradient of EtOAc/PE (1:2 to 1:1). This resulted in 13 g (65%) of the title compound as a white solid. MS-ESI: 322 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.72 (s, 2H), 6.29 (s, 1H), 1.49 (d, J=2.0 Hz, 6H), 1.27 (s, 9H).




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Intermediate 1



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N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
Step 1: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 250-mL round-bottom flask, was placed a solution of tert-butyl 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoylcarbamate (3.21 g, 10 mmol) in HCl/dioxane (4 M, 50 mL). The resulting solution was stirred for 1 h at RT. The solution was concentrated to give the title compound (3.2 g, crude, yellow oil). MS-ESI: 222 (M+1).


Step 2: N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 250-mL round-bottom flask, was placed 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (3.2 g crude, 10 mmol) in THF (100 mL), and then DIEA (3.87 g, 30 mmol) was added in the reaction solution at RT. TBSCl (3.0 g, 20 mmol) was added to the solution in portions. The resulting solution was stirred for 16 h at RT. The solution was concentrated, and the crude product was eluted from silica gel with EtOAc/ PE (1:1) to give the title compound (2.3 g, yield 70%, yellow solid). MS-ESI: 336 (M+1).




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Intermediate 3



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N′-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
Step 1: (2-Bromothiazol-4-yl)methanol

Into a 100-mL round-bottom flask, was placed a solution of ethyl 2-bromo-1,3-thiazole-4-carboxylate (3.0 g, 12.7 mmol) in EtOH (30 mL). To the stirred solution was added NaBH4 (1.0 g, 25.41 mmol) in portions with an ice/water bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 100 mL of water in an ice/water bath. The resulting solution was extracted with 3×100 ml of EtOAc and the combined organic layers were concentrated. This resulted in 2.0 g (81%) of the title compound as yellow oil. MS-ESI: 196.2/194.2 (M+1).


Step 2: 2-Bromo-4-((tert-butyldimethylsilyloxy)methyl)thiazole

Into a 100-mL round-bottom flask, was placed a solution of (2-bromo-1,3-thiazol-4-yl)methanol (2.0 g, 10.3 mmol) in THF (20 mL). To the solution was added NaH (60% wt. oil dispersion, 1.2 g, 30.9 mmol) in portions with an ice/water bath. After stirring for 15 minutes at RT, a solution of TBSCl (4.7 g, 30.9 mmol) in THF (5 mL) was added dropwise in an ice/water bath. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×100 ml of EtOAc, the organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:30). This resulted in 2.5 g (79%) of the title compound as yellow oil. MS-ESI: 310.2/308.2 (M+1).


Step 3: 2-(4-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)propan-2-ol

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-4-((tert-butyldimethylsilyloxy)methyl)thiazole (2.5 g, 8.11 mmol) in THF (30 mL). To this solution was added n-BuLi (2.5 M in hexane, 4.86 mL, 12.2 mmol) dropwise at −78° C., and the resulting mixture was stirred for 30 min at −78° C. To the above was added acetone (0.9 g, 16.2 mmol) dropwise at −78° C., then stirred for 1 h at RT. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:10). This resulted in 2.0 g (86%) of the title compound as yellow oil. MS-ESI: 288.2 (M+1).


Step 4: 4-((Tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonyl chloride

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(4-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)propan-2-ol (2.0 g, 6.96 mmol) in THF (20 mL). To this solution was added n-BuLi (2.5 M in hexane, 8.4 mL, 20.9 mmol) dropwise at −78° C., and the resulting solution was stirred for 30 min at −78° C. Then SO2 was introduced in this solution for 10 minutes below −30° C. and stirred for 30 min at RT. The resulting solution was concentrated under vacuum. The crude solid was dissolved in DCM (30 ml), following by the addition of NCS (1.4 g, 10.4 mmol) in portions in an ice/water bath. The solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 2.5 g crude title compound as a yellow solid.


Step 5: 4-((Tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of 4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonyl chloride (2.5 g, 6.48 mmol) in DCM (30 mL). To the above was added a saturated solution of ammonia in DCM (10 mL) in an ice/water bath. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 1.2 g (51%) of the title compound as yellow oil. MS-ESI: 367.2 (M+1).


Step 6: N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide

To a solution of 4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (1.2 g, 3.27 mmol) in THF (20 mL), NaH (60% wt. oil dispersion, 0.4 g, 9.8 mmol) was added in portions with an ice/water bath. After stirring for 15 minutes at RT, a solution of TBSCl (1.5 g, 9.82 mmol) in THF (5 mL) was added dropwise in an ice/water bath. The resulting solution was stirred for 2 h at RT. The reaction was quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 ml of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 1.3 g (83%) of the title compound as yellow oil. MS-ESI: 481.2 (M+1).


Step 7: N′-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of PPH3Cl2 (1.4 g, 4.06 mmol) in CHCl3 (10 mL). TEA (0.80 g, 8.11 mmol) was then added dropwise in an ice/water bath. The solution was stirred at RT for 20 minutes. To this solution was added N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (1.3 g, 2.70 mmol) in CHCl3 (10 mL) dropwise in ice/water bath. The solution was stirred for 0.5 h at RT. The saturated solution of ammonia in DCM (20 mL) was poured into this solution at 0° C. The solution was stirred for 1 h at RT. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 600 mg (46%) of the title compound as a yellow solid. MS-ESI: 480.2 (M+1).




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Intermediate 4



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N-(tert-butyldimethylsilyl)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
Step 1: Methyl 2-(2-aminothiazol-4-yl)acetate

Into a 1-L round-bottom flask, was placed a solution of methyl 4-chloro-3-oxobutanoate (15.0 g, 100 mmol) in EtOH (350 mL). Then thiourea (7.6 g, 100 mmol) was added to the solution. The resulting solution was stirred overnight under reflux. The resulting mixture was cooled to RT and filtered to collect the solid. The solid thus obtained was washed with Et2O (2×200 mL) and dried in an oven at 50° C. overnight to give the title compound (15.4 g, 89.5%) as a yellow solid. MS-ESI: 173 (M+1).


Step 2: Methyl 2-(2-bromothiazol-4-yl)acetate

Into a 500 mL round-bottom flask, was placed a solution of methyl 2-(2-aminothiazol-4-yl)acetate (15.4 g, 89.5 mmol) in MeCN (250 mL). CuBr was added to the solution, followed by t-BuONO which was added dropwise at 0° C. The resulting solution was stirred for 30 min at RT and then stirred for 2 h at 70° C. The resulting mixture was concentrated and eluted from silica gel with EtOAc/PE (1:10) to give the title compound (12.3 g, 58.2%) as white solid. MS-ESI: 236/238 (M+1).


Step 3: 2-(2-Bromothiazol-4-yl)ethanol

Into a 1-L round-bottom flask, was placed a solution of methyl 2-(2-bromothiazol-4-yl)acetate (12.3 g, 51.9 mmol) in EtOH (200 mL). NaBH4 (3.9 g, 104 mmol) was added to the solution in portions at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 1 L of ice-water. The resulting solution was extracted with 3×500 ml of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. This resulted in 8.9 g (82.1%) of the title compound as yellow oil. MS-ESI: 208/210 (M+1).


Step 4: 2-Bromo-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)thiazole

Into a 500 mL round-bottom flask, was placed a solution of 2-(2-bromothiazol-4-yl)ethanol (8.9 g, 42.6 mmol) in THF (400 mL). NaH (60% wt. oil dispersion, 2.56 g, 63.9 mmol) was added to the mixture in portions at 0° C. The mixture was stirred at 0° C. for another 1 h, and TBSCl (10.2 g, 68.2 mmol) was added to the mixture in portions at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 300 mL of ice-water. The resulting solution was extracted with 3×300 ml of EtOAc; the combined organic phase was dried over Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:30). This resulted in 7.6 g (55%) of the title compound as yellow oil. MS-ESI: 322/324 (M+1). Steps 5-9 used the same procedures for converting compound 34 to Intermediate 3 shown in Scheme 11 to afford Intermediate 4 from compound 43. MS-ESI: 494 (M+1).




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Intermediate 5



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N′-(tert-butyldimethyl silyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide
Step 1: Methyl 2-mercaptothiazole-5-carboxylate

Into a 2-L round-bottom flask was placed methyl 2-bromothiazole-5-carboxylate (100 g, 450 mmol) and EtOH (1.0 L). To the stirred solution was added sodium hydrogen sulfide (50 g, 890 mmol) in portions with stirring. The resulting solution was stirred for 2 h at 80° C. and then was cooled to 0° C. with a water/ice bath. The pH of the solution was adjusted to 3 with hydrogen chloride (1 M). The solids were collected by filtration. This resulted in 63.2 g (80%) of the title compound as a light yellow solid. MS-ESI: 176.0 (M+1).


Step 2: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

Into a 1-L round-bottom flask was placed methyl 2-mercaptothiazole-5-carboxylate (30 g, 170 mmol) and acetic acid (300 mL). This was followed by the addition of sodium hypochlorite (300 mL, 8.0%-10% wt.) in portions at 0° C. The resulting solution was stirred for 2 h at RT and then was diluted with 500 mL of water. The solution was extracted with 3×300 mL of DCM, and the combined organic layers were washed with 2×300 mL of brine and dried over anhydrous Na2SO4. The crude product as a yellow solution in DCM was used in the next step.


Step 3: Methyl 2-sulfamoylthiazole-5-carboxylate

Into a 2-L round-bottom flask was placed methyl 2-(chlorosulfonyl)thiazole-5-carboxylate as a crude solution in DCM (900 mL). To the solution was introduced NH3 (g) below 0° C. for 20 minutes. The resulting solution was stirred for 1 h at RT and then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5 to 1:3). This resulted in 23 g (75%, 2 steps) of the title compound as a white solid. MS-ESI: 223.0 (M+1).


Step 4: 5-(2-Hydroxypropan-2-yl)thiazole-2-sulfonamide

Into a 500-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of methyl 2-sulfamoylthiazole-5-carboxylate (15 g, 67.5 mmol) in THF (150 mL). This was followed by the addition of MeMgBr/THF (3 M, 90 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at RT and then was quenched by the addition of 100 mL of NH4Cl (sat.). The resulting solution was extracted with 3×150 mL of DCM and the organic layers combined and dried over anhydrous Na2SO4, then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5 to 1:3). This resulted in 11.5 g (78%) of the title compound as a white solid. MS-ESI: 223.0 (M+1).


Steps 5-6 used similar procedure for converting compound 19 to Intermediate 1 shown in Scheme 8A to afford Intermediate 5 from compound 53. MS-ESI: 336.1 (M+1).




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Intermediate 5



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N′-(tert-butyldimethyl silyl)-5 -(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide
Step 1: Methyl 2-mercaptothiazole-5-carboxylate

Into a 2-L round-bottom flask was placed methyl 2-bromothiazole-5-carboxylate (100 g, 450 mmol) and EtOH (1.0 L). To the stirred solution was added sodium hydrogen sulfide (50 g, 890 mmol) in portions with stirring. The resulting solution was stirred for 2 h at 80° C. and then was cooled to 0° C. with a water/ice bath. The pH value of the solution was adjusted to 3 with hydrogen chloride (1 M). The solids were collected by filtration. This resulted in 63.2 g (80%) of the title compound as a light yellow solid. MS-ESI: 176.0 (M+1).


Step 2: Methyl 2-(chlorosulfonyl)thiazole-5-carboxylate

Into a 1-L round-bottom flask was placed methyl 2-mercaptothiazole-5-carboxylate (30 g, 170 mmol) and acetic acid (300 mL). This was followed by the addition of sodium hypochlorite (300 mL, 8.0%-10% wt.) in portions at 0° C. The resulting solution was stirred for 2 h at RT and then was diluted with 500 mL of water. The solution was extracted with 3×300 mL of DCM. The combined organic layers were washed with 2×300 mL of brine and dried over anhydrous Na2SO4. The crude product as a yellow solution in DCM was used in the next step.


Step 3: Methyl 2-sulfamoylthiazole-5-carboxylate

Into a 2-L round-bottom flask was placed methyl 2-(chlorosulfonyl)thiazole-5-carboxylate as a crude solution in DCM (900 mL). To the solution was introduced NH3 (g) below 0° C. for 20 minutes. The resulting solution was stirred for 1 h at RT and then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5 to 1:3). This resulted in 23 g (75%, 2 steps) of the title compound as a white solid. MS-ESI: 223.0 (M+1).


Step 4: 5-(2-Hydroxypropan-2-yl)thiazole-2-sulfonamide

Into a 500-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of methyl 2-sulfamoylthiazole-5-carboxylate (15 g, 67.5 mmol) in THF (150 mL). This was followed by the addition of MeMgBr/THF (3 M, 90 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 14 h at RT and then was quenched by the addition of 100 mL of NH4Cl (sat.). The resulting solution was extracted with 3×150 mL of DCM. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5 to 1:3). This resulted in 11.5 g (78%) of the title compound as a white solid. MS-ESI: 223.0 (M+1).


Step 5: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (5.0 g, 22.5 mmol) in THF (100 mL). Then to the above was added NaH (60% wt. oil dispersion, 1.8 g, 45.0 mmol) in portions in an ice/water bath. After stirring for 20 minutes in a water/ice bath, a solution of TBSCl (4.1 g, 27.2 mmol) in THF (10 mL) was added dropwise with stirring at 0° C. The resulting solution was stirred for 4 h at RT. The reaction was quenched with sat. NH4Cl (100 mL). The resulting solution was extracted with 3×100 mL of EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The crude solid was washed with EtOAc/hexane (1:5) (2×100 mL). This resulted in 6.81 g (90%) of the title compound as a yellow solid. MS-ESI: 337.1 (M+1), 335.1 (M−1) in positive and negative ion mode, respectively.


Step 6: N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide

Into a 100-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of PPH3Cl2 (3.0 g, 9.0 mmol) in CHCl3 (100 mL). This was followed by the addition of DIEA (1.54 g, 11.9 mmol) dropwise with stirring at RT. The resulting solution was stirred for 10 min at RT. This was followed by the addition of a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonamide (2.0 g, 5.9 mmol) in CHCl3 (30 mL) dropwise with stirring in an ice/water bath. The resulting solution was stirred for 30 min in an ice/water bath. To the above was introduced NH3 (g) below 0° C. for 15 minutes. The resulting solution was stirred for 20 minutes at RT. The solids were filtered out and the filtrate was concentrated, and the residue was dissolved in 300 mL of EtOAc. The solution was washed with brine (2×100 mL), dried over Na2SO4 and concentrated under vacuum. The crude solid was washed with CHCl3 (100 mL). Then the filtrate was concentrated under vacuum and the residue was eluted from silica gel with EtOAc/PE (1:10 to 1:3). The original washed solid and solid from silica gel purification were combined. This resulted in 1.2 g (60%) of the title compound as a white solid. MS-ESI: 336.1 (M+1).



1H-NMR (300 MHz, DMSO-d6) δ 7.66 (s, 1H), 7.12 (s, 2H), 5.78 (s, 1H), 1.51 (s, 6H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H).









TABLE 2







The Intermediates in the following Table were prepared using the similar procedures for


converting compound 49 to Intermediate 5 shown in Scheme 13B from appropriate starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 6


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N′-(tert-butyldimethylsilyl)-4-(2- hydroxypropan-2-yl)-5- methylthiazole-2-sulfonimidamide
350











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Intermediate 7



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N′-(tert-butyldimethyl silyl)-4-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide
Step 1: (2-Bromothiazol-4-yl)methanol

Into a 500-mL round-bottom flask was placed a solution of ethyl 2-bromothiazole-4-carboxylate (14 g, 59.3 mmol) in EtOH (200 mL). This was followed by the addition of NaBH4 (2.3 g, 60.5 mmol) in portions at 0° C. The resulting solution was stirred for 3 h at RT and was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 2×200 mL of DCM. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. This resulted in 10.0 g (87%) of the title compound as colorless oil. MS-ESI: 195.9/193.9 (M+1).


Step 2: 2-Bromothiazole-4-carbaldehyde

Into a 250-mL round-bottom flask was placed a solution of (2-bromothiazol-4-yl)methanol (10.0 g, 51.5 mmol) in DCM (100 mL). To the solution was added Dess-Martin reagent (24.0 g, 56.6 mmol). The resulting solution was stirred for 2 h at RT and was then concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:50 to 1:20). This resulted in 8.0 g (81%) of the title compound as yellow oil. MS-ESI: 193.9/191.9 (M+1).


Step 3: 1-(2-Bromothiazol-4-yl)ethanol

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-bromothiazole-4-carbaldehyde (8.0 g, 41.7 mmol) in THF (100 mL). This was followed by the addition of MeMgBr (3 M in THF, 15 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT and then was quenched by the addition of 100 mL of NH4Cl (sat.). The resulting solution was extracted with 3×100 mL of DCM, and the combined organic layers were concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:10 to 1:5). This resulted in 6.0 g (69%) of the title compound as brown oil. MS-ESI: 209.9/207.9 (M+1).


Step 4: 2-Bromo-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole

Into a 250-mL round-bottom flask was placed a solution of 1-(2-bromothiazol-4-yl)ethanol (6.0 g, 28.8 mmol) and 1H-imidazole (4.0 g, 58.8 mmol) in DMF (50 mL). To the solution was added TBDPSCl (8.7 g, 31.6 mmol). The resulting solution was stirred for 12 h at RT and was then diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of DCM, and the combined organic layers were concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:100 to 1:50). This resulted in 10.0 g (78%) of the title compound as light yellow oil. MS-ESI: 448.1/446.1 (M+1).


Step 5: 4-(1-(Tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonyl chloride

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of 2-bromo-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole (10.0 g, 22.4 mmol) in THF (100 mL). This was followed by the addition of n-BuLi (2.5 M in THF, 11 mL) dropwise with stirring at −78° C. The resulting solution was stirred for 30 min at −78° C. To the above SO2 gas was introduced. The reaction was warmed to RT and stirred for 30 min and then was concentrated under vacuum. The residue was dissolved in DCM (100 mL) and then NCS (3.6 g, 26.9 mmol) was added. The resulting solution was stirred for 30 min at RT and then was concentrated under vacuum. This resulted in 8.0 g (crude, 77%) of the title compound as a white solid. The crude product was used in the next step.


Step 6: N-tert-butyl-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonamide

Into a 100-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of 4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonyl chloride (8.0 g, 17.2 mmol) in DCM (50 mL). To the solution were added TEA (3.5 g, 34.6 mmol) and 2-methylpropan-2-amine (1.9 g, 26.0 mmol). The resulting solution was stirred for 2 h at RT and was then concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:15 to 1:5). This resulted in 8.0 g (71%, 2 steps) of the title compound as brown oil. MS-ESI: 503.2 (M+1).


Step 7: N-tert-butyl-4-(1-hydroxyethyl)thiazole-2-sulfonamide

Into a 250-mL round-bottom flask was placed a solution of N-tert-butyl-4-(1-(tert-butyldiphenylsilyloxy)ethyl)thiazole-2-sulfonamide (8.0 g, 15.9 mmol) in THF (100 mL). To the solution was added TBAF (9.6 g, 293 mmol). The resulting solution was stirred for 2 h at RT and then was diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of DCM , and the combined organic layers were concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:10 to 1:3). This resulted in 4.0 g (95%) of the title compound as light yellow oil. MS-ESI: 265.1 (M+1).


Step 8: 4-Acetyl-N-tert-butylthiazole-2-sulfonamide

Into a 100-mL round-bottom flask, was placed a solution of N-tert-butyl-4-(1-hydroxyethyl)thiazole-2-sulfonamide (4.0 g, 15.1 mmol) in DCM (50 mL). To the solution was added Dess-Martin reagent (7.1 g, 16.6 mmol). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:10 to 1:3). This resulted in 3.5 g (88%) of the title compound as light yellow oil. MS-ESI: 363.0 (M+1).


Step 9: 4-Acetylthiazole-2-sulfonamide

Into a 100-mL round-bottom flask was placed a solution of 4-acetyl-N-tert-butylthiazole-2-sulfonamide (3.5 g, 13.3 mmol) in DCM (5 mL). To the solution was added TFA (20 mL). The resulting solution was stirred for 14 h at 40° C. and then was concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:10 to 1:3). This resulted in 2.5 g (91%) of the title compound as a gray solid. MS-ESI: 207.0 (M+1).


Steps 10-12 used similar procedures for converting compound 23 to Intermediate 1 shown in Scheme 8B to afford Intermediate 7 from compound 64. MS-ESI: 336.1 (M+1).




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Intermediate 8



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N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-4-sulfonimidamide


Step 1: 2-(4-(Benzylthio)thiazol-2-yl)propan-2-ol

Into a 250-mL round-bottom flask, and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-(4-bromo-1,3-thiazol-2-yl)propan-2-ol (2.0 g, 9.0 mmol) in DME (50 mL). This was followed by the addition of phenylmethanethiol (11.2 g, 90.0 mmol). To this was added Na2CO3 (1.91 g, 18.0 mmol) and Xphos Pd G2 (2.4 g, 2.7 mmol). The resulting solution was stirred for an overnight at 80° C. The resulting mixture was diluted with 150 mL of H2O. The resulting solution was extracted with 2×300 mL of EtOAc dried over anhydrous sodium sulfate and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 800 mg (33%) of the title compound as a white solid. MS-ESI: 226.1 (M+1).


Step 2: 2-(2-Hydroxypropan-2-yl)thiazole-4-sulfonyl chloride

Into a 100-mL round-bottom flask, was placed a solution of 2-(4-(benzylthio)thiazol-2-yl)propan-2-ol (750 mg, 2.83 mmol) in MeCN (20 mL). To the solution was added AcOH (0.75 mL) and H2O (0.50 mL). This was followed by the addition of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (1.67 g, 8.48 mmol) at 0° C. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The resulting mixture was diluted with 20 mL of H2O. The resulting solution was extracted with 3×75 mL of DCM and dried over anhydrous sodium sulfate and concentrated. This resulted in 550 mg (80.5%) of the title compound as a crude solid. MS-ESI: 242 (M+1).


Step 3: 2-(2-Hydroxypropan-2-yl)thiazole-4-sulfonamide

Into a 100-mL round-bottom flask, was placed a solution of 2-(2-hydroxypropan-2-yl)thiazole-4-sulfonyl chloride (550 mg, 2.28 mmol) in DCM (30 mL). To the above NH3 (g) was introduced for 10 min at 0° C. The resulting solution was stirred for 20 min at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel with EtOAc/PE (1:1). This resulted in 450 mg (89%) of the title compound as a yellow solid. MS-ESI: 223 (M+1).


Steps 4-5 used similar procedures for converting compound 24 to Intermediate 1 shown in Scheme 8B to convert Intermediate 8 from compound 70. MS-ESI: 336 (M+1).




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Intermediate 9



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N′-(tert-butyldimethyl silyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2-sulfonimidamide
Step 1: Methyl 5-(chlorosulfonyl)-2-methylthiophene-3-carboxylate

Into a 250-mL round-bottom flask, was placed methyl 2-methylthiophene-3-carboxylate (5.0 g, 32 mmol), CHCl3 (70 mL). This was followed by the addition of ClSO2OH (5.6 g, 48 mmol) dropwise with stirring. To this was added PCl5 (13g, 64 mmol) with stirring. The resulting solution was stirred for 2 h at 60° C. in an oil bath. The reaction was then quenched by the addition of 150 mL of water/ice. The resulting solution was extracted with 3×80 ml of DCM and dried over anhydrous sodium sulfate and concentrated. This resulted in 5.2 g (64%) of the title compound as a yellow solid.


Steps 2-5 used similar procedures for converting compound 51 to intermediate 5 shown in Scheme 13B to


Intermediate 9 from compound 73. MS-ESI: 349 (M+1).









TABLE 3







The Intermediate in the following Table was prepared using similar procedure as shown


in Scheme 16 above for converting compound 72 to Intermediate 9 starting from the appropriate


materials.










Intermediate


Exact Mass


#
Structure
IUPAC Name
[M + H]+





Intermediate 10


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N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan- 2-yl)thiophene-2-sulfonimidamide
335.1





Intermediate 11


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N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan- 2-yl)thiophene-2-sulfonimidamide
335.1





Intermediate 12


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N′-(tert-butyldimethylsilyl)-3-fluoro-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
353.1











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Intermediate 13



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N′-(tert-butyldimethyl silyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3 -sulfonimidamide
Step 1: Ethyl 3-nitro-1-phenyl-1H-pyrazole-5-carboxylate

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of oxygen, was placed ethyl 3-nitro-1H-pyrazole-5-carboxylate (5 g, 27 mmol) in tetrahydrofuran (150 mL). To the stirred solution was added phenylboronic acid (6.6 g, 54 mmol), Cu(OAc)2 (7.38 g, 41 mmol) and pyridine (8.54 g, 108 mmol). The resulting solution was stirred overnight at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 3.1 g (44%) of the title compound as an off-white solid. MS-ESI: 262 (M+1).


Step 2: Ethyl 3-amino-1-phenyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed ethyl 3-nitro-1-phenyl-1H-pyrazole-5-carboxylate (3.92 g, 15 mmol) and methanol (50 mL). To the stirred solution was added Pd/C (wet 10% wt, 400 mg). The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred overnight at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 2.8 g (81%) of the title compound as a light yellow solid. MS-ESI: 232 (M+1).


Step 3: Ethyl 3-(chlorosulfonyl)-1-phenyl-111-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed ethyl 3-amino-1-phenyl-1H-pyrazole-5-carboxylate (1.8 g, 7.78 mmol) in HCl (6 M, 15 mL). This was followed by the addition of a solution of NaNO2 (646 mg, 9.36 mmol) in water (2 mL) dropwise with stirring at −10° C. The resulting solution was stirred for 30 min at −10° C. The above mixture was added to a saturated solution of SO2 in AcOH (20 mL) dropwise with stirring at 0° C. Then to the above was added CuCl2 (1.05 g, 7.81 mmol). The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 2.2 g (90%) of the title compound as a light yellow solid.


Step 4: Ethyl 1-phenyl-3-sulfamoyl-1H-pyrazole-5-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of ethyl 3-(chlorosulfonyl)-1-phenyl-1H-pyrazole-5-carboxylate (2.2 g, 6.99 mmol) in DCM (10 mL). Then to the above was introduced NH3 gas bubbled at 0° C. for 10 min. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was applied onto silica gel with EtOAc/PE (1:1). This resulted in 1.07 g (52%) of the title compound as a light yellow solid. MS-ESI: 296 (M+1).


Step 5: 5-(2-Hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of ethyl 1-phenyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (1.65 g, 5.59 mmol) in tetrahydrofuran (30 mL). This was followed by the addition of MeMgBr (3 M in THF, 18.6 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of 30 mL of NH4Cl (sat.). The resulting solution was extracted with 3×30 mL of DCM and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2:1). This resulted in 1.35 g (86%) of the title compound as a yellow solid. MS-ESI: 282 (M+1).


Step 6: N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide

Into a 100-mL round-bottom flask, was placed 5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3- sulfonamide (500 mg, 1.78 mmol) in tetrahydrofuran (10 mL). This was followed by the addition of sodium hydride (60% wt. oil dispersion, 143 mg, 3.58 mmol) in portions at 0° C. Then to the above was added TBSCl (538 mg, 3.57 mmol). The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 660 mg (94%) of the title compound as a light yellow solid. MS-ESI: 396 (M+1).


Step 7: N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed the solution of PPH3Cl2 (1.67 g, 5.01 mmol) in chloroform (30 mL). This was followed by the addition of DIEA (1.29 g, 9.98 mmol) dropwise with stirring at RT. The resulting solution was stirred for 10 min at RT and the reaction system was cooled to 0° C. To this was added a solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonamide (660 mg, 1.67 mmol) in chloroform (3 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. To the mixture was introduced NH3 gas bubble for 15 min at 0° C. The resulting solution was stirred for 2 h at RT, after which it was diluted with 30 mL of water. The resulting solution was extracted with 3×30 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 530 mg (81%) of the title compound as a light yellow solid. MS-ESI: 395 (M+1).




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Intermediate 14



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N′-(tert-butyl dimethyl silyl)-5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3 -sulfonimidamide
Step 1: Ethyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate

Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed the solution of ethyl 3-nitro-1H-pyrazole-5-carboxylate (1.0 g, 5.41 mmol) in DMF (20 mL). This was followed by the addition of K2CO3 (1.49 g, 10.8 mmol) in portions at 0° C. Then to the above was added CH3I (922 mg, 6.49 mmol) dropwise at 0° C. in an ice bath. The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 3×10 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 807 mg (75%) of the title compound as a light yellow solid. MS-ESI: 200 (M+1).


Steps 2-7 used similar procedures for converting compound 78 to intermediate 13 shown in Scheme 17 to afford intermediate 14 from compound 84. MS-ESI: 333 (M+1).




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Intermediate 15



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N′-(tert-butyldimethylsilyl)-1-isopropyl-1H-pyrazole-3 -sulfonimidamide
Step 1: 1-Isopropyl-3-nitro-1H-pyrazole

Into a 250-mL round-bottom flask was placed a solution of 3-nitro-1H-pyrazole (10 g, 88.4 mmol) in DMF (100 mL). This was followed by the addition of NaH (60% wt., 3.9 g, 97.5 mmol) in portions at 0° C. The resulting solution was stirred for 0.5 h at 0° C. This was followed by the addition of 2-bromopropane (14.1 g, 115 mmol) dropwise with stirring at 0° C. in 10 min. The resulting solution was stirred for 16 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 3×100 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:5 to 1:3). This resulted in 11.8 g (86%) of the title compound as yellow oil. MS-ESI: 156.1 (M+1).


Steps 2-6 used similar procedures for converting compound 78 to intermediate 13 shown in Scheme 17 to afford intermediate 15 from compound 91. MS-ESI: 333 (M+1).




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Intermediate 16



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N′-(tert-butyldimethyl silyl)-1-(difluoromethyl)-1H-pyrazole-3 -sulfonimidamide
Step 1: 1-(Difluoromethyl)-3-nitro-1H-pyrazole

Into a 250-mL round-bottom flask, was placed a solution of 3-nitro-1H-pyrazole (5 g, 44 mmol) in DMF (40 mL). To the stirred solution was added Cs2CO3 (14.4 g, 44 mmol) and F2ClCCOONa (13.4 g, 88 mmol). The resulting solution was stirred for 30 min at 120° C. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3×100 mL of EtOAc. The resulting mixture was washed with 3×100 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 4.3 g (59.6%) of 1-(difluoromethyl)-3-nitro-1H-pyrazole as yellow oil.


Steps 2-7 used similar procedures for converting compound 78 to intermediate 13 shown in Scheme 17 to afford intermediate 16 from compound 96. MS-ESI: 311 (M+1).




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Intermediate 17



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N′-(tert-butyldimethyl silyl)-6-(2-hydroxypropan-2-yl)-2-methylpyridine-3-sulfonimidamide
Step 1: Methyl 5-amino-6-methylpicolinate

Into a 50-mL seal tube was placed methyl 6-bromo-2-methylpyridin-3-amine (500 mg, 2.67 mmol) in MeOH (15 mL). To the stirred solution was added Pd(OAc)2 (120 mg, 0.53 mmol), dppf (444 mg, 0.80 mmol) and TEA (809 mg, 8.01 mmol) with stirring. The seal tube was evacuated and flushed three times with CO. The resulting solution was stirred for 5 h at 100° C. under 10 atm of CO. Then the solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 351 mg (79.2%) of the title compound as a light yellow solid. MS-ESI: 167 (M+1).


Steps 2-6 used similar procedures for converting compound 79 to Intermediate 13 shown in Scheme 17 to afford Intermediate 17 from compound 103″. MS-ESI: 344 (M+1).









TABLE 4







The Intermediates in the following Table were prepared using the similar procedures for


converting compound 102″ to Intermediate 17 shown in Scheme 21 from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 18


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N′-(tert-butyldimethylsilyl)-6-(2- hydroxypropan-2-yl)pyridine-3- sulfonimidamide
330











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Intermediate 19



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N′-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)benzenesulfonimidamide
Step 1: 4-Nitrobenzoyl chloride

Into a 500-mL round-bottom flask was placed 4-nitrobenzoic acid (20 g, 120 mmol) in DCM (200 mL) and DMF (0.2 mL). This was followed by the addition of oxalyl chloride (15 mL, 135 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 4 h at RT and then was concentrated under vacuum. This resulted in 22 g crude title compound as yellow oil. The crude product was used in the next step.


Step 2: N,N-dimethyl-4-nitrobenzamide

Into a 500-mL round-bottom flask was placed dimethylamine hydrochloride (9.8 g, 120 mmol) in DCM (200 mL) and TEA (41.5 mL, 300 mmol). This was followed by the addition of 4-nitrobenzoyl chloride (22 g, crude) dropwise with stirring at 0° C. The resulting solution was stirred for 6 h at RT and then was concentrated under vacuum. The resulting mixture was washed with 2×50 mL of water. The solids were collected by filtration. This resulted in 16 g (69%, 2 steps) of the title compound as a white solid. MS-ESI: 195.1 (M+1).


Step 3: 4-Amino-N,N-dimethylbenzamide

Into a 250-mL round-bottom flask was placed N,N-dimethyl-4-nitrobenzamide (16 g, 82.4 mmol) in MeOH (100 mL), to the above solution was added Pd/C (wet.10% wt., 1.0 g). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, and the filtrate was concentrated under vacuum. This resulted in 13 g (96%) of the title compound as a white solid. MS-ESI: 165.1 (M+1).


Step 4: 4-(Dimethylcarbamoyl)benzene-1-sulfonyl chloride

Into a 50-mL round-bottom flask was placed 4-amino-N,N-dimethylbenzamide (3.0 g, 18.3 mmol) in HCl (6 M, 12 mL). This was followed by the addition of a solution of NaNO2 (1.5 g, 21.7 mmol) in water (3 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. The above mixture was added to a saturated solution of SO2 in AcOH (100 mL) dropwise with stirring at 0° C. To the above was added CuCl2 (4.8 g, 35.7 mmol). The resulting solution was stirred for 2 h at RT and then was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2×100 mL of DCM. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. This resulted in 5 g crude title compound as yellow oil. The crude product was used in the next step.


Step 5: N,N-dimethyl-4-sulfamoylbenzamide

Into a 250-mL round-bottom flask was placed 4-(dimethylcarbamoyl)benzene-1-sulfonyl chloride (5 g, 20.2 mmol) in DCM (20 mL). To the above solution was added a saturated solution of ammonia in DCM (80 mL). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The resulting mixture was washed with 3×100 mL of EtOAc. The solids were filtered out. The resulting filtrate was concentrated under vacuum. This resulted in 3.1 g (67%) of the title compound as a white solid. MS-ESI: 229.1 (M+1).


Step 6: 4-((Dimethylamino)methyl)benzenesulfonamide

Into a 100-mL round-bottom flask purged with and maintained under nitrogen was placed a solution of N,N-dimethyl-4-sulfamoylbenzamide (1.8 g, 7.9 mmol) in THF (50 mL). This was followed by the addition of 9-BBN (5.8 g, 47.5 mmol) in portions at 0° C. The resulting solution was stirred for 12 h at 70° C. and then was quenched by the addition of 20 mL of water/ice. The resulting solution was extracted with 3×100 mL of EtOAc and the organic layers were combined. The resulting mixture was washed with 200 mL of water and then the organic layer was concentrated under vacuum. The residue was Pd/C a silica gel with DCM/MeOH (20:1 to 15:1). This resulted in 1.0 g (59%) of the title compound as a white solid. MS-ESI: 215.1 (M+1).


Steps 7-8 used similar procedures for converting compound 82 to intermediate 13 shown in Scheme 17 to afford Intermediate 19 from compound 114″. MS-ESI: 328 (M+1).









TABLE 4







The Intermediates in the following Table were prepared using the similar procedures for


converting compound 108″ to Intermediate 19 shown in Scheme 22 from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 20


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N′-(tert-butyldimethylsilyl)-4- ((dimethylamino)methyl)-2- fluorobenzenesulfonimidamide
346.2











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Intermediate 21



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N′-(tert-butyldimethyl silyl)-4-((dimethylamino)methyl)-N-methylbenzenesulfonimidamide

Steps 1-7 used similar procedures for converting compound 108″ to compound 115″ shown in Scheme 22 to afford compound 123″ from compound 116″. MS-ESI: 329 (M+1).


Step 9: N′-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-N-methylbenzenesulfonimidamide

Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed the solution of PPH3Cl2 (13 g, 39 mmol) in chloroform (150 mL). This was followed by the addition of DIEA (10 g, 78 mmol) dropwise with stirring at RT. The resulting solution was stirred for 10 min at RT and the reaction system was cooled to 0° C. To this was added a solution of N-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)benzenesulfonamide (3.2 g, 9.76 mmol) in chloroform (30 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 30 min at 0° C. To the mixture was added CH3NH2 (14.6 mL, 29.3 mmol, 2 M) for 15 min at 0° C. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×200 mL of DCM. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (36/64). This resulted in 1.43 g (43%) of the title compound as a yellow solid. MS-ESI: 342 (M+1).




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Intermediate 22 and Intermediate 22A (mixture)



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N′-(tert-butyldimethylsilyl)-4-(1-hydroxycyclopropyl)thiophene-2-sulfonimidamide and N′-(tert-butyldimethylsilyl)-4-propionylthiophene-2-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 72 to compound 74 shown in Scheme 16 to afford compound 126″ from compound 124″. MS-ESI: 221 (M+1).


Step 3: Mixture of 4-(1-hydroxycyclopropyl)thiophene-2-sulfonamide and 4-propionylthiophene-2-sulfonamide

To a solution of methyl 5-sulfamoylthiophene-3-carboxylate (5.0 g, 22.6 mmol) in THF (100 mL) under nitrogen was added Ti(Oi-Pr)4 (1.28 g, 4.52 mmol) dropwise at 0° C. This was followed by the addition of EtMgBr (3 M in Et2O, 45 mL, 135 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched with 50 mL of sat. NH4Cl (aq.). The resulting solution was extracted with 5×100 mL of EtOAc. The combined organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (25:1). This resulted in 1.66 g (33.5%) of the title compounds (˜1:1 mixture) as a light yellow solid. MS-ESI: both 220 (M+1). Steps 4-5 used similar procedures for converting compound 82 to Intermediate 13 shown in Scheme 17 to afford the mixture (˜1:1) of Intermediate 22 and Intermediate 22A from mixture of compound 127″ and 127A″. MS-ESI: both 333 (M+1).


Steps 4-5 used similar procedures for converting compound 82 to intermediate 13 shown in Scheme 17 to afford intermediate 22 from compound 127″. MS-ESI: 333 (M+1).




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Intermediate 23



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N′-(tert-butyldimethylsilyl)-4-isopropylthiophene-2-sulfonimidamide
Step 1: 4-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen was placed a solution of methyl 5-sulfamoylthiophene-3-carboxylate (4.42 g, 20 mmol) in THF (200 mL). This was followed by the addition of MeMgBr (3 M in THF, 40 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 16 h at RT and was then quenched by the addition of 100 mL of NH4Cl (sat.). The resulting solution was extracted with 3×100 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and then concentrated under vacuum. The residue was applied onto a silica gel and eluted with a gradient of EtOAc/PE (1:3 to 1:1). This resulted in 2.21 g (50%) of the title compound as a light yellow solid. MS-ESI: 220.2 (M−1).


Step 2: 4-Isopropylthiophene-2-sulfonamide

Into a 250-mL round-bottom flask, was placed a solution of 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (1.5 g, 6.79 mmol) in DCM (20 mL). To the stirred solution was added TFA (3.9 g, 34 mmol) and Et3SiH (2.32 g, 20 mmol). The resulting solution was stirred for overnight at RT. The mixture was concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:5 to 1:3). This resulted in 1.1 g (79%) of the title compound as a light yellow solid. MS-ESI: 206 (M+1).


Steps 3-5 used similar procedures for converting compound 82 to intermediate 13 shown in Scheme 17 to afford intermediate 23 from compound 130″. MS-ESI: 319 (M+1).




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Intermediate 24



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N′-(tert-butyldimethylsilyl)-1-isopropyl-1H-pyrazole-4-sulfonimidamide

Steps 1-4 used similar procedures for converting compound 98 to intermediate 16 shown in Scheme 20 to afford intermediate 24 from compound 133″. MS-ESI: 303 (M+1).




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Intermediate 25



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N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)-4-(methoxymethyl)thiazole-5-sulfonimidamide
Step 1: 2-Bromo-4-(methoxymethyl)thiazole

Into a 500-mL round-bottom flask, was placed a solution of (2-bromothiazol-4-yl)methanol (10 g, 51.8 mmol) in THF (200 mL). To a stirred solution was added NaH (60% wt. oil dispersion, 4.15 g, 104 mmol) in three times at 0° C. in an ice/ethanol bath. To this reaction solution was added MeI (11 g, 77.7 mmol) dropwise with stirring at 0° C. in an ice/ethanol bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water (50 mL) at 0° C. The resulting solution was extracted with 3×300 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 8.58 g (80%) of the title compound as a white solid. MS-ESI: 208/210 (M+1).


Steps 2-6 used similar procedures for converting compound 34 to intermediate 3 shown in Scheme 11 to afford intermediate 25 from compound 137″. MS-ESI: 380 (M+1).




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Intermediate 26



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Tert-butyl (amino(4-((dimethylamino)methyl)phenyl)(oxo)-λ6-sulfaneylidene)carbamate
Step 1: 1-(4-Bromophenyl)-N,N-dimethylmethanamine

To a solution of 1-bromo-4-(bromomethyl)benzene (125 g, 500 mmol) in DCM (2.5 L) was added Et0H/MeNH2 (268 mL, 33% in EtOH). The resulting mixture was heated to reflux for 6 h. The reaction was then cooled to room temperature and poured onto sat. NaHCO3 (1.2 L), before extracting with EtOAc (4×1.0 L). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by a silica gel with EtOAc/petrol ether (1:1). This resulted in 83 g (77%) of the title compound as a yellow solid. MS-ESI: 214/216 (M+1).


Steps 2-7 used similar procedures for converting compound 26 to intermediate 2 shown in Scheme 9 to afford intermediate 26 from compound 143″. MS-ESI: 314 (M+1).




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Intermediate 27



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N′-(tert-butyl dimethyl silyl)-4-fluoro-5 -(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide
Step 1: Methyl 3-fluorothiophene-2-carboxylate

Into a 250-mL round-bottom flask, was placed 3-fluorothiophene-2-carboxylic acid (10 g, 68 mmol) in MeOH (10 mL) and H2SO4 (50 mL). The resulting solution was stirred for overnight at 60° C. The reaction was then quenched by the addition of 100 mL of water/ice. The resulting solution was extracted with 2×100 mL of ethyl acetate. The organic layers were combined, dried, and concentrated. This resulted in 9.6 g (87.60%) of methyl 3-fluorothiophene-2-carboxylate as a grey solid. MS-ESI: 161 (M+1).


Step 2 used similar procedures for converting compound 72 to compound 73 shown in Scheme 16 to compound 151″ from compound 150″.

Steps 3-6 used similar procedures for converting compound 51 to intermediate 5 shown in Scheme 13B to Intermediate 27 from compound 151″. MS-ESI: 353 (M+1).


Schemes for phenylacetic acid Intermediates: Schemes 30-36 illustrate the preparation of amino pyridines intermediates.




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Intermediate 28



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3,5-Diisopropylpyridin-4-amine
Step 1: 3,5-Di(prop-1-en-2-yl)pyridin-4-amine

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3,5-dibromopyridin-4-amine (5.0 g, 20 mmol) in dioxane (150 mL) and water (15 mL). To the stirred solution was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (10 g, 60 mmol), Cs2CO3 (19.6 g, 60 mmol) and Pd(dppf)Cl2 (1.46 g, 2.0 mmol). The resulting solution was stirred for 15 h at 90° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:3). This resulted in 3.0 g (87%) of the title compound as light yellow oil. MS-ESI: 175 (M+1).


Step 2: 3,5-Diisopropylpyridin-4-amine

Into a 250-mL round-bottom flask, was placed 3,5-bis(prop-1-en-2-yl)pyridin-4-amine (3.0 g, 17.2 mmol) in MeOH (50 mL), and Pd/C (wet.10% wt., 300 mg). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at RT under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 2.8 g (91%) of the title compound as a light yellow solid. MS-ESI: 178 (M+1).









TABLE 6







The Intermediates in the following Table were prepared using the similar procedures for


converting compound 155″ to Intermediate 28 shown in Scheme 30 from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 29


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5-fluoro-2,4-diisopropylpyridin-3- amine
197





Intermediate 30


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2-fluoro-3,5-diisopropylpyridin-4- amine
197





Intermediate 31


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2,4-Diisopropylpyridin-3-amine
179











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Intermediate 32



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2,3, 5,6-Tetramethylpyridin-4-amine
Step 1: 3,5-Dibromo-2,6-dimethylpyridin-4-amine

Into a 250-mL round-bottom flask, was placed 2,6-dimethylpyridin-4-amine (5.0 g, 40.9 mmol) in ACN (100 mL). This was followed by the addition of NBS (14.6 g, 81.9 mmol) in several batches at 0° C. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 10.6 g (93%) of the title compound as a yellow solid. MS-ESI: 279/281/283(M+1).


Step 2: 2,3,5,6-Tetramethylpyridin-4-amine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3,5-dibromo-2,6-dimethylpyridin-4-amine (2.0 g, 7.1 mmol) in dioxane (30 mL) and H2O (6.0 mL). To the above solution was added Cs2CO3 (4.66 g, 14.3 mmol), methylboronic acid (941 mg, 15.7 mmol) and Pd(dppf)Cl2 (523 mg, 0.71 mmol). The resulting solution was stirred for 16 h at 100° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 220 mg (20.5%) of the title compound as a red solid. MS-ESI: 151 (M+1).




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Intermediate 33



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1,2,3,5,6,7-Hexahydrodicyclopenta[b,e]pyridin-8-amine
Step 1: 2-Aminocyclopent-1-ene-1-carbonitrile

Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of adiponitrile (10.8 g, 100 mmol) in toluene (250 mL). The reaction mixture was heated to 65° C., and t-BuOK (112 g, 100 mmol) was added into the solution at 65° C. in portions. The resulting solution was stirred for at 80° C. for 8 h. The reaction mixture was then cooled to RT and quenched by the addition of 200 mL of water/ice. The solids were collected by filtration. The filter cake was washed with water (100 mL) and hexane (200 mL), after which it was dried under an infra-red lamp. This resulted in 9.18 g (85.0%) of the title compound as an off-white solid. MS-ESI: 109 (M+1).


Step 2: 1,2,3,5,6,7-Hexahydrodicyclopenta[b,e]pyridin-8-amine

Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-aminocyclopent-1-ene-1-carbonitrile (5.0 g, 46.2 mmol) in xylene (125 mL). To the above solution was added cyclopentanone (7.8 g, 93 mmol) and ZnC12 (6.9 g, 51 mmol). The resulting solution was stirred for overnight at 140° C. in an oil bath. The resulting solution was diluted with 150 mL of MeOH, after which a solution of KOH (25 mL, 5.0 M) was dropped into it. The solids were filtered out. The resulting mixture was concentrated. The residue was dissolved in 250 mL of EtOAc. The solids were collected by filtration. This resulted in 4.2 g (52%) of the title compound as a brown solid. MS-ESI: 175 (M+1).









TABLE 7







The Intermediate 33 and Intermediate 34 in the following Table were separated from the


same reaction using the similar procedures for converting compound 160″ to Intermediate 33


shown in Scheme 32A from 3-methylcyclopentanone.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 34


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2-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-amine
189





Intermediate 35


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1-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-amine
189
















TABLE 8







The Intermediates in the following Table were prepared using the similar procedures for


converting compound 160″ to Intermediate 33 shown in Scheme 32A from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 36


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2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]quinolin-9-amine
188





Intermediate 37


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2,2-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-amine
203





Intermediate 38


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3-ethyl-2-phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
239





Intermediate 39


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3-methyl-2-phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
225





Intermediate 40


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2-phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
211





Intermediate 41


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2,3-dimethyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
163





Intermediate 42


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2-ethyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
163





Intermediate 43


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3,5-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-amine
203





Intermediate 44


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2-cyclopropyl-3-methyl-6,7- dihydro-5H-cyclopenta[b]pyridin- 4-amine
189











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Intermediate 33



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1,2,3 ,5,6,7-Hexahydrodicyclopenta[b,e]pyridin-8-amine

Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 2-aminocyclopent-1-enecarbonitrile (5.4 g, 50 mmol) in DCE (125 mL). To this solution was added cyclopentanone (8.4 g, 100 mmol). Then BF3. Et2O (46.5% wt., 14.5 g) was added to this solution at 0° C. in an ice bath. The reaction was heated to 75° C. for 6 h. The reaction cooled to RT, after which it was quenched by the addition of 100 mL of water/ice and extracted with DCM (2×50 mL). The aqueous phase was collected. The pH value was adjusted to 14 with NaOH (6 M) until the solid was precipitated. The solids were collected by filtration. The filter cake was washed with water (150 mL) then dried by infra-red drying, this resulted of the title compound (7.0 g, yield 80%, light yellow solid). MS-ESI: 175 (M+1).









TABLE 9







The Intermediates in the following Table were prepared using the similar procedures for


converting compound 160″ to Intermediate 33 shown in Scheme 32B from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 45


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3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-amine
189





Intermediate 46


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3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-amine
203





Intermediate 47


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1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′-amine
201





Intermediate 48


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2-cyclopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
175





Intermediate 49


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2-isopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
177











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Intermediate 50



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3-Isopropyl-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 3-Bromo-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

Into a 100-mL round-bottom flask, was placed 2-phenyl-5H,6H,7H-cyclopenta[b]pyridin-4-amine (1.36 g, 6.47 mmol) in ACN (20 mL). To the stirred solution was added NBS (1.38 g, 7.76 mmol). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The residue was eluted from a silica gel with EtOAc/PE (1:2). This resulted in 680 mg (36.4%) of the title compound as a yellow solid. MS-ESI: 289/291 (M+1).


Step 2: 2-Phenyl-3-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 3-bromo-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (680 mg, 2.35 mmol) in dioxane (15 mL) and H2O (3 mL). To the stirred solution was added Cs2CO3 (1.53 g, 4.7 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (474 mg, 2.8 mmol), and Pd(dppf)Cl2 (86 mg, 0.12 mmol). The resulting solution was stirred for 16 h at 100° C. in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel with EtOAc/PE (1:2). This resulted in 350 mg (59%) of the title compound as a light yellow solid. MS-ESI: 251 (M+1).


Step 3: 3-Isopropyl-2-phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of H2, was placed 2-phenyl-3-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (350 mg, 1.4 mmol) in MeOH (15 mL). To the stirred solution was added Pd/C (wet 10% wt., 50 mg, 0.47 mmol). The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 16 h at 50° C. under an atmosphere of hydrogen. The Pd/C catalysts were filtered out, the filtrate was concentrated under vacuum. This resulted in 250 mg (71%) of the title compound as a yellow solid. MS-ESI: 253 (M+1).









TABLE 10







The Intermediates in the following Table were prepared using the similar procedures


for converting intermediate 40 to Intermediate 50 shown in Scheme 33 from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 51


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3-ethyl-2-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
177





Intermediate 52


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3-isopropyl-2-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-amine
191





Intermediate 53


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2-propyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
177





Intermediate 54


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2-cyclopropyl-3-ethyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-amine
203











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Intermediate 55



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3-Fluoro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine
Step 1: N-(1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)acetamide

Into a 2-L 3-necked round-bottom flask, was placed a solution of 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (35 g, 201 mmol) in Ac2O (805 mL). This was followed by the addition of triethylamine (61 g, 603 mmol) dropwise with stirring at 0° C. in 5 min. The resulting solution was stirred for overnight at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 14 with aq. KOH (20 M). The solids were collected by filtration. This resulted in 31 g (71%) of the title compound as a brown solid. MS-ESI: 217 (M+1).


Step 2: 8-Acetamido-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide

Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)acetamide (31.4 g, 145 mmol) in DCM (250 mL). This was followed by the addition of m-CPBA (75 g, 436 mmol) dropwise with stirring at 0° C. in 5 min. The resulting solution was stirred for overnight at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (24:1). This resulted in 14 g (42%) of the title compound as a white solid. MS-ESI: 233(M+1).


Step 3: 8-Acetamido-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl acetate

Into a 250-mL round-bottom flask, was placed 8-acetamido-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide (14.9 g, 64 mmol) in Ac2O (80 mL). The resulting solution was stirred for 1 h at 100° C. in an oil bath. The resulting mixture was concentrated. This resulted in 16 g crude title compound as a black crude solid. MS-ESI: 275 (M+1).


Step 4: N-(3-hydroxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)acetamide

Into a 250-mL round-bottom flask, was placed a solution of 8-acetamido-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl acetate (4.5 g, 16.4 mmol) in ethanol (100 mL), to the above solution was added KOH (550 mg, 9.84 mmol) with stirring. The resulting solution was stirred for overnight at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (26:1). This resulted in 2.1 g (55%) of the title compound as a light yellow solid. MS-ESI: 233 (M+1).


Step 5: 8-Amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-ol

Into an 8-mL sealed tube, was placed a solution of N-(3-hydroxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)acetamide (200 mg, 0.86 mmol) in HCl (4 M, 3 mL). The resulting solution was stirred for 40 min at 100° C. The pH value of the solution was adjusted to 7 with NaOH (1 M). The resulting mixture was concentrated. The residue was applied onto a silica gel with DCM/MeOH (3:1). This resulted in 80 mg (49%) of the title compound as a yellow solid. MS-ESI: 191 (M+1).


Step 6: 3-Fluoro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

Into an 8-mL sealed tube, was placed a solution of 8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-ol (200 mg, 1.05 mmol) in DCM (2 mL). To the solution was added DAST (254 mg, 1.58 mmol) at 0° C. The resulting solution was stirred for 2 h at RT. The residue was eluted from a silica gel with DCM/MeOH (8:1). This resulted in 85 mg (42%) of the title compound as a yellow solid. MS-ESI: 193 (M+1).




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Intermediate 56



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3 -((Tert-butyldimethylsilyl)oxy)-1,2,3, 5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

Into a 100-mL round-bottom flask, was placed 8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-ol (1.0 g, 5.26 mmol) in DMF (10 mL, 129 mmol). To the stirred solution was added DBU (1.6 g, 11 mmol) and TBSCl (1.58 g, 11 mmol). The resulting solution was stirred for 4 h at RT. The reaction was then quenched by the addition of 1 mL of water. The resulting solution was extracted with 3×15 mL of EtOAc. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was eluted from silica gel with EtOAc/PE (41%). This resulted in 1.07 g (67%) of the title compound as a white solid.




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Intermediate 57



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8-Amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide
Step 1: Tert-butyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (500 mg, 2.87 mmol) in THF (3 mL). This was followed by the addition of LiHMDS (1 M in THF, 5.7 mL, 5.7 mmol) dropwise with stirring at 80° C. The mixture was stirred for an additional 1 h. To this was added (Boc)2O (1.88 g, 8.61 mmol) at 80° C. The resulting solution was stirred for 16 h at 80° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3×30 mL of EtOAc and concentrated. The residue was eluted from a silica gel with DCM/MeOH (15:1). This resulted in 300 mg (38%) of the title compound as a dark yellow solid. MS-ESI: 275(M+1).


Step 2: 8-((Tert-butoxycarbonyl)amino)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (900 mg, 3.28 mmol) in DCM (15 mL). To the above solution was added m-CPBA (1.13 g, 6.56 mmol). The resulting solution was stirred for 16 h at RT. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3×30 mL of EtOAc and concentrated. The residue was eluted from a silica gel with DCM/MeOH (15:1). This resulted in 750 mg (78.7%) of the title compound as a dark yellow solid. MS-ESI: 291(M+1).


Step 3: 8-Amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 8-((tert-butoxycarbonyl)amino)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide (550 mg, 1.89 mmol) in DCM (8.0 mL) and TFA (4.0 mL). The resulting solution was stirred for 20 min at RT. The pH value of the solution was adjusted to 7 with Na2CO3. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (8:1). This resulted in 184 mg (51%) of the title compound as a yellow solid. MS-ESI: 191(M+1).




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Intermediate 58



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4,6-diisopropyl-2-(trifluoromethyl)pyrimidin-5-amine
Step 1: 4-Bromo-2-(trifluoromethyl)pyrimidin-5-amine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(trifluoromethyl)pyrimidin-5-amine (2.0 g, 12.26 mmol) in acetonitrile (20 mL). To this stirred solution was added NBS (2.62 g, 14.7 mmol). The resulting solution was stirred for 12 h at RT. The resulting solution was diluted with 40 mL of water, extracted with 2×30 mL of DCM, and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:50 to 1:20). This resulted in 1.6 g (54%) of the title compound as a brown solid. MS-ESI: 242/244 [M+1]


Step 2: 4-(Prop-1-en-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-2-(trifluoromethyl)pyrimidin-5-amine (1.6 g, 6.61 mmol) in dioxane (20 mL). This was followed by the addition of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (1.44 g, 8.57 mmol), Pd(dppf)Cl2 (242 mg, 0.33 mmol), and Cs2CO3 (3.23 g, 9.92 mmol). The resulting solution was stirred for 14 h at 100° C. in an oil bath. The resulting solution was diluted with 40 mL of water. The resulting solution was extracted with 3×30 mL of DCM and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 1.1 g (82%) of the title compound as a brown solid. MS-ESI: 204 [M+1].


Step 3: 4-Isopropyl-2-(trifluoromethyl)pyrimidin-5-amine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-(prop-1-en-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine (1.2 g, 5.91 mmol) in MeOH (20 mL), to the stirred solution was added Pd/C (10% wt., 200 mg). The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred 16 h at RT under hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 1.1 g (91%) of the title compound as a brown solid. MS-ESI: 206 [M+1].


Step 4: 4-Bromo-6-isopropyl-2-(trifluoromethyl)pyrimidin-5-amine

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-(propan-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine (1.1 g, 5.36 mmol) in acetonitrile (20 mL), to this solution was added NBS (1.15 g, 6.46 mmol) in portions with stirring. The resulting solution was stirred for 12 h at RT. The resulting solution was diluted with 40 mL of water. The resulting solution was extracted with 2×30 mL of DCM and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:40 to 1:30). This resulted in 1.0 g (66%) of the title compound as a brown solid. MS-ESI: 284/286 [M+1].


Step 5: 4-Isopropyl-6-(prop-1-en-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-bromo-6-(propan-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine (1.2 g, 4.2 mmol) in dioxane (20 mL) and H2O (4 mL). To the stirred solution was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.92 g, 5.5 mmol), Pd(dppf)Cl2 (155 mg, 0.21 mmol) and Cs2CO3 (2.06 g, 6.3 mmol). The resulting solution was stirred for 16 h at 100° C. in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel with EtOAc/PE (1:3). This resulted in 870 mg (84%) of the title compound as a yellow solid.


Step 6: 4,6-Diisopropyl-2-(trifluoromethyl)pyrimidin-5-amine

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of H2, was placed 4-isopropyl-6-(prop-1-en-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine (870 mg, 3.5 mmol) in MeOH (20 mL). To the stirred solution was added Pd/C (10% wt., 125 mg). The flask was evacuated and filled three times with hydrogen. The resulting solution was stirred 16 h at RT under hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 830 mg (99.2%) of the title compound as yellow oil.




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Intermediate 59



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Phenyl 5-fluoro-2,4-diisopropylpyridin-3-ylcarbamate

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 5-fluoro-2,4-diisopropylpyridin-3-amine (200 mg, 1.02 mmol) in THF (10 mL). To the stirred solution was added NaH (60% wt. oil dispersion, 122 mg, 3.06 mmol) at 0° C. The resulting solution was stirred for 10 min at RT. Then phenyl chloroformate (160 mg, 1.02 mmol) was added at 0° C. The resulting solution was allowed to react, with stirring, for an additional 20 h at RT. The reaction mixture was used in the next step directly without further purification.









TABLE 11







The Intermediates in the following Table were prepared using the similar procedures


for converting intermediate 29 to Intermediate 59 shown in Scheme 38 from appropriated starting


materials.













Quenched with





MeOH, Exact


Intermediate #
Structure
IUPAC Name
Mass [M + H]+





Intermediate 60


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Phenyl 2,4-diisopropylpyridin-3- ylcarbamate
237





Intermediate 61


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Phenyl (1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamate
233











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Intermediate 62



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2,2,2-Trichloroethyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate

Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (6.7 g, 38 mmol) in THF (500 mL). To the above solution was added DIEA (9.92 g, 76.9 mmol) dropwise at RT. Then 2,2,2-trichloroethyl chloroformate (16 g, 76.9 mmol) was dropped into the reaction solution at 0° C. The resulting solution was stirred for 16 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/hexane (1:4). This resulted in 7.3 g (54.4%) of the title compound as a yellow solid. MS-ESI: 349/351 (M+1).









TABLE 12







The Intermediates in the following Table were prepared using the similar procedures


for converting intermediate 33 to Intermediate 62 shown in Scheme 39 from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 63


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2,2,2-trichloroethyl (3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamate
377/379





Intermediate 64


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trichloromethyl (1′,5′,6′,7′- tetrahydro-2′H-spiro[cyclopropane- 1,3′-dicyclopenta[b,e]pyridin]-8′- yl)carbamate
361/363





Intermediate 65


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2,2,2-trichloroethyl (3-ethyl-2- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamate
351/353





Intermediate 66


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2,2,2-trichloroethyl (3-isopropyl-2- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamate
365/367





Intermediate 67


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trichloromethyl (3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamate
349/351





Intermediate 68


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2,2,2-trichloroethyl (2-cyclopropyl- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamate
363/365





Intermediate 69


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2,2,2-trichloroethyl (2-cyclopropyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamate
349/351





Intermediate 70


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2,2,2-trichloroethyl (3-((tert- butyldimethylsilyl)oxy)-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamate
479/481





Intermediate 71


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2,2,2-trichloroethyl (4,6- diisopropyl-2- (trifluoromethyl)pyrimidin-5- yl)carbamate
422/424





Intermediate 72


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2,2,2-trichloroethyl (3,5-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamate
377/379





Intermediate 73


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2,2,2-trichloroethyl (2-cyclopropyl- 3-ethyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamate
377/379





Intermediate 74


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2,2,2-trichloroethyl (2-isopropyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamate
351/353





Intermediate 75


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2,2,2-trichloroethyl (3-fluoro- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamate
367/369











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Intermediate 76



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N-(1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)-1H-imidazole-1-carboxamide

Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (2.0 g, 11.5 mmol) in DMF (22 mL). To the stirred solution was added NaH (60% wt. oil dispersion, 1.38 g, 34.5 mmol) at 0° C. The resulting solution was stirred for 30 min at RT. Then CDI (2.79 g, 17.3 mmol) was added to the solution. The resulting solution was stirred for 1 h at RT. The crude product was used directly without work-up.









TABLE 13







The Intermediates in the following Table were prepared using the similar procedures


for converting intermediate 33 to Intermediate 76 shown in Scheme 40 from appropriated starting


materials.













Quenched with





MeOH, Exact


Intermediate #
Structure
IUPAC Name
Mass [M + H]+





Intermediate 77


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N-(3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)-1H-imidazole-1-carboxamide
265





Intermediate 78


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N-(3,5-diisopropylpyridin-4-yl)- 1H-imidazole-1-carboxamide
237





Intermediate 79


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N-(2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]quinolin-9-yl)-1H- imidazole-1-carboxamide
247





Intermediate 80


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N-(3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)-1H-imidazole-1-carboxamide
261





Intermediate 81


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N-(2-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)-1H-imidazole-1-carboxamide
247





Intermediate 82


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N-(1-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)-1H-imidazole-1-carboxamide
247





Intermediate 83


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N-(2,2-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)-1H-imidazole-1-carboxamide
261





Intermediate 84


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8-(1H-imidazole-1-carboxamido)- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridine 4-oxide
249





Intermediate 85


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N-(2,3,5,6-tetramethylpyridin-4- yl)-1H-imidazole-1-carboxamide
209





Intermediate 86


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N-(2-propyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)-1H- imidazole-1-carboxamide
235











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Intermediate 87



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2-Fluoro-4-isocyanato-3,5-diisopropylpyridine

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-fluoro-3,5-diisopropylpyridin-4-amine (100 mg, 0.51 mmol) in THF (20 mL). To the stirred solution was added TEA (155 mg, 1.53 mmol) and BTC (75 mg, 0.26 mmol). The resulting solution was stirred for 2 h at 60° C. in an oil bath. The resulting mixture was concentrated. This resulted in 150 mg crude title product as a grey solid.









TABLE 14







The Intermediates in the following Table were prepared using the similar procedures


for converting intermediate 30 to Intermediate 87 shown in Scheme 41 from appropriated starting


materials.













Quenched with





MeOH, Exact


Intermediate #
Structure
IUPAC Name
Mass [M + H]+





Intermediate 88


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5-fluoro-3-isocyanato-2,4- diisopropylpyridine
255





Intermediate 89


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8-isocyanato-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridine
247





Intermediate 90


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4-isocyanato-3-isopropyl-2-phenyl- 6,7-dihydro-5H- cyclopenta[b]pyridine
311





Intermediate 91


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3-ethyl-4-isocyanato-2-phenyl-6,7- dihydro-5H-cyclopenta[b]pyridine
297





Intermediate 92


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4-isocyanato-3-methyl-2-phenyl- 6,7-dihydro-5H- cyclopenta[b]pyridine
283





Intermediate 93


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4-isocyanato-2-phenyl-6,7-dihydro- 5H-cyclopenta[b]pyridine
269





Intermediate 94


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4-isocyanato-2,3-dimethyl-6,7- dihydro-5H-cyclopenta[b]pyridine
221





Intermediate 95


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2-ethyl-4-isocyanato-6,7-dihydro- 5H-cyclopenta[b]pyridine
221





Intermediate 96


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8′-isocyanato-1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridine]
259





Intermediate 97


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2-cyclopropyl-4-isocyanato-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridine
247











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Intermediate 98



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2,3-Dihydro-1H-cyclopenta[c]quinolin-4-amine
Step 1: 2-Oxo-N-phenylcyclopentane-1-carboxamide

Into a 250-mL round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed methyl 2-oxocyclopentane-1-carboxylate (10 g, 70 mmol) in xylene (100 mL), to the stirred solution was added aniline (6.6 g, 71 mmol). The resulting solution was stirred for 6 h at 140° C. in an oil bath. The resulting mixture was concentrated. This resulted in 13.4 g (93%) of the title compound as brown oil. MS-ESI: 204 (M+1).


Step 2: 2,3-Dihydro-1H-cyclopenta[c]quinolin-4(5H)-one

Into a 250-mL round-bottom flask, was placed 2-oxo-N-phenylcyclopentane-1-carboxamide (13.4 g, 65.7 mmol) in H2SO4 (50 mL). The resulting solution was stirred for overnight at 30° C. in an oil bath. The resulting solution was carefully poured 1.0 L of H2O. The pH value of the solution was adjusted to 7 with aq. NaOH (10% wt.). The solids were filtered out. The resulting solution was extracted with 2×250 ml of ethyl acetate dried over anhydrous sodium sulfate and concentrated. This resulted in 3.7 g of the title compound as a dark yellow solid. MS-ESI: 186 (M+1).


Step 3: 4-chloro-2,3-dihydro-1H-cyclopenta[c]quinolone

Into a 100-mL round-bottom flask, was placed 2,3-dihydro-1H-cyclopenta[c]quinolin-4(5H)-one (950 mg, 5.13 mmol) in POCl3 (20 mL, 215 mmol). The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated. The resulting solution was diluted with 50 mL of ethyl acetate. The resulting mixture was washed with 3×25 mL of H2O. The mixture was dried over anhydrous sodium sulfate and then concentrated. This resulted in 975 mg (93%) of the title compound as a dark yellow solid. MS-ESI: 204 (M+1).


Step 4: N-(4-methoxybenzyl)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine

Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 4-chloro-2,3-dihydro-1H-cyclopenta[c]quinoline (780 mg, 3.83 mmol) in dioxane (25 mL), to the above solution was added 1-(4-methoxyphenyl) methanamine (788 mg, 5.74 mmol), Pd2(dba)3 (351 mg, 0.38 mmol), DavePhos (151 mg, 0.38 mmol) and t-BuOK (1.29g, 11.5 mmol). The resulting solution was stirred for 4 h at 100° C. in an oil bath. The resulting mixture was concentrated. The residue was eluted from a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 768 mg (66%) of the title compound as a dark yellow solid. MS-ESI: 304 (M+1).


Step 5: 2,3-Dihydro-1H-cyclopenta[c]quinolin-4-amine

Into a 50-mL round-bottom flask, was placed N-(4-methoxybenzyl)-2,3-dihydro-1H-cyclopenta[c]quinolin-4-amine (800 mg, 2.63 mmol) in CHCl3 (15 mL), to the above solution was added TFA (17.1 mL, 150 mmol) dropwise. The resulting solution was stirred for 4 h at 65° C. in an oil bath. The resulting mixture was concentrated. The resulting solution was diluted with ?? mL of ethyl acetate. The pH value of the solution was adjusted to 8 with the solution of Na2CO3 (10% wt.). The resulting solution was extracted with 2×150 ml of ethyl acetate and the organic layers combined and concentrated. This resulted in 750 mg crude title compound as a yellow solid. MS-ESI: 185 (M+1).


Intermediate 99



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2,2,2-Trichloroethyl 2,3-dihydro-1H-cyclopenta[c]quinolin-4-ylcarbamate
Intermediate 99 was prepared using similar procedures for converting Intermediate 33 to Intermediate 62 shown in Scheme 39 from Intermediate 98. MS-ESI: 359/361 (M+1).

Schemes of Sulfonimidoylamide Intermediates: Schemes 43-67 illustrate the preparation of sulfonimidoylamide intermediates.




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N′-(tert-butyldimethylsilyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-sulfonimidamide
Step 1: 3-Nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole

To a stirred solution of 3-nitro-1H-pyrazole (10 g, 88.5 mmol) in DMF (100 mL) in a 250-mL round-bottom flask was added Cs2CO3 (57.7 g, 177 mmol) at RT, followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (20.5 g, 88.5 mmol) dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The solids were filtered out.


The resulting mixture was diluted with 200 mL of EtOAc then washed with 3×300 mL of water. The organic layer was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 10.5 g (61%) of the title compound as a yellow solid. MS-ESI: 196 (M+1).


Step 2: 1-(2,2,2-Trifluoroethyl)-1H-pyrazol-3-amine

To a stirred solution of 3-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole (7.2 g, 36.9 mmol) in MeOH (70 ml) in a 100-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 720 mg) in portions. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred overnight at RT under hydrogen with a balloon. The solid was filtered out. The resulting mixture was concentrated under reduced pressure. This resulted in 5.8 g (95%) of the title compound as a yellow solid. MS-ESI: 166.1 (M+1).


Step 3: 1-(2,2,2-Trifluoroethyl)-1H-pyrazole-3-sulfonyl chloride

To a stirred solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-amine (5.0 g, 30.3 mmol) in HCl (6 M, 50 mL) in a 250-mL 3-necked round-bottom flask was added NaNO2 (2.5 g, 36.4 mmol) in H2O (20 mL) dropwise with stirring at 0° C. over 10 min. The resulting solution was stirred for 30 min at 0° C., this solution was assigned as solution A. Then CuSO4 (14.5 g, 90.8 mmol) was added to a 500-mL single necked round-bottom flask with AcOH (90 mL) as the solvent. Then SO2 (g) was bubbled to the solution with stirring at RT for 20 min, this solution was assigned as solution B. To the solution B was added solution A dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. The residue was diluted with 200 mL of water and extracted with 3×200 mL of DCM. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 5.6 g (crude) of the title compound as yellow oil.


Step 4: 1-(2,2,2-Trifluoroethyl)-1H-pyrazole-3-sulfonamide

To a stirred solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-sulfonyl chloride solution (crude; from the Step above) in DCM (100 mL) in a 250 mL round bottom flask was bubbled NH3 (g) at 0° C. for 10 min. The resulting solution was stirred for 2 h at RT. The solution was concentrated under vacuum. The crude product was eluted from silica gel with DCM/MeOH (95:5). This resulted in 4.7 g (67% over two steps) of the title compound as a yellow solid. MS-ESI: 230 (M+1).


Step 5: N-(tert-butyldimethylsilyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-sulfonamide

To a stirred solution of 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-sulfonamide (3.2 g, 14 mmol) in DCM (100 mL) in 250 mL round-bottom flask was added DIEA (7.2 g, 55.7 mmol) at RT, then TBSCl (3.2 g, 20.9 mmol) was added in portions at RT. The resulting solution was stirred for 2 h at RT. The resulting mixture was washed with 5×100 mL of H2O. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 4.0 g (83%) of the title compound as a yellow solid. MS-ESI: 344 (M+1).


Step 6: N′-(tert-butyldimethylsilyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-sulfonimidamide

To a stirred solution of PPH3Cl2 (15.5 g, 46.6 mmol) in CHCl3 (100 mL) in a 250 mL 3-necked round-bottom flask under nitrogen was added DIEA (7.51 g, 58.2 mmol) dropwise with stirring at 0° C. After stirred for 10 min at RT, to the above was added a solution of N-(tert-butyldimethylsilyl)-1-(2,2,2-trifluoroethyl)-1H- pyrazole-3-sulfonamide (4.0 g, 11.7 mmol) in CHCl3 (30 mL) dropwise with stirring at 0° C. The resulting solution was allowed to react for 30 min at 0° C. To the mixture was bubbled NH3 (g) with stirring at 0° C. for 15 min. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 3×200 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (95:5). This resulted in 1.8 g (45%) of the title compound as a white solid. MS-ESI: 343 (M+1).




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Intermediate 101



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N′-(tert-butyldimethylsilyl)-1-isopropyl-4-methyl-1H-pyrazole-3-sulfonimidamide
Step 1: 1-Isopropyl-4-methyl-3-nitro-1H-pyrazole

To a stirred solution of 4-methyl-3-nitro-1H-pyrazole (10 g, 78.7 mmol) in DMF (100 mL) in a 250 mL round-bottom flask under nitrogen was added K2CO3 (32.6 g, 236 mmol) in portions, then 2-bromopropane (19.4 g, 157 mmol) was added dropwise at RT. The resulting solution was stirred for 2 days at RT. The solids were filtered out. The resulting mixture was diluted with 100 mL of EtOAc. The resulting mixture was washed with 5×200 mL of water. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 12.3 g (92%) of the title compound as yellow oil. MS-ESI: 170 (M+1).


Steps 2-7 used similar procedures for converting compound 182 to intermediate 100 shown in Scheme 43 to afford intermediate 101 from compound 188. MS-ESI: 317 (M+1).









TABLE 25







The Intermediates in the following table were prepared using similar procedures for


converting compound 187 to Intermediate 101 shown in Scheme 44 from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 102


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N′-(tert-butyldimethylsilyl)-1-ethyl-1H- pyrazole-3-sulfonimidamide
289





Intermediate 103


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N′-(tert-butyldimethylsilyl)-1-methyl-1H- pyrazole-3-sulfonimidamide
275











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Intermediate 104



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N′-(tert-butyldimethylsilyl)-1-(difluoromethyl)-1H-pyrazole-4-sulfonimidamide
Step 1: 1-(Difluoromethyl)-4-nitro-1H-pyrazole

To a stirred solution of 4-nitro-1H-pyrazole (15 g, 133 mmol) in DMF (150 mL) in a 500-mL round-bottom flask was added Na2CO3 (21.1 g, 199 mmol) and sodium 2-chloro-2,2-difluoroacetate (24.3 g, 159 mmol) at RT. The resulting solution was stirred for 3 h at 90° C. The reaction was then quenched by the addition of 100 mL of water. The resulting solution was extracted with 2×100 mL of EtOAc and the organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 16 g (97%) of the title compound as red liquid. MS-ESI: 164 (M+1).


Steps 2-7 used similar procedures for converting compound 182 to intermediate 100 shown in Scheme 43 to afford intermediate 104 from compound 195. MS-ESI: 311 (M+1).




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Intermediate 105



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N′-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide


Step 1 used similar procedures for converting compound 187 to compound 188 shown in Scheme 44 to afford compound 202 from compound 201. MS-ESI: 198 (M+1).

Steps 2-3 used similar procedures for converting compound 183 to compound 185 shown in Scheme 43 to afford compound 204 from compound 202. MS-ESI: 262 (M+1).


Step 4: 4-(Hydroxymethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

To a stirred solution of ethyl 1-isopropyl-3-sulfamoyl-1H-pyrazole-4-carboxylate (1.5 g, 5.3 mmol) in THF (10 mL) in a 100 mL round-bottom flask under nitrogen was added BH3-THF (1 M, 6.4 mL, 6.4 mmol) dropwise at 0° C. in a water/ice bath. The resulting solution was stirred for 2 h at RT. The resulting mixture was quenched by the addition of 50 mL of water and extracted with 2×100 mL of EtOAc, the organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/1). This resulted in 1.1 g (94%) of the title compound as a white solid. MS-ESI: 220 (M+1).


Step 5: N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-1-isopropyl-1H pyrazole-3-sulfonamide

To a stirred solution of 4-(hydroxymethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide (1.2 g, 6.0 mmol) in THF (20 mL) in a 250 mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 867 mg, 36 mmol) in portions at 0° C., followed by the addition of TBSCl (1.8 g, 12.0 mmol) in small portions at 0° C. The resulting solution was stirred for 3 h at RT. The resulting mixture was quenched by the addition of 50 mL of water and extracted with 2×100 mL of EtOAc and the organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 1.2 g (crude) of the title compound as a yellow solid. MS-ESI: 448 (M+1).


Steps 6-7 used similar procedures for converting compound 186 to Intermediate 100 shown in Scheme 43 to afford intermediate 105 from compound 206. MS-ESI: 447 (M+1).




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Intermediate 106



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N′-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

Steps 1-4 used similar procedures for converting compound 187 to compound 191 shown in Scheme 44 to afford compound 212 from compound 208. MS-ESI: 246 (M−1).


Step 5: 5-(Hydroxymethyl)-1-isopropyl-1H-pyrazole-3-sulfonamide

To a stirred solution of methyl 1-isopropyl-3-sulfamoyl-1H-pyrazole-5-carboxylate (2.4 g, 9.7 mmol) in ethanol (150 mL) in a 500 mL round-bottom flask under nitrogen was added NaBH4 (1.84 g, 48.5 mmol) in portions at 0° C. The resulting solution was stirred overnight at RT. The reaction was quenched by the addition of sat. NH4Cl (aq.) (20 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. The mixture was adjusted to pH 7 with HCl (aq.). The resulting mixture was extracted with 3×50 mL EtOAc. The combined organic layer was washed with water (3×20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (3:1). This resulted in 1.5 g (70%) of the title compound as a light yellow solid. MS-ESI: 220 (M+1).


Steps 6-8 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 106 from compound 216. MS-ESI: 447 (M+1).




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Intermediate 107



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N′-(tert-butyldimethylsilyl)-4-chloro-1-isopropyl-1H-pyrazole-3-sulfonimidamide
Step 1: 1-Isopropyl-1H-pyrazol-3-amine

To a stirred solution of isopropylhydrazine hydrochloride (60 g, 546 mmol) in H2O (600 mL) in a 1 L round-bottom flask was added K2CO3 (226 g, 1.64 mol) in portions at 0° C. The resulting solution was stirred for 2 h at RT. Then 2-chloroacrylonitrile (28 g, 328 mmol) was added to the solution dropwise at 0° C. The resulting solution was stirred overnight at 50° C. The resulting solution was extracted with 3×500 mL of EtOAc. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 36 g (90%) of the title compound as yellow oil. MS-ESI: 126 (M+1).


Step 2: 4-chloro-1-isopropyl-1H-pyrazol-3-amine

To a stirred solution of 1-isopropyl-1H-pyrazol-3-amine (30 g, 240 mmol) in ACN (300 mL) in a 500 mL round-bottom flask under nitrogen was added NCS (32 g, 240 mmol) in portions. The resulting solution was stirred for 2 h at RT. The resulting mixture was quenched by the addition of 500 mL of water and extracted with 3×500 mL of EtOAc and the organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 25 g (65%) of the title compound as a dark yellow solid. MS-ESI: 160 (M+1).


Steps 3-7 used similar procedures for converting compound 183 to Intermediate 100 shown in Scheme 43 to afford Intermediate 108 from compound 218. MS-ESI: 337 (M+1).




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Intermediate 108



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N′-(tert-butyldimethylsilyl)-1-isopropyl-1H-imidazole-4-sulfonimidamide

Steps 1-3 used similar procedures for converting compound 185 to Intermediate 100 shown in Scheme 43 to afford Intermediate 108 from compound 223. MS-ESI: 303 (M+1).




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Intermediate 109



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N′-(tert-butyldimethylsilyl)-1-(4-fluorophenyl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonimidamide
Step 1: Methyl 1-(4-fluorophenyl)-3-nitro-1H-pyrazole-5-carboxylate

To a stirred solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (10 g, 58.4 mmol) in DCM (200 mL) in a 500 mL round-bottom flask was added (4-fluorophenyl)boronic acid (24.5 g, 175 mmol) and pyridine (9.25 g, 117 mmol), followed by the addition of Cu(OAc)2 (15.9 g, 88 mmol) at RT. The resulting solution was stirred for 16 h at RT. The solids were filtered out. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 6.4 g (41%) of the title compound as an off-white solid. MS-ESI: 266 (M+1).


Steps 2-4 used similar procedures for converting compound 182 to compound 185 shown in Scheme 43 to afford compound 230 from compound 227. MS-ESI: 298 (M−1).


Step 5: 1-(4-Fluorophenyl)-5-(2-hydroxypropan-2-yl)-1H-pyrazole-3-sulfonamide

To a stirred solution of methyl 1-(4-fluorophenyl)-3-sulfamoyl-1H-pyrazole-5-carboxylate (2.8 g, 9.4 mmol) in THF (100 mL) in a 250 mL round-bottom flask under nitrogen was added MeMgBr in THF (3 M, 16 mL, 48 mmol) dropwise at 0° C. in an ice bath. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of 20 mL of water/ice. The resulting solution was extracted with 3×100 mL of EtOAc. The organic layers combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 1.2 g (43%) of the title compound as a yellow solid. MS-ESI: 300 (M+1).


Steps 6-7 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 109 from compound 231. MS-ESI: 432 (M+1).




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Intermediate 110



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N′-(tert-butyldimethylsilyl)-1-phenyl-1H-pyrazole-3-sulfonimidamide

Steps 1-4 used similar procedures for converting compound 226 to compound 230 shown in Scheme 50 to afford compound 237 from compound 233. MS-ESI: 222 (M−1).


Steps 5-7 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 110 from compound 237. MS-ESI: 337 (M+1).




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Intermediate 111



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N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

Steps 1-4 used similar procedures for converting compound 187 to compound 191 shown in Scheme 44 to afford compound 244 from compound 240. MS-ESI: 246 (M−1).


Steps 5-8 used similar procedures for converting compound 230 to Intermediate 109 shown in Scheme 50 to afford Intermediate 111 from compound 244. MS-ESI: 361 (M+1).




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Intermediate 112



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N′-(tert-butyldimethyl silyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3 -sulfonimidamide
Step 1: 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a stirred solution of 1,2-dihydro-3H-pyrazol-3-one (42 g, 500 mmol) in DMF (500 mL) in a 1 L round-bottom flask under nitrogen was added K2CO3 (138 g, 1.0 mol) in portions at RT. Followed by the addition of 1,3-dibromopropane (111 g, 550 mmol) dropwise at RT. The resulting mixture was stirred for 16 h at 130° C. The insoluble matter was filtered out, the filtrate was poured into 1.5 L of water and extracted with 3×500 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with petroleum ether/EtOAc (20:1) to afford 24.8 g (40%) the title compound as a yellow solid. MS-ESI: 125 (M+1). 1H NMR (400 MHz, CDCl3): δ 7.31 (d, J=2.0 Hz, 1H), 5.48 (d, J=2.0 Hz, 1H), 4.28 (t, J=5.2 Hz, 2H), 4.18 (t, J=6.2 Hz, 2H), 2.30-2.23 (m, 2H).


Step 2: 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride

A solution of 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (24 g, 194 mmol) in chlorosulfonic acid (143 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was stirred for 16 h at 80° C. The reaction mixture was poured into 1.5 L of water/ice very slowly and extracted with 3×500 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was washed with 300 mL of PE. This resulted in 28.1 g (65.0%) of the title compound as a yellow solid. MS-ESI: 223/225 (M+1).


Step 3: 6, Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

To a stirred solution of ammonia (30% wt., 40 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonyl chloride (28 g, 126 mmol) in THF (80 mL) dropwise at RT. The resulting solution was stirred for 16 h at 60° C. The organic solvent was removed by concentrated under reduced pressure. The water layer was extracted with 3×100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was eluted from a silica gel column with PE/EtOAc (1:1). This resulted in 16.9 g (66%) of the title compound as a light yellow solid. MS-ESI: 202 (M−1). 1H NMR (300 MHZ, DMSO-d6): δ 7.47 (s, 1H), 7.08 (s, 2H), 4.40 (t, J=5.1 Hz, 2H), 4.10 (t, J=6.0 Hz, 2H), 2.25-2.15 (m, 2H).


Steps 4-5 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 112 from compound 251. MS-ESI: 317 (M+1).




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Intermediate 113



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N′-(tert-butyldimethylsilyl)-4-(1-(tert-butyldimethylsilyloxy)ethyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
Step 1: 1-(2-Aminothiazol-4-yl)ethanol

To a stirred solution of 1-(2-aminothiazol-4-yl)ethan-1-one (5.6 g, 39.4 mmol) in MeOH (100 mL) in a 500 mL 3-necked round-bottom flask under nitrogen was added NaBH4 (2.24 g, 59.2 mmol) in portions below 5° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 500 mL of water/ice. The resulting solution was extracted with 3×300 mL of EtOAc. The combined organic layer was washed with 3×300 ml of brine. The mixture was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 5.68 g (99%) of the crude title compound as a light yellow solid. MS-ESI: 145 (M+1).


Step 2: 1-(2-Bromothiazol-4-yl)ethanol

To a stirred solution of 1-(2-aminothiazol-4-yl)ethanol (5.68 g, crude) in ACN (100 mL) in a 250 mL round-bottom flask under nitrogen was added CuBr (8.48 g, 59.1 mmol) and tert-butyl nitrite (6.09 g, 59.1 mmol). The resulting solution was stirred for 2 h at 65° C. The insoluble matter was filtered out and the filtrate was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 3.03 g (37%, over two steps) of the title compound as a light yellow solid. MS-ESI: 208 (M+1).


Step 3: 2-Bromo-4-(1-(tert-butyldimethylsilyloxy)ethyl)thiazole

To a stirred solution of 1-(2-bromothiazol-4-yl)ethanol (4.0 g, 19.2 mmol) in THF (70 mL) in a 250 mL round-bottom flask under nitrogen was added NaH (60% wt., dispersion in mineral oil, 1.54 g, 38.4 mmol) at 0° C. This was followed by the addition of a solution of TBSCl (5.80 g, 38.4 mmol) in THF (10 mL) dropwise at 0° C. over 3 min. The resulting solution was stirred for 10 h at RT. The resulting solution was diluted with H2O (100 mL) and extracted with 3×100 mL of DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 7.0 g (crude) of the title compound as light yellow oil. MS-ESI: 322 (M+1).


Step 4: 2-(4-(1-(Tert-butyldimethylsilyloxy)ethyl)thiazol-2-yl)propan-2-ol

To a stirred solution of 2-bromo-4-(1-(tert-butyldimethylsilyloxy)ethyl)thiazole (5.2 g, 16.1 mmol) in THF (100 mL) in a 500 mL three-neck round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 16 mL, 40.3 mmol) dropwise at −70° C. in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 50 min at −70° C. Then propan-2-one (9.37 g, 161 mmol) was added dropwise to the above solution at −70° C. The resulting solution was allowed to react with stirring for an additional 60 min at RT. The reaction was then quenched by the addition of 100 mL of sat. NH4Cl. The resulting solution was extracted with 3×200 mL of EtOAc and the organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:30). This resulted in 3.03 g (62%) of the title compound as a white solid. MS-ESI: 302 (M+1).


Step 5: 4-(1-(Tert-butyldimethylsilyloxy)ethyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide

To a stirred solution of 2-(4-(1-(tert-butyldimethylsilyloxy)ethyl)thiazol-2-yl)propan-2-ol (300 mg, 1.0 mmol) in THF (20 mL) in a 100 mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 2.0 mL, 5.0 mmol) dropwise at −70° C. in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 30 min at −70° C. Then SO2 was bubbled into the above solution at −70° C. for 30 min. Then the resulting solution was stirred for 2 h at RT. The reaction solution was concentrated under vacuum. The crude product was dissolved in DCM (15 mL). Then NCS (199 mg, 1.5 mmol) was added in small portions at RT to the above solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at RT. The resulting mixture was quenched with 15 mL H2O, the organic layer was collected and washed with 3×15 mL of water, then dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 400 mg (crude) of the title compound as a light yellow solid.


Step 6: N-(tert-butyldimethylsilyl)-4-(1-(tert-butyldimethylsilyloxy)ethyl)-2-(2-hydroxypropan-2-yl) thiazole-5-sulfonamide

To a stirred solution of 4-(1-(tert-butyldimethylsilyloxy)ethyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (400 mg, crude from the Step above) in DCM (20 mL) in a 100 mL round-bottom flask was bubbled NH3 (gas) for 10 min at 0° C. The reaction was stirred for 30 min at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1) to afford the title compound (1.49 g, 52%, over two steps) as a yellow solid. MS-ESI: 495 (M+1).


Steps 7-8 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 113 from compound 259. MS-ESI: 494 (M+1).




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Intermediate 114



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N′-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(2-methoxypropan-2-yl)thiazole-5-sulfonimidamide
Step 1 used similar procedures for converting compound 212 to compound 213 shown in Scheme 47 to afford compound 262 from compound 261. MS-ESI: 194/196 (M+1).

Steps 2-3 used similar procedures for converting compound 255 to compound 257 shown in Scheme 54 to afford compound 264 from compound 262. MS-ESI: 288 (M+1).


Step 4: 4-((Tert-butyldimethylsilyloxy)methyl)-2-(2-methoxypropan-2-yl)thiazole

To a stirred solution of 2-(4-((tert-butyldimethylsilyloxy)methyl)thiazol-2-yl)propan-2-ol (2.4 g, 8.3 mmol) in THF (30 mL) in a 50 mL 3-necked round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 996 mg, 24.9 mmol) in portions at 0° C. followed by the addition of iodomethane (3.55 g, 25 mmol) dropwise at 0° C. in a water/ice bath. The resulting solution was stirred for 16 h at RT. The reaction was quenched with 50 mL water/ice. The resulting mixture was extracted with 3×100 mL of DCM. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 1.7 g (68%) of the title compound as a yellow solid. MS-ESI: 302 (M+1).


Steps 5-9 used similar procedures for converting compound 257 to Intermediate 113 shown in Scheme 54 to afford Intermediate 114 from compound 265. MS-ESI: 494 (M+1).




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Intermediate 115



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N′-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-24 sopropylthiazole-5-sulfonimidamide
Step 1: 4-((Tert-butyldimethylsilyloxy)methyl)-2-(prop-1-en-2-yl)thiazole

To a stirred solution of 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (41 g, 244 mmol) in dioxane (420 mL) and water (105 mL) in a 2 L 3-necked round-bottom flask under nitrogen was added 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (25 g, 81 mmol), Cs2CO3 (53 g, 162 mmol) and Pd(dppf)Cl2 (5.95 g, 8.1 mmol). The resulting solution was stirred overnight at 80° C. The solids were filtered out. The resulting solution was concentrated under vacuum and diluted with 400 mL of water. The resulting solution was extracted with 3×350 mL of DCM and the organic layers combined and dried over anhydrous Na2SO4. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (15:85). This resulted in 18 g (82%) of the title compound as yellow oil. MS-ESI: 270 (M+1).


Step 2: 4-((Tert-butyldimethylsilyloxy)methyl)-2-isopropylthiazole

To a solution of 4-((tert-butyldimethylsilyloxy)methyl)-2-(prop-1-en-2-yl)thiazole (19 g, 71 mmol) in isopropanol (350 mL) in a 1 L round-bottom flask under nitrogen was added Pd/C (10% wt., 2.0 g) in portions. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred overnight at RT under hydrogen with a balloon. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:9). This resulted in 15 g (78%) of the title compound as a yellow oil. MS-ESI: 272 (M+1).


Steps 3-6 used similar procedures for converting compound 257 to Intermediate 113 shown in Scheme 54 to afford Intermediate 115 from compound 272. MS-ESI: 464 (M+1).




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Intermediate 116



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N′-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide
Step 1: Ethyl 2-mercaptothiazole-4-carboxylate

To a stirred solution of ethyl 2-bromothiazole-4-carboxylate (30 g, 127 mmol) in EtOH (200 mL) in a 1 L round-bottom flask was added NaSH (36 g, 635 mmol) in portions. The resulting solution was stirred for 3 h at 85° C. under nitrogen. The resulting mixture was concentrated under vacuum. The residue was dissolved in 200 mL of H2O. The pH value of the solution was adjusted to 3 with HCl (1 M) below 5° C. The solids were collected by filtration. This resulted in 22 g (91.5%) of the title compound as a yellow solid. MS-ESI: 190 (M+1).


Step 2: Ethyl 2-(chlorosulfonyl)thiazole-4-carboxylate

To a stirred solution of ethyl 2-mercaptothiazole-4-carboxylate (16 g, 84.5 mmol) in HCl (6 M, 100 mL) in a 500 mL round-bottom flask was added NaClO (10% wt., 150 mL, 2.22 mol) dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction mixture was diluted with 500 mL of H2O. The resulting solution was extracted with 3×500 mL of DCM. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. This resulted in 10.8 g (crude) title compound as yellow oil.


Step 3: Ethyl 2-sulfamoylthiazole-4-carboxylate

To a stirred solution of ethyl 2-(chlorosulfonyl)thiazole-4-carboxylate (10.8 g, crude) in DCM (100 mL) in a 500 mL round-bottom flask was bubbled NH3 (g) for 20 min at 0° C. The resulting solution was stirred for 1 h at 0° C. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 18 g (65.5% over two steps) of the title compound as a light yellow solid. MS-ESI: 237 (M+1).


Step 4: 4-(Hydroxymethyl)thiazole-2-sulfonamide

To a stirred solution of ethyl 2-sulfamoylthiazole-4-carboxylate (18 g, 76 mmol) in EtOH (200 mL) in a 500 mL round-bottom flask under nitrogen was added NaBH4 (8.65 g, 229 mmol) in portions at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 300 mL of water and extracted with 2×300 mL of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 7.6 g (51.4%) of the title compound as a white solid. MS-ESI: 195 (M+1).


Step 5: N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)thiazole-2-sulfonamide

To a stirred solution of 4-(hydroxymethyl)thiazole-2-sulfonamide (3.1 g, 16 mmol) in THF (25 mL) in a 50 mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 3.06 g, 128 mmol) in several batches at 0° C. in a water/ice bath. The resulting solution was stirred for 10 min at 0° C. To the above was added TBSCl (7.22 g, 47.9 mmol) in portions at 0° C. The resulting solution was stirred for 1 h at RT. The reaction was then quenched with 50 mL water and extracted with 3×100 mL EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (5:1). This resulted in 3.06 g (45%) of the title compound as yellow oil. MS-ESI: 423 (M+1).


Step 6: N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)-5-(2-hydroxypropan-2-yl) thiazole-2-sulfonamide

To a stirred solution of N-(tert-butyldimethylsilyl)-4-((tert-butyldimethylsilyloxy)methyl)thiazole-2- sulfonamide (3.0 g, 7.1 mmol) in THF (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 4.0 mL, 10 mmol) dropwise at −78° C. in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 1 h at −78° C. This was followed by the addition of propan-2-one (4.12 g, 71 mmol) dropwise at −78° C. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 20 mL of water/ice and extracted with 3×50 mL of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 1.5 g (44%) of the title compound as yellow oil. MS-ESI: 481 (M+1).


Steps 7-8 used similar procedures for converting compound 186 to Intermediate 100 shown in Scheme 43 to afford Intermediate 116 from compound 282. MS-ESI: 480 (M+1).




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Intermediate 117



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N′-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide
Step 1: 2-(Thiazol-2-yl)propan-2-ol

To a stirred solution of 1-(thiazol-2-yl)ethanone (200 g, 1.6 mol) in THF (4 L) in a 10-L 4-necked round-bottom flask under nitrogen was added MeMgBr in THF (3 M, 942 mL, 2.83 mol) dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. the solution was stirred for 16 h at RT. Then the reaction was quenched by the addition of 3 L of sat.NH4Cl. The resulting solution was extracted with 3×1.0 L of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with a gradient of EtOAc/PE (1:3 to 1:1). This resulted in 210 g (93%) of the title compound as a brown oil. MS-ESI: 144.0 (M+1).


Step 2: Lithium 2-(2-hydroxypropan-2-yl)thiazole-5-sulfinate

To a stirred solution of 2-(thiazol-2-yl)propan-2-ol (20 g, 140 mmol) in THF (400 mL) in a 1-L 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.50 M, 140 mL, 350 mmol) dropwise at −78° C. Then the resulting solution was stirred for 1 h at −78° C. Then SO2 (g) was bubbled to the solution at −50° C. for 20 min. The resulting solution was allowed to react, with stirring, for an additional 2 h at RT. The resulting mixture was concentrated directly under vacuum. This resulted in 20 g (crude) of the title compound as a yellow crude solid. MS-ESI: 206 (M−1).


Step 3: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonamide

To a stirred solution of lithium 2-(2-hydroxypropan-2-yl)-1,3-thiazole-5-sulfinate (20 g, crude) in DCM (400 mL) in a 1-L round-bottom flask was added NCS (18.8 g, 141 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with 500 ml of water, then extracted with 3×500 mL of DCM and the organic layers were combined and dried over anhydrous Na2SO4. Then NH3 (g) was bubbled to the DCM mixture for 30 min at 0° C. The resulting solution was stirred for 2 h at RT and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/1). This resulted in 2.0 g (6.43% over two steps) of the title compound as a brown solid. MS-ESI: 223 (M+1).


Step 4: 2-(Prop-1-en-2-yl)thiazole-5-sulfonamide

To a stirred solution of 2-(2-hydroxypropan-2-yl)thiazole-5-sulfonamide (50 g, 225 mmol,) in CF3SO3H (60 mL) in a 500 mL round-bottom flask was added TFA (60 mL) dropwise at RT. The resulting solution was stirred for 16 h at 50° C. in an oil bath. The reaction mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8 with aq. NaOH (3% wt.). The resulting solution was extracted with 3×300 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 10 g (21%) of the title compound as an off-white solid. MS-ESI: 205 (M+1).


Step 5: 2-(1,2-Dihydroxypropan-2-yl)thiazole-5-sulfonamide

To a stirred solution of 2-(prop-1-en-2-yl)thiazole-5-sulfonamide (10 g, 49 mmol) in t-BuOH (40 mL) and acetone (40 mL) in a 250-mL round-bottom flask was added NMO (11.5 g, 97.9 mmol) and the resulting solution was stirred for 15 min at RT. Then to this was added a solution of OsO4 (1.24 g, 4.9 mmol) in H2O (60 mL) dropwise at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of saturated aq. Na2S2O3 (50 mL). The resulting solution was extracted with 3×200 mL EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was eluted from silica gel with MeOH/DCM (7:100). This resulted in 5.0 g (43%) of the title compound as yellow oil. MS-ESI: 239 (M+1).


Steps 6-8 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 117 from compound 289. MS-ESI: 466 (M+1).


Step 9: (R) and (S) 2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonamide

Compound 289 (5 g) was resolved by Prep-Chiral-HPLC with the following conditions: CHIRALPAK AD, 5*25 cm, 5 um; Mobile Phase A: CO2, Mobile Phase B: MeOH (2 mM NH3-MeOH); Flow rate: 200 mL/min; Gradient: 40% B; UV 220 nm; Rti: 3.5 min (Compound 289A); Rte: 5.6 min (Compound 289B). This resulted in 2.0 g (99% ee) of Compound 289A and 2.1 g (98% ee) of Compound 289B, both as white solids. MS-ESI: 237 (M−1).









TABLE 26A







The Intermediate 117A and 117B in the following Table were prepared using the


similar procedures for converting compound 289 to Intermediate 117 shown in Scheme 58 using


Compound 289A and Compound 289B.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]





Intermediate 117A


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(S) or (R) N′-(tert-butyldimethylsilyl)-2- (1-(tert-butyldimethylsilyloxy)-2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide
466





Intermediate 117B


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(R) or (S) N′-(tert-butyldimethylsilyl)-2- (1-(tert-butyldimethylsilyloxy)-2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide
466











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Intermediate 118



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N′-(tert-butyldimethylsilyl)-5-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-3-fluorothiophene-2-sulfonimidamide
Step 1: Methyl 5-(chlorosulfonyl)-4-fluorothiophene-2-carboxylate

To a stirred solution of methyl 4-fluorothiophene-2-carboxylate (10 g, 62.4 mmol) in CHCl3 (100 mL) in a 500-mL round-bottom flask was added ClSO3H (21.8 g, 187 mmol) dropwise at 0° C. The resulting solution was stirred for 12 h at RT. Then to the above was added PCl5 (65 g, 312 mmol) at 0° C. in an ice bath. The resulting solution was stirred for 2 h at 50° C. The reaction solution was poured into 500 mL of water/ice very slowly. The resulting solution was extracted with 3×500 mL of DCM and the organic layers were combined and dried over anhydrous Na2SO4. This resulted in a solution of the title compound in DCM (1.5 L) and used for next step directly without further purification.


Step 2: Methyl 4-fluoro-5-sulfamoylthiophene-2-carboxylate

To the DCM solution prepared in step above was bubbled NH3 (gas) at 0° C. for 15 minutes. The reaction solution was stirred for 3 h at RT and concentrated under reduced vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:3). This resulted in 7.3 g (49%, over two steps) of the title compound as a yellow solid. MS-ESI: 240 (M+1).


Step 3: 3-Fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of methyl 4-fluoro-5-sulfamoylthiophene-2-carboxylate (7.3 g, 30.5 mmol.) in THF (200 mL) in a 1 L 3-necked round-bottom flask under nitrogen was added MeMgBr in THF (3 M, 51 mL, 153 mmol) dropwise at 0° C. The resulting solution was stirred for 14 h at RT and then was quenched by the addition of 100 mL of sat. NH4Cl. The resulting solution was extracted with 3×150 mL of EtOAc and the organic layers were combined, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5 to 1:1). This resulted in 5.5 g (75%) of the title compound as a white solid. MS-ESI: 240 (M+1).


Steps 4-5 used similar procedures for converting compound 287 to compound 289 shown in Scheme 58 to afford compound 297 from compound 295. MS-ESI: 254 (M−1).


Step 6: (R) and (S)-5-(1,2-Dihydroxypropan-2-yl)-3-fluorothiophene-2-sulfonamide

Compound 297 (3.0 g) was resolved by Prep-Chiral-HPLC with the following conditions: Lux® 5 μm Amylose-1, 5*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH (2 mM NH3); Flow rate: 200 mL/min; Gradient: 50% B; UV 220 nm; Rt1: 3 min (297A); Rt2: 6.8 min (297B); This resulted in 1.1 g of Compound 297A (99% ee) and 1.0 g of Compound 297B (99% ee). MS-ESI: 254 (M−1).


Steps 7-9 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 118 from compound 297. MS-ESI: 483 (M+1).









TABLE 26







The Intermediates in the following Table were prepared using the similar procedures


for converting compound 297 to Intermediate 118 shown in Scheme 59 using Compound 297A


and Compound 297B.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 119


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(R, RS) or (S, RS) N′-flert- butyldimethylsilyl)-5-(1-((tert- butyldimethylsilyl)oxy)-2-hydroxypropan- 2-yl)-3-fluorothiophene-2- sulfonimidamide
483





Intermediate 120


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(S, RS) or (R, RS) N′-(tert- butyldimethylsilyl)-5-(1-((tert- butyldimethylsilyl)oxy)-2-hydroxypropan- 2-yl)-3-fluorothiophene-2- sulfonimidamide
483











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Intermediate 121



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N′-(tert-butyldimethylsilyl)-3-((tert-butyldimethylsilyloxy)methyl)-1-isopropyl-1H-pyrazole-4-sulfonimidamide


Step 1: 1-Isopropyl-1H-pyrazole-4-sulfonamide

To a stirred solution of 1-isopropyl-1H-pyrazole-4-sulfonyl chloride (6.0 g, 28.8 mmol) and in DCM (60 mL) in a 250 mL round bottom flask was bubbled NH3 (g) at 0° C. for 10 min. The reaction solution was stirred for 1 h at RT and concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 3.2 g (59%) of the title compound as a yellow solid. MS-ESI: 190 (M+1).


Step 2: 3-Bromo-1-isopropyl-1H-pyrazole-4-sulfonamide

To a stirred solution of 1-isopropyl-1H-pyrazole-4-sulfonamide (6.4 g, 33.8 mmol) in THF (100 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 30 mL, 74.4 mmol) dropwise at −78° C. in a liquid nitrogen/EtOH bath. Then the reaction was stirred for 1 h at −78° C. To the above mixture was added NBS (7.22 g, 40.6 mmol) in THF (20 mL) dropwise at −78° C. The resulting mixture was stirred for additional 2 h at RT. The reaction mixture was quenched by the addition of water/ice (50 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2.5 g (28%) of the title compound as a yellow solid. MS-ESI: 268 (M+1).


Step 3: Methyl 1-isopropyl-4-sulfamoyl-1H-pyrazole-3-carboxylate

To a stirred solution of 3-bromo-1-isopropyl-1H-pyrazole-4-sulfonamide (2.0 g, 7.46 mmol) in MeOH (100 mL) in a 250-mL round-bottom flask under nitrogen was added TEA (3.77 g, 37.3 mmol), Pd(PPh3)4 (862 mg, 0.75 mmol) and Pd(dppf)Cl2 (546 mg, 0.75 mmol). The resulting solution was stirred overnight at 80° C. under CO atmosphere (10 atm). The insoluble matter was filtered out and the filtrate was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 920 mg (50%) of the title compound as a yellow solid. MS-ESI: 248 (M+1).


Step 4: 3-(Hydroxymethyl)-1-isopropyl-1H-pyrazole-4-sulfonamide

To a stirred solution of methyl 1-isopropyl-4-sulfamoyl-1H-pyrazole-3-carboxylate (900 mg, 3.64 mmol) in THF (30 mL) in a 100-mL round-bottom flask under nitrogen was added BH3 in THF (1 M, 36 mg, 36 mmol) dropwise at 0° C. in an ice bath. The reaction solution was stirred overnight at 50° C. The reaction was quenched with MeOH (30 mL) at 0° C. The mixture was adjusted to pH 5-6 with HCl (6 M). The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 600 mg (75%) of the title compound as a yellow solid. MS-ESI: 220 (M+1).


Steps 5-6 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 121 from compound 304. MS-ESI: 447 (M+1).




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Intermediate 122



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N′-(tert-butyldimethylsilyl)-3-(2-hydroxypropan-2-yl)-5-isocyanobenzenesulfonimidamide


Steps 1-2 used similar procedures for converting compound 183 to compound 185 shown in Scheme 43 to afford compound 308 from compound 306. MS-ESI: 241 (M+1).


Steps 3-6 used similar procedures for converting compound 230 to Intermediate 109 shown in Scheme 50 to afford Intermediate 122 from compound 308. MS-ESI: 354 (M+1).









TABLE 27







The Intermediates in the following Table were prepared using similar procedures for


converting compound 306 to Intermediate 122 shown in Scheme 61 from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 123


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N′-(tert-butyldimethylsilyl)-3-(2- hydroxypropan-2- yl)benzenesulfonimidamide
329











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Intermediate 124



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N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)benzenesulfonimidamide
Step 1 used similar procedures for converting compound 300 to compound 301 shown in Scheme 60 to afford compound 313 from compound 312. MS-ESI: 214 (M−1).

Steps 2-5 used similar procedures for converting compound 230 to Intermediate 109 shown in Scheme 50 to afford Intermediate 124 from compound 313. MS-ESI: 329 (M+1).




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Intermediate 125



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N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)pyridine-3-sulfonimidamide

Steps 1-4 used similar procedures for converting compound 284 to compound 287 shown in Scheme 58 to afford compound 321 from compound 317. MS-ESI: 215 (M+1).


Steps 5-6 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 125 from compound 321. MS-ESI: 330 (M+1).




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Intermediate 126



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N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)pyridine-2-sulfonimidamide
Step 1 used similar procedures for converting compound 284 to compound 285 shown in Scheme 58 to afford compound 324 from compound 323. MS-ESI: 215 (M−1).

Steps 2-4 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 126 from compound 324. MS-ESI: 330 (M+1).




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Intermediate 127



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Tert-butyl (amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene)carbamate
Step 1: Methyl 2-(2-methoxypropan-2-yl)thiazole-5-sulfinate

To a stirred solution of methyl 2-(2-hydroxypropan-2-yl)-1,3-thiazole-5-sulfinate (40 g, 181 mmol) in THF (500 mL) in a 1-L round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 7.95 g, 199 mmol) in portions at 0° C. in an ice/ethanol bath. To this reaction solution was added MeI (51.3 g, 362 mmol) dropwise at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water (50 mL) at 0° C. The resulting solution was extracted with 3×300 mL of EtOAc and the organic layers were combined, dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 32 g (75.3%) of the title compound as a white solid. MS-ESI: 236 (M+1).


Step 2: 2-(2-Methoxypropan-2-yl)thiazole-5-sulfinamide

To a stirred solution of methyl 2-(2-methoxypropan-2-yl)-1,3-thiazole-5-sulfinate (20 g, 85 mmol) in THF (500 mL) in a 1-L 3-necked round-bottom flask under nitrogen was added KHMDS in THF (1 M, 1.0 L, 1.0 mol) dropwise at −78° C. in a liquid nitrogen/ethanol bath. The resulting solution was stirred for 3 h at −78° C. in a liquid nitrogen/ethanol bath. The reaction was quenched by the addition of water (50 mL). The resulting solution was extracted with 3×300 mL of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:3). This resulted in 14 g (74.8%) of the title compound as a white solid. MS-ESI: 221.0 (M+1).


Step 3: Tert-butyl ((2-(2-methoxypropan-2-yl)thiazol-5-yl)sulfinyl)carbamate

To a stirred solution of 2-(2-methoxypropan-2-yl)-1,3-thiazole-5-sulfinamide (10 g, 45.4 mmol) in THF (250 mL) in a 500-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 3.63 g, 90.8 mmol) in portions at 0° C. in an ice/ethanol bath. To this solution was added Boc2O (9.91 g, 45.4 mmol) in portions at 0° C. in an ice/ethanol bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of water (50 mL). The resulting solution was extracted with 3×300 mL of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 12 g (82.5%) of the title compound as a white solid. MS-ESI: 321.1 (M+1).


Step 4: Tert-butyl (chloro(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-4-sulfaneylidene)carbamate

To a stirred solution of tert-butyl N-[[2-(2-methoxypropan-2-yl)-1,3-thiazol-5-yl]sulfinyl]carbamate (11 g, 34.3 mmol) in THF (200 mL) in a 500-mL round-bottom flask under nitrogen was added NCS (13.8 g, 103 mmol) in small portions at 0° C. The resulting solution was stirred for 3 h at RT. This reaction solution was used to the next step directly without further purification.


Step 5: Tert-butyl (amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ6- sulfaneylidene)carbamate

NH3 gas was bubbled into a stirred solution of tert-butyl (chloro(2-(2-methoxypropan-2-yl)thiazol-5- yl)(oxo)-λ6-sulfaneylidene) carbamate (prepared from last step) in THF (200 mL) for 15 min at 0° C. The resulting solution was stirred for 1 h at RT and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE(1:1). This resulted in 7.0 g (60.8% over two steps) of the title compound as a white solid. MS-ESI: 336.1 (M+1).




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Intermediate 128



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N′-(tert-butyldimethylsilyl)-3-chloro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide
Step 1: Methyl 4-chlorothiophene-2-carboxylate

To a stirred solution 4-chlorothiophene-2-carboxylic acid (9.0 g, 55 mmol) in MeOH (100 mL) in a 100-mL round-bottom flask was added H2SO4 (8.0 mL) dropwise at 0° C. in an ice bath. The resulting solution was stirred for 16 h at 70° C. in an oil bath. The reaction solution was poured into 80 mL of water/ice slowly. The pH value of the solution was adjusted to 10 with KOH (sat.). The resulting solution was extracted with 3×80 mL of DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 8.0 g (81.8%) of methyl 4-chlorothiophene-2-carboxylate as a yellow oil. MS-ESI: 177/179 (M+1).


Steps 2-4 used similar procedures for converting compound 292 to compound 295 shown in Scheme 59 to afford compound 336 from compound 333. MS-ESI: 254/256 (M−1).


Steps 5-7 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 128 from compound 336. MS-ESI: 369/371 (M+1).









TABLE 28







The Intermediates in the following Table were prepared using the similar procedures


for converting compound 332 to Intermediate 128 shown in Scheme 66 from appropriated


starting materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 129


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N′-(tert-butyldimethylsilyl)-4-chloro-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
369/371





Intermediate 130


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N-(tert-butyldimethylsilyl)-5-(2- hydroxypropan-2-yl)-3-methylthiophene-2- sulfonimidamide
349





Intermediate 131


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N′-(tert-butyldimethylsilyl)-5-(2- hydroxypropan-2-yl)-4-methylthiophene- 2-sulfonimidamide
349





Intermediate 132


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3-Bromo-N′-(tert-butyldimethylsilyl)-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
413/415











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Intermediate 133



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N′-(tert-butyldimethylsilyl)-4-fluoro-5-(2-hydroxypropan-2-yl)thiophene-3-sulfonimidamide

Steps 1 used similar procedures for converting compound 332 to compound 333 shown in Scheme 66 to afford compound 333A from compound 332A. MS-ESI: 161 (M+1).


Step 2: Mixture of Methyl 5-(chlorosulfonyl)-3-fluorothiophene-2-carboxylate (Major) and methyl 4-(chlorosulfonyl)-3-fluorothiophene-2-carboxylate (Minor)

To a stirred solution of methyl 3-fluorothiophene-2-carboxylate (10 g, 62.5 mmol) in CHCl3 (100 mL) in a 500-mL round-bottom flask was added ClSO3H (21.8 g, 187 mmol) dropwise at 0° C. The resulting solution was stirred for 12 h at RT. Then to the above was added PCl5 (65 g, 312 mmol) at 0° C. in an ice bath. The resulting solution was stirred for 2 h at 60° C. The reaction solution was poured into 500 mL of water/ice very slowly. The resulting solution was extracted with 3×500 mL of DCM and the organic layers were combined and dried over anhydrous Na2SO4. This resulted in a mixture solution of the title compounds in DCM (1.5 L) and used for next step directly without further purification.


Step 3: Methyl 3-fluoro-5-sulfamoylthiophene-2-carboxylate (Major) and methyl 3-fluoro-4-sulfamoylthiophene-2-carboxylate (Minor)

To the DCM solution prepared in last step was bubbled NH3 (gas) at 0° C. for 15 minutes. The reaction solution was stirred for 3 h at RT, then concentrated under reduced vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:3). This resulted in 5.4 g (36% over two steps) of methyl 3-fluoro-5-sulfamoylthiophene-2-carboxylate (Compound 335B, major) and 1.8 g (12% over two steps) of methyl 3-fluoro-4-sulfamoylthiophene-2-carboxylate (Compound 335A, minor) both as a yellow solid. MS-ESI: 238 (M−1). Compound 335B: 1H NMR (300 MHz, DMSO-d6) δ 8.07 (br s, 2H), 7.63 (s, 1H), 3.86 (s, 3H). 19F NMR (300 MHz, DMSO-d6) δ-110.93. Compound 335A: 1H NMR (300 MHz, DMSO-d6) δ 8.38 (d, J=4.5 Hz, 1H), 7.87 (br s, 2H), 3.85 (s, 3H). 19F NMR (300 MHz, DMSO-d6) δ -113.16.


Steps 4-6 used similar procedures for converting compound 335 to Intermediate 128 shown in Scheme 66 to afford Intermediate 133 from compound 335A. MS-ESI: 353 (M+1).




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Intermediate 134



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N′-(tert-butyldimethylsilyl)-5-((dimethylamino)methyl)-3-fluorothiophene-2-sulfonimidamide
Step 1: (4-Fluorothiophen-2-yl)methanol

To a stirred solution of methyl 4-fluorothiophene-2-carboxylate (10 g, 62.4 mmol) in ethanol (300 mL) in a 1 L round-bottom flask under nitrogen was added NaBH4 (4.62 g, 125 mmol) in portions at 0° C. in an ice/ethanol bath. The reaction solution was stirred for 16 h at RT. The reaction was then quenched by the addition of 50 mL of water. Then the mixture was concentrated and extracted with 3×100mL of EtOAc. The organic layer was combined and dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 6.4 g (77.6%) of the title compound as a yellow oil. MS-ESI: 133 (M+1).


Step 2: 2-(Bromomethyl)-4-fluorothiophene

To a stirred solution of (4-fluorothiophen-2-yl)methanol (8.5 g, 64.3 mmol) in DCM (70 mL) in a 250-mL round-bottom flask was added PBr3 (19.2 g, 70.8 mmol) dropwise at 0° C. in an ice/ethanol bath. The resulting solution was stirred for 30 min at 0° C. The resulting solution was allowed to react for an additional 12 h at RT. The reaction was then quenched by the addition of 50 mL of water. Then the mixture was concentrated and extracted with 3×100 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (15/85). This resulted in 7.0 g (55.8%) of the title compound as yellow oil. MS-ESI: 194/196 (M+1).


Step 3: 1-(4-Fluorothiophen-2-yl)-N,N-dimethylmethanamine

To a stirred solution of 2-(bromomethyl)-4-fluorothiophene (7.4 g, 37.9 mmol) in CHCl3 (50 mL) in a 250-mL round-bottom flask was added butoxytributyl-λ4-azane sulfate (6.76 g, 19 mmol) and DMA (37 mL, 425 mmol) at RT. The resulting solution was stirred for 2 h at 60° C. The reaction was then quenched by the addition of 50 mL of water. Then organic solvent was removed and the residue was extracted with 3×100 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (17/83). This resulted in 5.1 g (85%) of the title compound as a yellow solid. MS-ESI: 160 (M+1).


Steps 4-9 used similar procedures for converting compound 257 to Intermediate 113 shown in Scheme 54 to afford Intermediate 134 from compound 342. MS-ESI: 352 (M+1).


Schemes for amino pyridines Intermediates: Schemes 68-83 illustrate the preparation of amino pyridines intermediates.




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Intermediate 135



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Ethyl 4-amino-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate
Step 1: Ethyl 4-amino-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate

To a stirred solution of 2-aminocyclopent-1-ene-1-carbonitrile (20 g, 185 mmol) in DCE (400 mL) in a 1 L round-bottom flask under nitrogen was added ethyl 2-oxobutanoate (24.1 g, 185 mmol) and BF3.Et2O (47% wt., 25 g, 370 mmol) dropwise at 0° C. The resulting solution was stirred for 4 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 500 mL of water. The pH value of the solution was adjusted to 8 with K2CO3 (sat.). The resulting solution was extracted with 3×500 mL of EtOAc. The organic layers were dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 900 mg (2.2%) of the title compound as a yellow solid. MS-ESI: 221 (M+1).









TABLE 29







The Intermediates in the following Table were prepared using the similar procedures


for converting compound 348 to Intermediate 135 shown in Scheme 68 from appropriated


starting materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 136


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2-(2,2,2-Trifluoroethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
217





Intermediate 137


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3-Methyl-2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
217





Intermediate 138


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2-Isopropyl-3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
191





Intermediate 139


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2-Cyclobutyl-3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
203





Intermediate 140


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3-Ethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- amine
203





Intermediate 141


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2,4,5,6-Tetrahydro-1H- cyclobuta[b]cyclopenta[e]pyridin-7- amine
161











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Intermediate 142



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2-Isopropyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine
Step 1: 3-Nitro-1,5,6,7-tetrahydro-211-cyclopenta[b]pyridin-2-one

To a stirred solution of 1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (5.0 g, 37 mmol) in DCM/conc. H2SO4 (10:1) (55 mL) in a 250 mL round-bottom flask was added KNO3 (4.11 g, 40.7 mmol) in portions at 0° C. in an ice bath. The resulting solution was stirred for 4 h at RT. The resulting solution was poured into 200 mL ice/water. The mixture was extracted with 3×200 mL DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 621 mg (9.3%) of the title compound as a yellow solid. MS-ESI: 181 (M+1).


Step 2: 2-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine

To a stirred solution of 3-nitro-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (621 mg, 3.4 mmol) in MeCN (30 mL) in a 100 mL round-bottom flask was added POCl3 (2.61 g, 17 mmol) dropwise at 0° C. The resulting solution was stirred for 6 h at 60° C. and concentrated under vacuum. The mixture was dissolved in DCM. Then the solution was poured into 10 mL water/ice and extracted with 3×30 mL DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 417 mg (61%) of the title compound as a yellow solid. MS-ESI: 199 (M+1).


Step 3: 3-Nitro-2-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine

To a stirred solution of 2-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (410 mg, 2.1 mmol) in 1,4-dioxane/H2O (5:1) (24 mL) in a 100 mL round-bottom flask under nitrogen was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (521 mg, 3.1 mmol), K3PO4 (890 mg, 4.2 mmol) and Pd(dtbpf)Cl2 (135 mg, 0.21 mmol). The resulting solution was stirred for 6 h at 60° C. The reaction mixture was diluted with 20 mL H2O and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 235 mg (55.7%) of the title compound as a brown solid. MS-ESI: 205 (M+1).


Step 4: 2-Isopropyl-6,7-dihydro-5H-cyclopenta[b]pyridin-3-amine

To a stirred solution of 3-nitro-2-(prop-1-en-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (235 mg, 1.15 mmol) in MeOH (10 mL) in a 50 mL round-bottom flask under nitrogen was added Pd/C (10% wt., 24 mg). The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred for 2 h at RT under an atmosphere of hydrogen with a balloon. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 197 mg (97%) of the title compound as a white solid. MS-ESI: 177 (M+1).




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Intermediate 143



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3-Ethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

Step 1 used similar procedures for converting compound 348 to intermediate 135 shown in Scheme 68 to afford compound 354 from compound 353. MS-ESI: 203 (M+1).


Step 2: 3-Bromo-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (1.5 g, 7.42 mmol) in MeCN (200 mL) in a 500-mL round-bottom flask under nitrogen was added NBS (10.6 g, 59.4 mmol). The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of 50 mL of sat. Na2S2O3 (aq). The mixture was extracted with 3×100 mL of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/3). This resulted in 1.1 g (53%) of the title compound as a dark yellow solid. MS-ESI: 281/283 (M+1).


Steps 3-4 used similar procedures for converting compound 351 to Intermediate 142 shown in Scheme 69 to afford Intermediate 143 from compound 355. MS-ESI: 231 (M+1).




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Intermediate 144



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5-Amino-4,6-diisopropylpicolinonitrile

Step 1 used similar procedures for converting compound 354 to compound 355 shown in Scheme 70 to afford compound 358 from compound 357. MS-ESI: 276/278 (M+1).


Step 2: 5-Amino-4,6-di(prop-1-en-2-yl)picolinonitrile

To a stirred solution of 5-amino-4,6-dibromopicolinonitrile (3.3 g, 12 mmol) in dioxane (125 mL) and H2O (17 mL) in a 500 mL round-bottom flask under nitrogen was added 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (5.0 g, 29.8 mmol), Cs2CO3 (11.7 g, 35.8 mmol) and Pd(dppf)Cl2 (1.74 g, 2.4 mmol). The resulting solution was stirred overnight at 90° C. in an oil bath. The resulting solution was concentrated under vacuum. The reaction solution was diluted with 200 mL H2O. The mixture was extracted with 3×200 mL EtOAc and the organic layers was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 1.96 g (82.5%) of the title compound as yellow oil. MS-ESI: 200 (M+1).


Step 3 used similar procedures for converting compound 352 to Intermediate 142 shown in Scheme 69 to afford Intermediate 144 from compound 359. MS-ESI: 204 (M+1).



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Intermediate 145



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2,6-Dicyclopropyl-3,5-dimethylpyridin-4-amine
Step 1: 2,6-Dibromo-3,5-dimethylpyridine 1-oxide

To a stirred solution of 2,6-dibromo-3,5-dimethylpyridine (2.0 g, 7.55 mmol) in TFA (20 mL) in a 100-mL round-bottom flask was added H2O2 (30% wt., 4.0 mL) dropwise at 0° C. The resulting solution was stirred for 12 h at 80° C. in an oil bath. The resulting solution was diluted with 100 mL of water. The mixture was extracted with 3×100 mL of DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 1.5 g (71%) of the title compound as a brown solid. MS-ESI: 280/282/284 (M+1).


Step 2: 2,6-Dibromo-3,5-dimethyl-4-nitropyridine 1-oxide

To a stirred solution of 2,6-dibromo-3,5-dimethylpyridine 1-oxide (1.50 g, 5.34 mmol) in conc. H2SO4 (20 mL) in a 100-mL round-bottom flask was added HNO3 (4.0 mL) dropwise at 0° C. in an ice bath. The resulting solution was stirred for 4 h at 60° C. in an oil bath. The reaction was poured into 100 mL of water/ice slowly. The resulting solution was extracted with 3×100 mL of DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum.


This resulted in 1.3 g (74.7%) of the title compound as a brown solid. MS-ESI: 325/327/329 (M+1).


Step 3: 2,6-Dibromo-3,5-dimethylpyridin-4-amine

To a stirred solution of 2,6-dibromo-3,5-dimethyl-4-nitropyridine 1-oxide (1.3 g, 3.99 mmol) in AcOH (20 mL) in a 100-mL round-bottom flask under nitrogen was added Fe powder (1.11 g, 0.020 mmol). The resulting mixture was stirred for 14 h at 35° C. The insoluble matter was filtered out and the filtrate was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10 to 1:3). This resulted in 900 mg (80.6%) of the title compound as a brown solid. MS-ESI: 278/280/282 (M+1).


Step 4 used similar procedures for converting compound 358 to Intermediate 359 shown in Scheme 71 to afford Intermediate 145 from compound 363. MS-ESI: 203 (M+1).




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Intermediate 146



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3,7-Dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 2-Methylhexanedinitrile

To a stirred of solution of LDA (76.4 mL, 153 mmol) in 200 mL THF in a 1-L 3-necked round-bottom flask under nitrogen was added a cold solution of adiponitrile (15 g, 139 mmol) in THF (50 mL) dropwise at −78° C. in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 1 h at −78° C. To the reaction was added CH3I (21.7 g, 153 mmol) in THF (50 mL) dropwise at −78° C. Then the reaction was stirred for 1 h at −10° C. The reaction was quenched with sat. NH4Cl (100 mL). The THF was removed and the mixture was extracted with 3×200 mL EtOAc and the organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 15 g (crude) title compound as yellow oil. MS-ESI: 123 (M+1).


Step 2: 2-Amino-3-methylcyclopent-1-ene-1-carbonitrile

To a stirred solution of 2-methylhexanedinitrile (15 g, 123 mmol) in THF (450 mL) in a 1-L 3-necked round bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 9.84 g, 246 mmol) in portions at 0° C. in an ice/EtOH bath. The reaction was stirred for 30 min at 0° C. and then overnight at 80° C. The reaction was quenched with 200 mL H2O. The mixture was extracted with 3×300 mL EtOAc. The combined organic layer was dried over anhydrous Na2SO4. The crude product was eluted from silica gel with EtOAc/PE (1:3). This resulted in 4.8 g (28%, over two steps) of the title compound as a yellow solid. MS-ESI: 123 (M+1).


Step 3 used similar procedures for converting compound 348 to Intermediate 135 shown in

Scheme 68 to afford Intermediate 146 from compound 366. MS-ESI: 231 (M+1).




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Intermediate 147



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2-Cyclopropyl-3,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 2-Cyclopropyl-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 2-amino-3-methylcyclopent-1-ene-1-carbonitrile (25.4 g, 208 mmol) in toluene (150 mL) in a 500-mL round-bottom flask under nitrogen was added 1-cyclopropylethan-1-one (35 g, 416 mmol) and ZnCl2 (31 g, 229 mmol) in portions. The resulting solution was stirred for 16 h at 110° C. in an oil bath. The reaction was then quenched by the addition of 200 mL of water. The pH value of the solution was adjusted to 14 with NaOH (3 M). The resulting solution was extracted with 3×300 mL of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). The crude product was further purified by Prep-HPLC with the following conditions:)(Bridge Prep C18 OBD Column 19×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 17% B to 18% B over 10 min; 254/210 nm; Rt: 9.30 min This resulted in 1.5 g (3.8%) of the title compound as light yellow oil. MS-ESI: 189 (M+1).


Step 2 used similar procedures for converting compound 354 to compound 355 shown in Scheme 70 to afford compound 368 from compound 367. MS-ESI: 267/269 (M+1).


Step 3: 2-Cyclopropyl-3,7-dimethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 3-bromo-2-cyclopropyl-7-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (1.5 g, 5.61 mmol) in dioxane (25 mL) and H2O (2.5 mL) in a 100-mL round-bottom flask under nitrogen was added Cs2CO3 (4.57 g, 14 mmol), Pd(dppf)Cl2.CH2Cl2 (0.46 g, 0.56 mmol) and 2,4,4,5,5-pentamethyl-1,3,2- dioxaborolane (1.99 g, 14 mmol). The resulting solution was stirred for 16 h at 90° C. in an oil bath. The reaction was then quenched by the addition of 50 mL water. The resulting solution was extracted with 3×50 mL of DCM and the organic layers was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 0.60 g (53%) of the title compound as light yellow oil. MS-ESI: 203 (M+1).









TABLE 30







The Intermediates in the following Table were prepared using the similar procedures


for converting compound 366 to Intermediate 147 shown in Scheme 74 from appropriated


starting materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 148


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3-Cyclopropyl-2-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
189











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Intermediate 149



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2-(Tert-butyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1 used similar procedures for converting compound 348 to Intermediate 135 shown in Scheme 68 to afford compound 369 from compound 348. MS-ESI: 191 (M+1).

Step 2 used similar procedures for converting compound 354 to compound 355 shown in Scheme 70 to afford compound 370 from compound 369. MS-ESI: 269/271 (M+1).


Step 3: 2-(Tert-butyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 3-bromo-2-(tert-butyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (550 mg, 2.04 mmol) in a 100-mL round-bottom flask under nitrogen was added Cs2CO3 (1.33 g, 4.09 mmol), 2,4,4,5,5- pentamethyl-1,3,2-dioxaborolane (435 mg, 3.06 mmol), Pd(dppf)Cl2 (145 mg, 0.20 mmol) and SPhos (84 mg, 0.20 mmol). The resulting solution was stirred overnight at 80° C. The reaction solution was diluted with 20 mL H2O. The resulting mixture was extracted with 3×50 mL EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (50:1). This resulted in 243 mg (58%) of the title compound as a brown solid. MS-ESI: 205 (M+1).









TABLE 31







The Intermediates in the following Table were prepared using the similar procedures


for converting compound 348 to Intermediate 149 shown in Scheme 75 from appropriated


starting materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 150


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2,3-Dicyclopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
215





Intermediate 151


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2-(Difluoromethyl)-3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
199





Intermediate 152


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2-Cyclopropyl-3-isopropyl-6,7-dihydro-5H- cpenta[b]pyridin-4-amine
217











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Intermediate 153



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2-(Cyclopropylmethyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Intermediate 154



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3-Cyclopropyl-2-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 2-Cyclopropylacetyl chloride

To a stirred solution of 2-cyclopropylacetic acid (10 g, 99.9 mmol) in DCM (200 mL) in a 500-mL round-bottom flask under nitrogen was added oxalyl chloride (14 g, 110 mmol) dropwise at 0° C. in ice bath. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 10 g (crude) of the title compound as colorless oil.


Step 2: 2-Cyclopropyl-N-methoxy-N-methylacetamide

To a stirred solution of 2-cyclopropylacetyl chloride (10 g, crude) in DCM (200 mL) in a 500-mL round-bottom flask was added TEA (25.7 g, 254 mmol), followed by the addition of N,O-dimethylhydroxylamine hydrochloride (16.4 g, 169 mmol) in DCM (50 mL) dropwise at 0° C. in an ice bath. The resulting solution was stirred for 2 h at RT. The resulting solution was diluted with 200 mL of water. The mixture was extracted with 3×200 mL of DCM and the organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 22 g (91%) of the title compound as colorless oil. MS-ESI: 144 (M+1).


Step 3: 1-Cyclopropylbutan-2-one

To a stirred solution of 2-cyclopropyl-N-methoxy-N-methylacetamide (20 g, 140 mmol) in THF (200 mL) in a 500-mL round-bottom flask under nitrogen was added EtMgBr in Et2O (2 M, 91 mL, 182 mmol) dropwise at 0° C. in an ice bath. The resulting solution was stirred for 14 h at RT. The reaction was then quenched by the addition of 200 mL water. The mixture was extracted with 3×200 mL of DCM and the organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 13 g (83%) of the title compound as brown liquid. MS-ESI: 113 (M+1).


Step 4: 2-(Cyclopropylmethyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine and 3-Cyclopropyl-2-ethyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 1-cyclopropylbutan-2-one (9.64 g, 89.1 mmol) in DCE (100 mL) in a 250-mL round-bottom flask under nitrogen was added 1-cyclopropylbutan-2-one (10 g, 89 mmol) and BF3.Et2O (47% wt., 19 g, 134 mmol) dropwise at 0° C. in an ice bath. The resulting solution was stirred for 14 h at 80° C. in an oil bath. The resulting solution was diluted with 100 mL of water. The pH value of the solution was adjusted to 9 with NaOH (3 M). The resulting solution was extracted with 3×300 mL of DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (100:1 to 10:1) and resulted in a mixture. Then the mixture was separated by SFC with the following conditions: Ultimate XB-NH2, 21.2*250 mm; Sum ; Mobile Phase A: CO2, Mobile Phase B:EtOH (8 mM NH3.MeOH); Flow rate: 60 mL/min; Gradient: 35% B over 9 min; UV 220 nm; Rt1: 6.25 min Intermediate 153; Rt2: 7.40 min Intermediate 154; Injection Volumn:1.1 ml; Number of runs:100; this resulted in Intermediate 153 (4.0 g) and Intermediate 154 (2.0 g). MS-ESI: 203 (M+1).




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Intermediate 155



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3-Methyl-2-(1-methylcyclopropyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

Steps 1-4 used similar procedures for converting compound 371 to Intermediate 153 shown in Scheme 76 to afford Intermediate 155 from compound 375. MS-ESI: 203 (M+1).




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Intermediate 156



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3-Methoxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine
Step 1: 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine

To a stirred solution of 1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (1.75 g, 10 mmol) in CHCl3 (80 mL) in a 500-mL round-bottom flask under nitrogen was added tert-butyl nitrite (2.06 g, 20 mmol) and CuCl2 (2.70 g, 20 mmol) in portions at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was washed with 3×50 mL of water and dried over anhydrous Na2SO4. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (10:1). This resulted in 1.1 g (57%) of the title compound as yellow oil. MS-ESI: 194/196 (M+1).


Step 2: 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide

To a stirred solution of 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine (1.10 g, 5.7 mmol) in CHCl3 (60 mL) in a 250-mL round-bottom flask was added m-CPBA (1.96 g, 11.4 mmol) in portions at 0° C. The resulting mixture was stirred for 3h at RT. The reaction was quenched with sat.Na2SO3 at 0° C. The resulting mixture was washed with 3×15 mL of water and dried with anhydrous Na2SO4. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (3:1). This resulted in 1.03 g (86.5%) of the title compound as yellow oil. MS-ESI: 210/212 (M+1).


Step 3: 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl acetate

A solution of 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine 4-oxide (1.0 g, 4.8 mmol) in Ac2O (50 mL) in a 100-mL round-bottom flask was stirred overnight at RT. The resulting mixture was concentrated under reduced pressure. This resulted in 550 mg (crude) of the title compound as yellow oil. MS-ESI: 252/254 (M+1).


Step 4: 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-ol

To a stirred solution of 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl acetate (550 mg, crude) in MeOH (25 mL) and H2O (5 mL) in a 100-mL round-bottom flask was added NaOH (224 mg, 5.6 mmol) in portions at 0° C. The reaction solution was stirred for 6 h at 60° C. The mixture was cooled to RT and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 550 mg (55%, over two steps) of the title compound as colorless oil. MS-ESI: 210/212 (M+1).


Step 5: 8-chloro-3-methoxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine

To a stirred solution of 8-chloro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-ol (550 mg, 2.6 mmol) in THF (25 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 208 mg, 5.2 mmol) in portions at 0° C. in an ice bath. The resulting mixture was stirred for 30 min at 0° C. To the above solution was added CH3I (745 mg, 5.2 mmol) at 0° C. The resulting mixture was stirred for 30 min at 0° C. The reaction was quenched with water/ice (5 mL) at 0° C. The mixture was extracted with 3×15 mL EtOAc. The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (10:1). This resulted in (500 mg, 85%) of the title compound as yellow oil. MS-ESI: 224/226 (M+1).


Step 6: 3-Methoxy-N-(4-methoxybenzyl)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

To a stirred solution of 8-chloro-3-methoxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine (500 mg, 2.2 mmol) in 1,4-dioxane (15 mL) and H2O (1 mL) in a 100-mL round-bottom flask under nitrogen was added (4-methoxyphenyl)methanamine (613 mg, 4.4 mmol) and Cs2CO3 (1.45 g, 4.4 mmol) and Pd2(dba)3 (20.5 mg, 0.022 mmol) and X-Phos (21.31 mg, 0.045 mmol). The resulting solution was stirred overnight at 100° C. The resulting mixture was concentrated under reduced pressure. The resulted mixture was diluted with H2O (10 mL) and extracted with 3×15 mL EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 370 mg (51%) of the title compound as a yellow solid. MS-ESI: 325 (M+1).


Step 7: 3-Methoxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

A solution of 3-methoxy-N-(4-methoxybenzyl)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (370 mg, 1.14 mmol) in TFA (10 mL) was stirred for 3 hat 80° C. The resulting mixture was concentrated under vacuum. This resulted in 450 mg (crude) of the title compound as a yellow solid. MS-ESI: 205 (M+1).




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Intermediate 157



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Ethyl 8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine-3-carboxylate
Step 1: Ethyl 8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine-3-carboxylate

To a stirred solution of P2O5 (27.3 g, 192 mmol) in toluene (100 mL) in a 250-mL round-bottom flask under nitrogen was added triethyl phosphate (22.5 g , 123 mmol) dropwise at 55˜60° C., followed by the addition of ethanol (2.20 g, 9.55 mmol) dropwise at 55˜60° C. The reaction was stirred for 30 min. The solution was cooled to RT, the mixture of 2-aminocyclopent-1-ene-1-carbonitrile (3.81 g, 35 mmol) and ethyl 2-oxocyclopentane-1-carboxylate (5.0 g, 32 mmol) in toluene (20 mL) at RT. Then the solution was stirred for 3.5 h at 55° C. The solution was cooled to RT, water (100 mL) was added dropwise below 40° C. in an ice bath. Then the solution was stirred at 55° C. for 30 min. The aqueous phase collected and adjusted the pH value to 8 with sat. Na2CO3 solution. The resulting solution was extracted with 3×150 mL of EtOAc, the combined organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (17:1). This resulted in 1.1 g (15%) of the title compound as a brown solid. MS-ESI: 247 (M+1).


Intermediate 158



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3-(Fluoromethyl)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine
Step 2: (8-Amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl)methanol

To a stirred solution of ethyl 8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine-3-carboxylate (680 mg, 2.76 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added LiBH4 (180 mg, 8.28 mmol) in portions at 0° C. in an ice bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 5 mL water. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (8:1). This resulted in 220 mg (39%) of the title compound as an off-white solid. MS-ESI: 205 (M+1).


Step 3: 3-(Fluoromethyl)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

To a stirred solution of (8-amino-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-3-yl)methanol (50 mg, 0.25 mmol) in DCM (10 mL) in a 50-mL 3-necked round-bottom flask under nitrogen was added DAST (197 mg, 1.22 mmol) dropwise 0° C. in an ice bath. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 5 mL MeOH. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). The crude product was purified by Prep-HPLC under the following conditions:)(Bridge Prep OBD C18 Column 30×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 42% B in 7 min; 254/210 nm; Rt: 6.83 min. This resulted in 75 mg (99%) of the title compound as a light yellow oil. MS-ESI: 247 (M+1).




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Intermediate 159



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1,2,3,6,7,8-Hexahydrodicyclopenta[b,d]pyridin-5-amine
Step 1: 2,3,4,6,7,8-Hexahydrodicyclopenta[b,d]pyridin-5(1H)-one

To a stirred solution of 2-oxocyclopentane-1-carboxamide (2.0 g, 15.7 mmol) in toluene (80 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added cyclopentanone (1.32 g, 15.7 mmol) and TsOH (1.63 g, 9.44 mmol). The resulting solution was stirred for 4 h at 120° C. in an oil bath. The mixture was concentrated under reduced pressure. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 301 mg (11%) of the title compound as a yellow solid. MS-ESI: 176 (M+1).


Step 2: 5-chloro-1,2,3,6,7,8-hexahydrodicyclopenta[b,d]pyridine

A stirred solution of 2,3,4,6,7,8-hexahydrodicyclopenta[b,d]pyridin-5(1H)-one (301 mg, 1.72 mmol) in phosphoryl trichloride (25 mL) in a 100-mL round-bottom flask was stirred for 16 h at 150° C. in an oil bath. The reaction was then quenched by the addition of H2O (200 mL). The pH value of the solution was adjusted to 7 with NaOH (3 M). The resulting solution was extracted with 3×150 mL of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions: XBridge Prep C18 OBD Column 19×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 35% B to 80% B in 8 min; 254 /210 nm; Rt: 7.00 min. This resulted in 152 mg (46%) of the title compound as a white solid. MS-ESI: 194/196 (M+1).


Step 3: N-(4-methoxybenzyl)-1,2,3,6,7,8-hexahydrodicyclopenta[b,d]pyridin-5-amine

To a stirred solution of 5-chloro-1,2,3,6,7,8-hexahydrodicyclopenta[b,d]pyridine (156 mg, 0.81 mmol) in dioxane (25 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added 1-(4-methoxyphenyl)methanamine (221 mg, 1.62 mmol), t-BuOK (272 mg, 2.43 mmol), Pd2(dba)3 (74 mg, 0.081 mmol), and Davephos (32 mg, 0.081 mmol). The resulting solution was stirred for 4 h at 100° C. in an oil bath. The reaction mixture was diluted with H2O (20 mL) and extracted with 3×50 mL EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 168 mg (71%) of the title compound as yellow oil. MS-ESI: 295 (M+1).


Step 4: 1,2,3,6,7,8-Hexahydrodicyclopenta[b,d]pyridin-5-amine

To a stirred solution of N-(4-methoxybenzyl)-1,2,3,6,7,8-hexahydrodicyclopenta[b,d]pyridin-5-amine (100 mg, 0.34 mmol) in CHCl3 (5 mL) in a 50-mL round-bottom flask was added TFA (5 mL) dropwise at 0° C. The resulting solution was stirred for 2 h at 65° C. in an oil bath. The solution was concentrated under vacuum. The residue was dissolved in DCM (10 mL). The pH value of the solution was adjusted to 10 with NaOH (3 M). The resulting mixture was extracted with 3×20 mL of EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 50 mg (84%) of the title compound as a white solid. MS-ESI: 175 (M+1).




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Intermediate 160



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Phenyl (4-cyclopropyl-6-methylpyrimidin-2-yl)carbamate
Step 1: 4-Cyclopropyl-6-methylpyrimidin-2-amine

To a stirred solution of 1-cyclopropylbutane-1,3-dione (2.0 g, 16 mmol) in DMF (20 mL) in a 100-mL sealed tube was added K2CO3 (4.42 g, 32 mmol) and guanidine hydrochloride (3.02 g, 32 mmol). The resulting solution was stirred for 4 h at 150° C. in an oil bath. The resulting mixture was concentrated under vacuum. The mixture was dissolved into 20 mL EtOAc. The resulting mixture was washed with 2×50 mL of H2O. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 1.6 g (68%) of the title compound as a yellow solid. MS-ESI: 150 (M+1).


Step 2: Phenyl (4-cyclopropyl-6-methylpyrimidin-2-yl)carbamate

To a stirred solution of 4-cyclopropyl-6-methylpyrimidin-2-amine (100 mg, 0.67 mmol) in THF (20 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 53.6 mg, 1.34 mmol) and phenyl chloroformate (115 mg, 0.74 mmol). The resulting solution was stirred for 24 h at RT. The reaction solution was quenched with H2O (10 mL). The mixture was extracted with 3×20 mL EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 150 mg (83%) of the title compound as a white solid. MS-ESI: 270 (M+1).




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Intermediate 161



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(R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine
Step 1: (R)-3-Methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine

A stirred solution of 3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-amine (47 g, 250 mmol) in isopropyl alcohol (423 mL) was heated to 80° C. in a 1 L 3-neck flask with condenser and stirring bar. The solution was kept stirring for 0.5 h. The solution was cooled to about 50° C. The solution was filtered at that temperature though a Buchner funnel to remove insoluble impurities. The solid was washed with isopropyl alcohol (3×10 mL). The filtrate was transfer to a round bottle and concentrated to 350 g. The solution was transferred to a 2 L 3-necked round-bottom flask equipped with a mechanical stir and reflux condenser in an oil bath. The round bottle was washed with 27 g isopropyl alcohol to transfer all the material to the 2 L 3-necks flask. The resulting solution was heated to 80° C. and a solution of (R)-(−)-Mandelic acid (38 g, 250 mmol) in isopropyl alcohol (188 mL) was added dropwise at that temperature. The resulting mixture was stirred at 80° C. for 5 min. The system was cooled in 5° C. step and a small amount of the seed crystals of the product was added. If the seed dissolved, repeat the above operation. When the system was cooled to 65° C., the seed was undissolved and crystals started to grow, the system turned to cloudy slowly, the solution was stirred for 30 minute at this temperature. From then on, the solution was stirred and maintained for 30 minute while the temperature was cooled in 5° C. steps until the system temperature was 40° C. Turn off the heating switch of oil bath and the mixture was slowly cooled to 28° C. After 16 h, the ee value of solid was monitored (96% ee). The solid was collected by filtered. The resulting solid was slurry in isopropyl alcohol (180 mL) for 1 h and filtrated again. The filtrate was decanted, and the precipitate was washed with chromatographic isopropyl alcohol (30 mL) to give the title compound as a white solid (35 g, 40.5% yield, 98% ee, which contain 13.8% IPA). The solid was dissolved in water (420 mL) and concentrated to afford 29.2 g white solid (KF=5.1%). The mother liquid was combined and concentrated to afford 56.7 g S-isomer (75% ee, contain 17.8% IPA) as a foam. Then 26.9 g (R) salt was freed by aq. Na2CO3 (4 M, 500 mL) and exacted with 3×300 mL EA, then the organic phase was washed with 500 mL of brine and dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 14.3g (38% yield, 98% ee, LCAP=96%) of the title compound as a white solid. MS-ESI: 189 (M+1). Chiral analysis method: Column, CHIRALPAK IC 4.6*150 mm, 3 μm. Mobile phase: Hex(0.1%DEA):IPA=85:15. Column Temperature: 30° C. Flow Rate: 1.0 mL/min. Monitor: UV 254 nm. Intermediate 161 is the first peak with a retention time of 5.8 min. The S enantiomer is the second peak with a retention time of 7.0 min.


In a separate experiment, crystals were obtained from Intermediate 45 and (S)-(+)-Mandelic acid using similar procedures. The structure of this salt was solved by single crystal X-ray crystallography to be the (S) enantiomer of Intermediate 45. Therefore, Intermediate 161 has the (R) configuration.




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Intermediate 162



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Ethyl 3-methyl-4-(((2,2,2-trichloroethoxy)carbonyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate
Step 1: Ethyl 3-methyl-4-(((2,2,2-trichloroethoxy)carbonyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate

To a stirred solution of ethyl 4-amino-3-methyl-5H,6H,7H-cyclopenta[b]pyridine-2-carboxylate (500 mg, 2.27 mmol) in THF (30 mL) in a 100-mL round-bottom flask under nitrogen was added DIEA (587 mg, 4.54 mmol) at RT, followed by the addition of 2,2,2-trichloroethyl chloroformate (962 mg, 4.54 mmol) dropwise at RT. The resulting solution was stirred overnight at RT. The reaction solution was quenched with H2O (10 mL). Th mixture was extracted with 3×50 mL EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE(1:1). This resulted in 610 mg (68%) of the title compound as a brown yellow solid. MS-ESI: 395/397/399 (M+1).









TABLE 32







The Interme in the following Table were prepared using the similar procedures


for converting Intermediate 135 to Intermediate 162 shown in Scheme 83 from appropriated


starting materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 163


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2,2,2-trichloroethyl (2-(2,2,2-trifluoroethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
391/393/395





Intermediate 164


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2,2,2-trichloroethyl (3-methyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
391/393/395





Intermediate 165


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2,2,2-trichloroethyl (2-isopropyl-3-methyl- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamate
365/367/369





Intermediate 166


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2,2,2-trichloroethyl (2-cyclobutyl-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
377/379/381





Intermediate 167


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2,2,2-trichloroethyl (3-ethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamate
377/379/281





Intermediate 168


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2,2,2-trichloroethyl (2,4,5,6-tetrahydro- 1H-cyclobuta[b]cyclopenta[b,e]pyridin-7- yl)carbamate
335/337/339





Intermediate 169


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2,2,2-trichloroethyl (2-isopropyl-6,7- dihydro-5H-cyclopenta[b]pyridin-3- yl)carbamate
351/353/355





Intermediate 170


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2,2,2-trichloroethyl (3-ethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
405/407/409





Intermediate 171


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2,2,2-trichloroethyl (3,7-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
405/407/409





Intermediate 172


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2,2,2-trichloroethyl (2,6-dicyclopropyl- 3,5-dimethylpyridin-4-yl)carbamate
377/379/381





Intermediate 173


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2,2,2-trichloroethyl (6-cyano-2,4- diisopropylpyridin-3-yl)carbamate
378/380/382





Intermediate 174


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2,2,2-trichloroethyl (2-cyclopropyl-3,7- dimethyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
377/379/381





Intermediate 175


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2,2,2-trichloroethyl (3-cyclopropyl-2- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
363/365/367





Intermediate 176


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2,2,2-trichloroethyl (2-(tert-butyl)-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
379/381/383





Intermediate 177


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2,2,2-trichloroethyl (2,3-dicyclopropyl- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamate
389/391/393





Intermediate 178


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2,2,2-trichloroethyl (2-(difluoromethyl)-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
373/375/377





Intermediate 179


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2,2,2-trichloroethyl (2- (cyclopropylmethyl)-3-methyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4-yl) carbamate
377/379/381





Intermediate 180


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2,2,2-trichloroethyl (3-cyclopropyl-2- ethyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
377/379/381





Intermediate 181


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2,2,2-trichloroethyl (3-methyl-2-(1- methylcyclopropyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
377/379/381





Intermediate 182


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2,2,2-trichloroethyl (3-methoxy- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamate
379/381/383





Intermediate 183


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ethyl 8-(((2,2,2- trichloroethoxy)carbonyl)amino)- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridine-3- carboxylate
421/423/425





Intermediate 184


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2,2,2-trichloroethyl (1,2,3,6,7,8- hexahydrodicyclopenta[b,d]pyridin-5- yl)carbamate
349/351/353





Intermediate 185


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2,2,2-trichloroethyl (R)-(3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamate
363/365/367





Intermediate 186


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2,2,2-trichloroethyl (2-cyclopropyl-3- isopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
391/393/395





Intermediate 187


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2,2,2-trichloroethyl (3-(fluoromethyl)- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamate
381/383/385











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Intermediate 188



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N′-(tert-butyldimethylsilyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide
Step 1: 2,2-Dimethyl-5-(thiazol-2-yl)-1,3-dioxan-5-ol

To a stirred solution of 2-bromothiazole (4.89 g, 30.0 mmol) in THF (200 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 12.0 mL, 30 mmol) dropwise at −70° C. in a liquid nitrogen/ethanol. The resulting solution was stirred for 1 h at −70° C. Then 2,2-dimethyl-1,3-dioxan-5-one (3.9 g, 30 mmol) in THF (10 mL) was added dropwise at −70° C. The resulting solution was stirred for an additional 30 min at RT. The reaction solution was quenched with H2O (200 mL). The resulting mixture was extracted with EtOAc (3×200 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/10). This resulted in 3.2 g (50%) of the title compound as a yellow solid. MS-ESI: 216 (M+1).


Steps 2-5 used similar procedures for converting compound 257 to Intermediate 113 shown in Scheme 54 to afford Intermediate 188 from compound 394. MS-ESI: 408 (M+1).




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Intermediate 189



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N′-(tert-butyldimethylsilyl)-1-(1,1-difluoroethyl)-1H-pyrazole-3-sulfonimidamide
Step 1: 1-(2-Bromo-1,1-difluoroethyl)-3-nitro-1H-pyrazole

To a stirred solution of 2-bromo-1,1-difluoroethene (8.5 g, 59 mmol) in MeCN (30 mL) in a 100-mL round-bottom flask under nitrogen was added 3-nitro-1H-pyrazole (6.7 g, 59 mmol) in small portions at −30° C. followed by the addition of DBU (18.1 g, 119 mmol) dropwise at −30° C. The resulting solution was stirred for 4 h at −20° C. The reaction solution was concentrated under vacuum. The resulted mixture was diluted with water (100 mL). The resulting mixture was extracted with 3×100 mL of DCM. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 4.2 g (28%) of the title compound as yellow oil. MS-ESI: 256/258 (M+1).


Step 2: 1-(2-Bromo-1,1-difluoroethyl)-1H-pyrazol-3-amine

To a stirred solution of 1-(2-bromo-1,1-difluoroethyl)-3-nitro-1H-pyrazole (2.0 g, 7.81 mmol) in MeOH (20 mL) in a 100-mL round-bottom flask under nitrogen was added Pd(OH)2/C (20% wt., 395 mg) in portions at RT. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred for 2 days at RT under atmosphere of hydrogen with a balloon. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 200 mg (11%) of the title compound as brown oil. MS-ESI: 226/228 (M+1).


Steps 3-4 used similar procedures for converting compound 183 to compound 185 shown in Scheme 43 to afford compound 402 from compound 400. MS-ESI: 290/292 (M+1).


Step 5: 1-(1,1-Difluoroethyl)-1H-pyrazole-3-sulfonamide

To a stirred solution of 1-(2-bromo-1,1-difluoroethyl)-1H-pyrazole-3-sulfonamide (1.0 g, 3.45 mmol) in MeOH (40 mL) in a 100-mL pressure tank reactor under nitrogen was added Pd(OH)2/C (20% wt., 200 mg) in portions at 0° C. The resulting solution was stirred for 24 h at 70° C. under the atmosphere of hydrogen (10 atm). The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 620 mg (85%) of the title compound as a white solid. MS-ESI: 210 (M−1).


Steps 6-7 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 189 from compound 403. MS-ESI: 325 (M+1).




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Intermediate 190



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N′-(tert-butyl di methyl silyl)-4-ethylthiophene-2-sulfonimidamide

Steps 1-6 used similar procedures for converting compound 257 to Intermediate 133 shown in


Scheme 54 to afford Intermediate 190 from compound 405. MS-ESI: 305 (M+1).




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Intermediate 191



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N′-(tert-butyldimethylsilyl)-5-ethyl-3-fluorothiophene-2-sulfonimidamide
Step 1: 4-Fluorothiophene-2-carboxylic acid

To a stirred solution of methyl 4-fluorothiophene-2-carboxylate (300 mg, 1.87 mmol) in MeOH (10 mL) in a 50-mL round-bottom flask was added a solution of NaOH (300 mg, 7.49 mmol) in H2O (10 mL) dropwise at 0° C. The resulting solution was stirred for 2 h at RT. The pH value of the solution was adjusted to 4 with HCl (6 M). The resulting solution was extracted with 3×20 mL of EtOAc and dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 200 mg (73%) of the title compound as a white solid. MS-ESI: 145 (M−1).


Step 2: 4-Fluoro-N-methoxy-N-methylthiophene-2-carboxamide

To a stirred solution of 4-fluorothiophene-2-carboxylic acid (200 mg, 1.37 mmol) in THF (15 mL) in a 50-mL round-bottom flask under nitrogen was added TEA (346 mg, 3.42 mmol) and N,O-dimethyl- hydroxylamine hydrochloride (202 mg, 2.06 mmol) at RT. To the stirred solution was added T3P in EtOAc (50% wt., 1.74 g, 2.74 mmol) dropwise at 0° C. The resulting solution was stirred for 4 h at RT. The reaction solution was quenched with 20 mL water. The resulting solution was extracted with 3×20 mL of EtOAc, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 200 mg (77%) of the title compound as yellow oil. MS-ESI: 190 (M+1).


Step 3: 1-(4-Fluorothiophen-2-yl)ethan-1-one

To a stirred solution of 4-fluoro-N-methoxy-N-methylthiophene-2-carboxamide (200 mg, 1.06 mmol) in THF (10 mL) in a 50-mL 3-necked round-bottom flask under nitrogen was added MeMgBr in THF (3.0 M, 0.53 mL, 1.59 mmol) dropwise with stirring at 0° C. in 5 min. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 5.0 mL of NH4Cl (aq). The resulting solution was extracted with 3×10 mL of DCM. The combine extract was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 120 mg (79%) of the title compound as yellow oil. MS-ESI: 145 (M+1).


Step 4: 2-(4-Fluorothiophen-2-yl)-2-methyl-1,3-dioxolane

To a stirred solution of 1-(4-fluorothiophen-2-yl)ethan-1-one (120 mg, 0.83 mmol) in toluene (10 mL) in a 100-mL round-bottom flask was added ethane-1,2-diol (103 mg, 1.66 mmol) and 4-methylbenzenesulfonic acid (14 mg, 0.083 mmol). The resulting solution was stirred for 16 h at 110° C. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 121 mg (77%) of the title compound as yellow oil. MS-ESI: 189 (M+1).


Steps 5-6 used similar procedures for converting compound 257 to compound 259 shown in Scheme 54 to afford compound 417 from compound 415. MS-ESI: 268 (M+1).


Step 7: 5-Acetyl-3-fluorothiophene-2-sulfonamide

To a stirred solution of 3-fluoro-5-(2-methyl-1,3-dioxolan-2-yl)thiophene-2-sulfonamide (360 mg, 1.35 mmol) in THF (10 mL) in a 50-mL round-bottom flask was added HCl (4 M, 10 mL, 40 mmol) dropwise at 0° C. The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 8 with sat. Na2CO3. The resulting mixture was extracted with EtOAc (3×30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 300 mg (99%) of the title compound as yellow oil. MS-ESI: 224 (M+1).


Step 8: 5-Ethyl-3-fluorothiophene-2-sulfonamide

To a stirred solution of 5-acetyl-3-fluorothiophene-2-sulfonamide (300 mg, 1.34 mmol) in TFA (1.53 g, 13.4 mmol) in a 50-mL round-bottom flask under nitrogen was added triethylsilane (1.56 g, 13.4 mmol) dropwise at RT. The resulting solution was stirred for 16 h at 30° C. in an oil bath. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 8 with sat. Na2CO3. The resulting mixture was extracted with EtOAc (3×30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 240 mg (85%) of the title compound as yellow oil. MS-ESI: 210 (M+1).


Steps 9-11 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 191 from compound 419. MS-ESI: 323 (M+1).




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Intermediate 192



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N-(tert-butyldimethylsilyl)-2-((R)-2-hydroxy-1-(2-methoxyethoxy)propan-2-yl)thiazole-5-sulfonimidamide
Step 1: (R)-2-hydroxy-2-(5-sulfamoylthiazol-2-yl)propyl 4-methylbenzenesulfonate

To a stirred solution of (R)-2-(1,2-dihydroxypropan-2-yl)thiazole-5-sulfonamide (Compound 289A, 4.0 g, 17 mmol) in pyridine (40 mL) in a 250-mL round-bottom flask under nitrogen was added 4-methylbenzenesulfonyl chloride (4.8 g, 25 mmol) in portions at 0° C. The resulting solution was stirred overnight at RT and then diluted with HCl (1 M, 40 mL) and extracted with 3×40 mL EtOAc. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:1). This resulted in 5.2 g (79%) of the title compound as a yellow solid. MS-ESI: 391 (M−1).


Step 2: (R)-2-(2-hydroxy-1-(2-methoxyethoxy)propan-2-yl)thiazole-5-sulfonamide

To a stirred solution of 2-methoxyethan-1-ol (1.94 g, 25 mmol) in THF (30 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 2.04 g, 51 mmol) in portions at 0° C. The resulting mixture was stirred for 30 min at 0° C. To the solution was added (R)-2-hydroxy-2-(5-sulfamoylthiazol-2-yl)propyl 4-methylbenzenesulfonate (2.0 g, 5.1 mmol) in portions at 0° C. The resulting mixture was stirred for 32 hat 35° C. The reaction solution was quenched with water (20 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (2×200 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:3). This resulted in 1.18 g (78%) of the title compound as yellow oil. MS-ESI: 295 (M+1).


Steps 3-5 used similar procedures for converting compound 205 to Intermediate 105 shown in Scheme 46 to afford Intermediate 192 from compound 423. MS-ESI: 410 (M+1).




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Intermediate 193



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N-(tert-butyldimethylsilyl)-3-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-N-methylbenzenesulfonamide
Step 1: N1,N3-bis(tert-butyldimethylsilyl)-N1-methylbenzene-1,3-disulfonamide

To a stirred solution of N-methylbenzene-1,3-disulfonamide (220 mg, 0.88 mmol) in THF (6.0 mL) in a 25-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 211 mg, 5.28 mmol) in portions at 0° C. The resulting solution was stirred for 20 min at RT. To the solution was added TBSCl (397 mg, 2.64 mmol) in portions at 0° C. The resulting solution was stirred overnight at RT. The reaction solution was quenched with 10 mL water. The mixture was extracted with 3×20 mL EtOAc. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 400 mg (95%) of the title compound as yellow oil. MS-ESI: 479 (M+1).


Steps 2-4 used similar procedures for converting compound 186 to Intermediate 100 shown in Scheme 43 to afford Intermediate 193 from compound 427. MS-ESI: 478 (M+1).




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Intermediate 194



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N′-(tert-butyldimethylsilyl)-4-chloro-1-ethyl-1H-pyrazole-3 -sulfonimidamide
Step 1: 1-Ethyl-3-nitro-1H-pyrazole

To a stirred solution of 3-nitro-1H-pyrazole (30 g, 265 mmol) in DIVIF (150 mL) in a 500-mL round-bottom flask was added K2CO3 (73.3 g, 530 mmol) in portions at RT. Iodoethane (82.8 g, 530 mmol) was added dropwise at RT. The resulting solution was stirred for 1 h at 80° C. The reaction was then quenched by the addition of 500 mL of water. The resulting mixture was extracted with 4×200 mL of EtOAc and dried over anhydrous Na2SO4. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 36 g (96%) of the title compound as yellow oil. MS-ESI: 142 (M+1).


Step 2: 1-Ethyl-1H-pyrazol-3-amine

To a stirred solution of 1-ethyl-3-nitro-1H-pyrazole (10 g, 71 mmol) in MeOH (100 mL) in a 250-mL round-bottom flask under nitrogen was added Pd/C (10% wt., 1.13 g) in portions at 0° C. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred for 16 h at RT under hydrogen using a balloon. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (15:1). This resulted in 5.7 g (72%) of the title compound as yellow oil. MS-ESI: 112 (M+1).


Steps 3-5 used similar procedures for converting compound 218 to compound 221 shown in Scheme 48 to afford compound 434 from compound 431. MS-ESI: 290 (M+1).


Step 6: N-(tert-butyldimethylsilyl)-4-chloro-1-ethyl-1H-pyrazole-3-sulfonamide

To a stirred solution of N-(tert-butyldimethylsilyl)-1-ethyl-1H-pyrazole-3-sulfonamide (100 mg, 0.35 mmol) in DMF (10 mL) in a 25-mL round-bottom flask under nitrogen was added NCS (50.7 mg, 0.38 mmol) in portions at 0° C. The resulting solution was stirred overnight at RT. The reaction solution was diluted with 10 mL H2O. The resulting mixture was extracted with 3×20 mL of EtOAc, the combined organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 80 mg (71.5%) of the title compound as a yellow solid. MS-ESI: 324/326 (M+1).


Steps 7-8 used similar procedures for converting compound 186 to Intermediate 100 shown in Scheme 43 to afford Intermediate 194 from compound 435. MS-ESI: 323 (M+1).


Schemes of Sulfonimidamide Intermediates: Schemes 91-106 illustrate the preparation of sulfonimidamide intermediates.




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Intermediate 195



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N′-(tert-butyldimethylsilyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-sulfonimidamide
Step 1: 1-(2-(Benzyloxy)ethyl)-3-nitro-1H-pyrazole

To a stirred solution of 3-nitro-1H-pyrazole (10 g, 88 mmol) in DMF (120 mL) in a 500-mL 3-necked round-bottom flask was added K2CO3 (18 g, 133 mmol) and ((2-bromoethoxy)methyl)benzene (20 g, 93 mmol) in portions at RT. The resulting solution was stirred for 16 h at 60° C. in an oil bath. The reaction was then quenched by the addition of 150 mL of water. The resulting solution was extracted with 3×200 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1:3). This resulted in 21.1 g (96.7%) of the title compound as yellow oil. MS-ESI: 248 (M+1).


Step 2: 1-(2-(Benzyloxy)ethyl)-1H-pyrazol-3-amine

To a stirred solution of 1-(2-(benzyloxy)ethyl)-3-nitro-1H-pyrazole (20 g, 81 mmol) in THF (200 mL) and AcOH (50 mL) in a 1-L round-bottom flask under nitrogen was added Fe powder (45 g, 810 mmol). The resulting mixture was stirred for 4 h at RT. The solids were filtered out, to the filtrate was added 400 mL of water. The resulting solution was extracted with 3×300 mL of EtOAc, the organic layers were combined and dried over anhydrous Na2SO4. The residue was eluted from silica gel with EtOAc/PE (3:1). This resulted in 14.8 g (84%) of the title compound as pink oil. MS-ESI: 218 (M+1).


Step 3: 1-(2-(Benzyloxy)ethyl)-1H-pyrazole-3-sulfonyl chloride

To a stirred solution of 1-(2-(benzyloxy)ethyl)-1H-pyrazol-3-amine (10 g, 46 mmol) in MeCN (100 ml) in a 500-mL round-bottom flask was added HBF4 (aq., 40% wt., 15 g, 69.1 mmol) at RT, followed by the addition of tert-butyl nitrite (7.12 g, 69 mmol) dropwise below 5° C. in an ice/water bath. The resulting solution was stirred for 1.5 h at 0˜5° C., this solution was assigned as solution A. Then CuCl (13.7 g, 138 mmol) was added to a 500-mL single necked round-bottom flask with MeCN (200 mL) as the solvent. Then SO2 (g) was bubbled to the solution with stirring at RT for 20 min, this solution was assigned as solution B. To the solution B was added solution A dropwise with stirring at 0° C. The resulting solution was stirred for additional 3 h at RT. The reaction was then quenched by the addition of 500 mL of water. The resulting solution was extracted with 3×300 mL of EtOAc. The organic layers were combined and washed with 3×300 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 12.8 g (crude) of the title compound as brown yellow oil. MS-ESI: 301 (M+1).


Step 4: 1-(2-(Benzyloxy)ethyl)-1H-pyrazole-3-sulfonamide

A solution of 1-(2-(benzyloxy)ethyl)-1H-pyrazole-3-sulfonyl chloride (crude from last step, 12.8 g) in MeOH/NH3 (7 M, 300 mL) in a 500-mL round-bottom flask was stirred for 16 h at RT. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (20:1). This resulted in 5.4 g (42%, over two steps) of the title compound as brown yellow oil. MS-ESI: 282 (M+1).


Step 5: 1-(2-Hydroxyethyl)-1H-pyrazole-3-sulfonamide

To a stirred solution of 1-(2-(benzyloxy)ethyl)-1H-pyrazole-3-sulfonamide (5.4 g, 19.2 mmol) in MeCN (100 mL) in a 250-mL round-bottom flask under nitrogen was added KI (6.37 g, 38 mmol) in portions at RT. To the stirred solution was added BF3.Et2O (47% wt., 13 g, 192 mmol) dropwise at RT. The resulting solution was stirred for 4 h at RT. The reaction was then quenched by the addition of 5.0 mL of water. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (15:1). This resulted in 4.6 g (93%) of the title compound as a yellow solid. MS-ESI: 192 (M+1).


Step 6: N-(tert-butyldimethylsilyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-sulfonamide

To a stirred solution of 1-(2-hydroxyethyl)-1H-pyrazole-3-sulfonamide (4.1 g, 21 mmol) in THF (60 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 3.86 g, 96.5 mmol) at 0° C. in a water/ice bath. The resulting mixture was stirred for 20 min at RT. To the stirred mixture was added TBSCl (13.6 g, 90 mmol) at 0° C. The resulting mixture was stirred for 5 h at RT. The reaction was then quenched by the addition of 300 mL of water. The resulting mixture was extracted with 3×150 mL of EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 6.2 g (69%) of the title compound as an off-white solid. MS-ESI: 420 (M+1).


Step 7: N′-(tert-butyldimethylsilyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazole-3-sulfonimidamide

To a stirred solution of PPH3Cl2 (1.51 g, 3.57 mmol) in CHCl3 (15 ml) in a 50-mL 3-necked round-bottom flask under nitrogen was added DIEA (924 mg, 7.15 mmol) dropwise at 0° C. The resulting solution was stirred for 20 min at 0° C. To the stirred solution was added N-(tert-butyldimethylsilyl)-1-(2-((tert-butyldimethyl silyl)oxy)ethyl)-1H-pyrazole-3 -sulfonamide (600 mg, 1.43 mmol) in CHCl3 (5.0 ml) dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. NH3(g) was bubbled into the reaction solution for 15 min at 0° C. Then the solution was stirred for another 2 h at RT. The reaction was then quenched by the addition of 20 mL of H2O. The resulting solution was extracted with 3×20 mL of DCM. The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE(1:3). This resulted in 320 mg (53%) of the title compound as a yellow solid. MS-ESI: 419 (M+1).




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Intermediate 196



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N′-(tert-butyldimethylsilyl)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazole-3-sulfonimidamide
Step 1: Methyl 1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-pyrazole-5-carboxylate

To a stirred solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (5.0 g, 29 mmol) in MeCN (50 mL) in a 250-mL round-bottom flask was added Cs2CO3 (19 g, 58 mmol) at RT. To the stirred solution was added ethyl 2-bromoacetate (5.36 g, 35 mmol) dropwise at RT. The resulting solution was stirred for 0.5 h at 50° C. The mixture was diluted with 100 mL of H2O. The resulting solution was extracted with 3×50 mL of EtOAc. The combined organic layer was dried with anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 3.8 g (50%) of the title compound as yellow oil. MS-ESI: 258 (M+1).


Step 2: Methyl 3-amino-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-5-carboxylate

To a stirred solution of methyl 1-(2-ethoxy-2-oxoethyl)-3-nitro-1H-pyrazole-5-carboxylate (1.4 g, 5.43 mmol) in MeOH (30 mL) in a 250 round-bottom flask was added Pd/C (10% wt., 300 mg) under nitrogen in portions. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred overnight at RT under hydrogen with a balloon. The solid was filtered out. The resulting solution was concentrated under vacuum. This resulted in 1.18 g (95%) of the title compound as a white solid. MS-ESI: 228 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 6.94 (br s, 2H), 6.29 (s, 1H), 5.11 (s, 2H), 4.14 (q, J=7.1 Hz, 2H), 3.79 (s, 3H), 1.19 (t, J=7.1 Hz, 3H). The structure of compound 446 was confirmed by NOESY.


Step 3: Methyl 3-(chlorosulfonyl)-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-5-carboxylate

To a stirred solution of methyl 3-amino-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-5-carboxylate (1.18 g, 5.17 mmol) in HCl (6 M, 30 mL) in a 100 mL 3-necked round-bottom flask was added NaNO2 (1.07 g, 15.5 mmol) in H2O (1.0 mL) dropwise at −10° C. The resulting mixture was stirred for 1 h at −10° C., this solution was assigned as solution A. Then CuCl2(348 mg, 2.59 mmol) was added to a 250-mL single necked round-bottom flask with AcOH (30 mL) as the solvent, SO2 (g) was bubbled to the solution with stirring at RT for 20 min, this solution was assigned as solution B. To the solution B was added solution A dropwise with stirring at −10° C. The resulting solution was stirred for additional 1 h at 0° C. The resulting mixture was extracted with DCM (3×30 mL). The combined organic layers were washed with water (3×30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. This resulted in 1.7 g (crude) of the title compound as a yellow solid.


Step 4: Methyl 1-(2-ethoxy-2-oxoethyl)-3-sulfamoyl-1H-pyrazole-5-carboxylate

To the solution of methyl 3-(chlorosulfonyl)-1-(2-ethoxy-2-oxoethyl)-1H-pyrazole-5-carboxylate (1.7 g, crude) in DCM (50 mL) in a 250 mL round-bottom flask was introduced NH3 (g) bubbled for 15 min at 0° C. The reaction was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (3:1). This resulted in 1.33 g (88%) of the title compound as a yellow solid. MS-ESI: 290 (M−1).


Step 5: 1-(2-Hydroxyethyl)-5-(hydroxymethyl)-1H-pyrazole-3-sulfonamide

To a stirred solution of methyl 1-(2-ethoxy-2-oxoethyl)-3-sulfamoyl-1H-pyrazole-5-carboxylate (1.33 g, 4.55 mmol) in EtOH (30 mL) in a 100 mL round-bottom flask was added NaBH4 (865 mg, 22.8 mmol) in portions at 0° C. The mixture was stirred overnight at RT. The reaction was quenched by the addition of sat. NH4Cl (aq.) (20 mL) at 0° C. The EtOH solvent was removed under vacuum. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with H2O (3×20 mL) and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (3:1). This resulted in 889 mg (88%) of the title compound as a light yellow solid. MS-ESI: 222 (M+1).


Steps 6-7 used similar procedures for converting compound 442 to Intermediate 195 shown in Scheme 91 to afford Intermediate 196 from compound 449. MS-ESI: 564 (M+1).




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Intermediate 197



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N-(tert-butyldimethylsilyl)-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonimidamide
Step 1: 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a stirred solution of 4-fluoro-1H-pyrazole (5.0 g, 58 mmol) in DMF (53 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 5.36 g, 134 mmol) in portions at 0° C. in an ice/water bath over 10 min. The resulting solution was stirred for 30 min at 10° C. To this was added SEM-Cl (22 g, 134 mmol) dropwise with stirring at 0° C. over 10 min. The resulting solution was stirred overnight at RT. The reaction was then quenched with 60 mL of water. The resulting solution was extracted with 60 mL of EtOAc. The combined organic layer was washed with 5×60 ml of sat. NaCl solution. The resulting mixture was concentrated. The residue was eluted from silica gel column EtOAc/PE (1:100). This resulted in 13.7 g (crude) of the title compound as a light yellow liquid. MS-ESI: 217 (M+1).


Step 2: Lithium 4-fluoro-1-((2-(trimethylsilyHethoxy)methyl)-1H-pyrazole-5-sulfinate

To a stirred solution of 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (13.7 g, 63 mmol) in THF (150 mL) in a 500-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 28 mL, 70 mmol) dropwise at −78° C. in a liquid nitrogen/EtOH over 15 min. The resulting solution was stirred for 1 h at −78° C. Then to the mixture was introduced SO2 (g) bubble for 20 min −78° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated. This resulted in 20.4 g (crude) of the title compound as a white solid.


Step 3: 4-Fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfonyl chloride

To a stirred solution of lithium 4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfinate (20.4 g, crude) in DCM (396 mL) and H2O (198 mL) in a 1-L 3-necked round-bottom flask was added NCS (10 g, 78 mmol) in portions at 0° C. The resulting solution was stirred for 1 h at 10° C. The crude product was used directly without work-up.


Step 4: N,N-dibenzyl-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfonamide

To the stirred solution of 4-fluoro-1-((2-(trimethyl silyl)ethoxy)methyl)-1H-pyrazole-5-sulfonyl chloride in DCM (396 mL) and H2O (198 mL) from last step was added Et3N (8.85 g, 87 mmol) and dibenzylamine (17 g, 84 mmol) dropwise at 0° C. The resulting solution was stirred for 1 h at 8° C. The reaction was then quenched by the addition of 300 mL of water. The resulting solution was extracted with 3×300 mL of DCM. The organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:19). This resulted in 22.5 g (81% over four steps) of the title compound as light yellow oil. MS-ESI: 476 (M+1).


Step 5: N,N-dibenzyl-4-fluoro-1-(hydroxymethyl)-1H-pyrazole-5-sulfonamide

To a stirred solution of N,N-dibenzyl-4-fluoro-1-((2-(trimethyl silyl)ethoxy)methyl)-1H-pyrazole-5-sulfonamide (22.5 g, 47 mmol) in DCM (25 mL) in a 250-mL round-bottom flask was added TFA (25 mL). The resulting solution was stirred overnight at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 15 g (85%) of the title compound as yellow oil. MS-ESI: 376 (M+1).


Step 6: N,N-dibenzyl-4-fluoro-1H-pyrazole-5-sulfonamide

To a stirred solution of N,N-dibenzyl-4-fluoro-1-(hydroxymethyl)-1H-pyrazole-5 -sulfonamide (15 g, 40 mmol) in dioxane (50 mL) in a 500-mL round-bottom flask was added NH3.H2O (30% wt., 50 mL) dropwise at 0° C. in an ice/water bath. The resulting solution was stirred for 3 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 12 g (87%) of the title compound as a white solid. MS-ESI: 346 (M+1).


Step 7: N,N-dibenzyl-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonamide and N,N-dibenzyl-1-ethyl-4-fluoro-1H-pyrazole-5-sulfonamide

To a stirred solution of N,N-dibenzyl-4-fluoro-1H-pyrazole-5-sulfonamide (1.1 g, 3.2 mmol) in DMF (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added K2CO3 (0.88 g, 6.4 mmol) in portions at RT and ethyl iodide (0.99 g, 6.4 mmol) dropwise at RT. The resulting solution was stirred for 3 h at 110° C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 mL of EtOAc. The organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (3:17). This resulted in 764 mg (64%) of 458A and 218 mg (18%) of 458B both as a light yellow solid. MS-ESI: 374 (M+1).


Step 8: 1-Ethyl-4-fluoro-1H-pyrazole-3-sulfonamide

To a stirred solution of N,N-dibenzyl-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonamide (764 mg, 2.0 mmol) in DCM (1.5 mL) in a 25-mL round-bottom flask was added H2SO4 (98% wt., 3.00 mL) dropwise at 0° C. in an ice/water bath. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 5.0 mL of water/ice. The mixture was extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with DCM/MeOH(93:7). This resulted in 317 mg (80%) of the title compound as a white solid. MS-ESI: 194 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 8.08 (d, J=4.7 Hz, 1H), 7.77 (s, 2H), 4.14 (q, J=7.3 Hz, 2H), 1.39 (t, J=7.3 Hz, 3H). The structure of compound 459 was confirmed by NOESY.


Steps 9-10 used similar procedures for converting compound 442 to Intermediate 195 shown in Scheme 91 to afford Intermediate 197 from compound 459. MS-ESI: 307 (M+1)









TABLE 44







The Intermediates in the following table were prepared using the similar procedures for


converting compound 451 to Intermediate 197 shown in Scheme 93.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 198


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N-(tert-butyldimethylsilyl)-1- (difluoromethyl)-4-fluoro-1H-pyrazole-3- sulfonimidamide
329











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Intermediate 199F



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N′-(tert-butyldimethylsilyl)-4-((S)-1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide
Step 1: 4-(Prop-1-en-2-yl)thiophene-2-sulfonamide

To a stirred solution of 4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (50 g, 226 mmol) in CF3SO3H (60 mL) in a 500 mL round-bottom flask was added TFA (60 mL) dropwise at RT. The resulting solution was stirred for 16 h at 50° C. in an oil bath. The reaction mixture was concentrated under reduced pressure. The pH value of the residue was adjusted to 8 with aq. NaOH (3% wt.). The resulting solution was extracted with 3×300 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 10 g (22%) of the title compound as an off-white solid. MS-ESI: 202 (M−1).


Step 2: 4-(1,2-Dihydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of 4-(prop-1-en-2-yl)thiophene-2-sulfonamide (10 g, 49 mmol) in t-BuOH (40 mL) and acetone (40 mL) in a 250-mL round-bottom flask was added NMO (11.5 g, 98 mmol) and the resulting solution was stirred for 15 min at RT. Then to this was added a solution of OSO4 (1.24 g, 4.9 mmol) in H2O (60 mL) dropwise at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of saturated aq. Na2S2O3 (50 mL). The resulting solution was extracted with 3×200 mL EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was eluted from silica gel with MeOH/DCM (7:100). This resulted in 5.0 g (43%) of the title compound as yellow oil. MS-ESI: 236 (M−1)


Step 3: (S) and (R) 4-(1,2-Dihydroxypropan-2-yl)thiophene-2-sulfonamide

The product from the Step above (462, 5.0 g) was resolved by prep-chiral HPLC using the following conditions: CHIRALPAK IG, 5*25 cm, 5 um; Mobile Phase A: CO2, Mobile Phase B: MeOH:ACN=1:1 (2 mM NH3-MeOH); Flow rate:150 mL/min; Gradient: 50% B; UV 220 nm; Rt1: 4.1 min (462F); Rt2: 7.4 min (462S). This resulted in 2.1 g (99% ee) of 462F and 2.2 g (98% ee) of 462S, both as white solids. MS-ESI: 236 (M−1).


Step 4: (S)-4-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of (S)-4-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide (2.1 g, 8.8 mmol) in THF (50 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 704 mg, 17.6 mmol) at 0° C. in a water/ice bath. The resulting solution was stirred for 20 min at RT. To the stirred solution was added TBSCl (2.64 g, 17.6 mmol) at 0° C. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 2.17 g (70%) of the title compound as an off-white solid. MS-ESI: 352 (M+1).


Steps 5-7 used similar procedures for converting compound 442 to Intermediate 195 shown in Scheme 91 to afford Intermediate 199F from compound 463F. MS-ESI: 465 (M+1).









TABLE 45







The Intermediates in the following Table were prepared using the similar procedures


for converting compound 462F to Intermediate 199F shown in Scheme 94 using 462S.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 199S


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N′-(tert-butyldimethylsilyl)-4-((R)-1-((tert- butyldimethylsilyl)oxy)-2-hydroxypropan- 2-yl)thiophene-2-sulfonimidamide
465











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Intermediate 200F



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5-((S)-1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)-N′-(tert-butyldimethylsilyl)thiophene-2-sulfonimidamide
Step 1: Methyl 5-(chlorosulfonyl)thiophene-2-carboxylate

To a stirred solution of methyl thiophene-2-carboxylate (2.13 g, 15 mmol) in CHCl3 (100 mL) in a 250-mL round-bottom flask was added ClSO3H (3.5 g, 30 mmol) dropwise at 0° C. in an ice/water bath. The resulting solution was stirred for 1 h at 0° C. This was followed by addition of PCl5 (6.25 g, 30 mmol) in portions at 0° C. The resulting solution was stirred overnight at 50° C. The reaction was quenched by the addition of ice/water (100 mL). The mixture was extracted with DCM (3×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 4.0 g (crude) of the title compound as yellow oil. MS-ESI: 241/243 (M+1)


Step 2: Methyl 5-sulfamoylthiophene-2-carboxylate

To a stirred solution of methyl 5-(chlorosulfonyl)thiophene-2-carboxylate (4.0 g, crude) in DCM (20 mL) in a 250-mL round-bottom flask was bubbled NH3 at 0° C. for 15 min. The resulting solution was stirred overnight at RT. The resulting mixture was washed with H2O (3×100 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 1.99 g (60%, over two steps) of the title compound as a yellow solid. MS-ESI: 222 (M+1).


Step 3: 5-(2-Hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of methyl 5-sulfamoylthiophene-2-carboxylate (1.0 g, 4.52 mmol) in THF (40 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added CH3MgBr in THF (3.0 M, 7.5 mL, 22.6 mmol) dropwise at 0° C. in an ice/water bath. The resulting solution was stirred overnight at RT. The reaction solution was then quenched by adding sat. NH4Cl (40 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×40 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 500 mg (50%) of the title compound as a yellow solid. MS-ESI: 222 (M+1).


Step 4: 5-(Prop-1-en-2-yl)thiophene-2-sulfonamide

To a stirred solution of 5-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (500 mg, 2.25 mmol) in THF(30 mL) in a 100-mL round-bottom flask under nitrogen was added Burgess reagent (1.15 g, 4.5 mmol) in portions at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was quenched by addition of H2O (10 mL) and extracted with EtOAc (3×20 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-TLC (PE/EtOAc=1:2). This resulted in 420 mg (91.5%) of the title compound as a white solid. MS-ESI: 204 (M+1).


Step 5: 5-(1,2-Dihydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of 5-(prop-1-en-2-yl)thiophene-2-sulfonamide (420 mg, 2.06 mmol) in t-BuOH (4.0 mL) and acetone (4.0 mL) in a 50-mL round-bottom flask was added NMO (483 mg, 4.12 mmol) and the resulting solution was stirred for 15 min at RT. Then to this was added a solution of OsO4 (53 mg, 0.21 mmol) in H2O (3.0 mL) dropwise at RT. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of saturated aq. Na2S2O3 (5.0 mL). The resulting solution was extracted with 3×10 mL EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was eluted from silica gel with MeOH/DCM (7:100). This resulted in 245 mg (50%) of the title compound as yellow oil. MS-ESI: 238 (M+1).


Step 6: (S) and (R)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide

The product from Step 5 above (471, 245 mg) was resolved by prep-chiral HPLC using the following conditions: CHIRALPAK AD-H SFC, 5*25 cm, 5 um; Mobile Phase A: CO2, Mobile Phase B: MeOH:ACN=1:1(2 mM NH3-MeOH); Flow rate:150 mL/min; Gradient: 50% B; 220 nm; Rt1: 4.1 min (471F); Rt2: 7.4 min (471S). This resulted in 100 mg (99% ee) of 471F and 110 mg (98% ee) of 471S, both as yellow oil. MS-ESI: 236 (M−1).


Step 7: (S)-2-hydroxy-2-(5-sulfamoylthiophen-2-yl)propyl 4-methylbenzenesulfonate

To a stirred solution of (S)-5-(1,2-dihydroxypropan-2-yl)thiophene-2-sulfonamide (100 mg, 0.42 mmol) in pyridine (8.0 mL) in a 50-mL round-bottom flask was added TsCl (239 mg, 1.26 mmol). The resulting solution was stirred for 16 h at RT. The resulting solution was diluted with 20 mL of H2O. The resulting solution was extracted with 3×20 mL of EtOAc and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 125 mg (76%) of the title compound as yellow oil. MS-ESI: 392 (M+1).


Step 8: (S)-5-(1-(2-(benzyloxy)ethoxy)-2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of 2-(benzyloxy)ethan-1-ol (243 mg, 1.6 mmol) in THF(10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 128 mg, 3.2 mmol) at 0° C. in an ice/water bath. The resulting mixture was stirred for 30 min at 0° C. To the above mixture was added (S)-2-hydroxy-2-(5-sulfamoylthiophen-2-yl)propyl 4-methylbenzenesulfonate (125 mg, 0.32 mmol) at 0° C. The resulting mixture was stirred for 32 h at 35° C. The reaction was quenched with H2O (10 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with PE/EtOAc (1:2). This resulted in 113 mg (95%) as yellow oil. MS-ESI: 372 (M+1).


Steps 9-11 used similar procedures for converting compound 442 to Intermediate 195 shown in Scheme 91 to afford Intermediate 200F from compound 473F. MS-ESI: 485 (M+1).




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Intermediate 201



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N′-(tert-butyldimethylsilyl)-2-((S)-16-hydroxy-1-phenyl-2,5,8,11,14-pentaoxaheptadecan-16-yl)thiazole-5-sulfonimidamide

Steps 1-6 used similar procedures for converting compound 471F to Intermediate 200F shown in Scheme 95 to afford Intermediate 201 from compound 289A. MS-ESI: 618 (M+1)




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Intermediate 202



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4-Acetyl-N′-(tert-butyldimethylsilyl)thiophene-2-sulfonimidamide
Step 1: Methyl 5-(N-(tert-butyldimethylsilyl)sulfamoyl)thiophene-3-carboxylate

To a stirred solution of methyl 5-sulfamoylthiophene-3-carboxylate (10 g, 45 mmol) in THF (120 mL) in a 250-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 5.42 g, 135 mmol) in portions at 0° C. in an ice/water bath. To the stirred solution was added TBSCl (8.17 g, 54 mmol). The resulting solution was stirred overnight at RT. The reaction was quenched by the addition of 100 mL of water. The resulting solution was extracted with 2×200 mL of EtOAc and dried over anhydrous Na2SO4 and concentrated. The resulting mixture was washed with 3 ×100 ml of PE. This resulted in 9.9 g (65%) of the title compound as an off-white solid. MS-ESI: 336 (M+1).


Step 2: 5-(N-(tert-butyldimethylsilyl)sulfamoyl)thiophene-3-carboxylic acid

To a stirred solution of methyl 5 -(N-(tert-butyl dimethyl silyl)sulfamoyl)thiophene-3-carboxylate (5.0 g, 14.9 mmol) in MeOH (100 mL) and H2O (5.0 mL) in a 250-mL round-bottom flask was added NaOH (1.19 g, 30 mmol) in portions at 0° C. in an ice/water bath. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 100 mL of H2O. The pH value was adjusted to 3 with HCl (6 M). The resulting solution was extracted with 2×150 mL of EtOAc and dried over anhydrous Na2SO4 and concentrated. This resulted in 4.7 g (98%) of the title compound as a yellow solid. MS-ESI: 322 (M+1).


Step 3: N-methoxy-N-methyl-5-sulfamoylthiophene-3-carboxamide

To a stirred solution of 5-(N-(tert-butyldimethylsilyl)sulfamoyl)thiophene-3-carboxylic acid (4.7 g, 14.6 mmol) in THF (125 mL) in a 250-mL round-bottom flask was added N,O-dimethylhydroxylamine (1.34 g, 22 mmol), DIEA (5.65 g, 43.8 mmol) and HATU (11.1 g, 29.2 mmol) at RT. The resulting solution was stirred overnight at RT. The reaction solution was diluted with H2O (100 mL). The mixture was extracted with EtOAc (3×100 mL). The organic layer was dried with anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 1.65 g (45%) of the title compound as a light yellow solid. MS-ESI: 251 (M+1).


Step 4: 4-Acetyl-N-(tert-butyldimethylsilyl)thiophene-2-sulfonamide

To a stirred solution of N-methoxy-N-methyl-5-sulfamoylthiophene-3-carboxamide (1.65 g, 6.57 mmol) in THF (60 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added MeMgBr in THF (3 M, 8.76 mL, 26.3 mmol) dropwise at 0° C. in an ice/water bath. The resulting solution was stirred for 2 h at 40° C. in an oil bath. The reaction was then quenched by the addition of 50 mL of ice/salt. The resulting solution was extracted with 3×100 mL of EtOAc and dried over anhydrous Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:5). This resulted in 1.93 g (92%) of the title compound as a light yellow solid. MS-ESI: 320 (M+1).


Steps 5-6 used similar procedures for converting compound 442 to Intermediate 195 shown in Scheme 91 to afford Intermediate 202 from compound 483. MS-ESI: 319 (M+1).




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Intermediate 203



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N′-(tert-butyldimethylsilyl)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide
Step 1: 5-(4-(((Tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,2-dimethyl-1,3-dioxan-5-ol

To a stirred solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (1.40 g, 4.55 mmol) in THF (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 1.8 mL, 4.55 mmol) dropwise at −78° C. in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 30 min at −78° C. Then to the mixture was added 2,2-dimethyl-1,3-dioxan-5-one (621 mg, 4.78 mmol) in portions at −78° C. The resulting mixture was stirred for 1 h at −78° C. The reaction was quenched by the addition of H2O (20 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-TLC (PE/EtOAc 10:1). This resulted in 1.1 g (67%) of the title compound as brown oil. MS-ESI: 360 (M+1).


Step 2: 4-0(Tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfinic acid


To a stirred solution of 5-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)-2,2-dimethyl-1,3-dioxan-5-ol (1.1 g, 3.06 mmol) in THF (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 2.7 mL, 6.73 mmol) dropwise at −78° C. in a liquid nitrogen/EtOH bath. The reaction solution was stirred for 30 min at −78° C. Then SO2 (g) was bubbled to the solution at −50° C. for 20 min. The resulting solution was allowed to react, with stirring, for an additional 2 h at RT. The resulting mixture was concentrated directly under vacuum. This resulted in 1.5 g (crude) of the title compound as a yellow solid. MS-ESI: 422 (M−1).


Step 3: 4-(((Tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5- sulfonyl chloride

To a stirred solution of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl) thiazole-5-sulfinic acid (1.5 g, crude) in THF (20 mL) in a 100-mL round-bottom flask was added NCS (610 mg, 4.59 mmol) in portions at 0° C. The resulting mixture was stirred for 2 h at 0° C. To the reaction solution was added NH3 in THF (0.5 M, 50 mL) in portions at 0° C. The resulting mixture was stirred for 2 h at 0° C. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (PE/EtOAc=7:1). This resulted in 685 mg (51%, over two steps) of the title compound as a brown solid. MS-ESI: 437 (M−1).


Steps 4-6 used similar procedures for converting compound 442 to Intermediate 195 shown in Scheme 91 to afford Intermediate 203 from compound 487. MS-ESI: 552 (M+1).




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Intermediate 190A



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N′-(tert-butyldimethylsilyl)-3-ethylthiophene-2-sulfonimidamide

Steps 1-2 used similar procedures for converting compound 485 to compound 487 shown in Scheme 98 to afford compound 407A from compound 405.


Step 3: 3-Ethylthiophene-2-sulfonamide and 4-Ethylthiophene-2-sulfonamide

To the mixture of 3-ethylthiophene-2-sulfonyl chloride and 4-ethylthiophene-2-sulfonyl chloride from last step in DCM (200 mL) was bubbled NH3 at 0° C. for 15 min. The solution was washed with brine (2×100 mL), dried over Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:20). This resulted in 5.0 g (29%) of 408A and 5.1 g (30%) of 408 both as a light yellow solid. MS-ESI: 190 (M−1).


Steps 4-6 used similar procedures for converting compound 442 to Intermediate 195 shown in Scheme 91 to afford Intermediate 190A from compound 408A. MS-ESI: 305 (M+1).




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Intermediate 204



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Step 1: 1-((Tert-butyldimethylsilyl)oxy)-2-(4-(((tert-butyldimethylsilyl)oxy)methyl)thiazol-2-yl)propan -2-ol

To a stirred solution of 2-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)thiazole (3.0 g, 9.7 mmol) in THF (100 mL) in a 250-mL 3-necked round-bottom flask under nitrogen was added n-BuLi in hexane (2.5 M, 4.0 mL, 9.7 mmol) dropwise at −78° C. in a liquid nitrogen/EtOH bath. The resulting solution was stirred for 30 min at −78° C. To the mixture was added 1-((tert-butyldimethylsilyl)oxy)propan-2-one (1.83 g, 9.7 mmol) at −78° C. in 10 min. The resulting solution was stirred for 12 h at RT. The reaction was then quenched by the addition of 10 mL of H2O (100 mL). The resulting mixture was extracted with 3×200 mL of DCM and the organic layers were combined and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:10). This resulted in 2.5 g (62%) of the title compound as yellow oil. MS-ESI: 418 (M+1).


Steps 2-7 used similar procedures for converting compound 485 to Intermediate 203 shown in Scheme 98 to afford Intermediate 204 from compound 490. MS-ESI: 610 (M+1).


Step 8: (S) and (R)-2-(1-((tert-butyldimethylsilyl)oxy)-2-hydroxypropan-2-yl)-4-(((tert-butyldimethylsilyl)oxy) methyl)thiazole-5-sulfonamide

The product from the Step above (493, 2.4 g) was resolved by prep-chiral-HPLC using the following conditions: CHIRALPAK AD-H SFC, 5*25 cm, 5 um; Mobile Phase A: CO2, Mobile Phase B: MeOH (2 mM NH3); Flow rate: 200 mL/min; Gradient: 50% B; UV 220 nm; Rt1: 4.3 min (493A); Rt2: 6.9 min (493B); This resulted in 1.1 g of 493A (99% ee) and 1.0 g of 493B (99% ee). MS-ESI: 495 (M−1)









TABLE 46







The Intermediates in the following Table were prepared using the similar procedures


for converting compound 493 to Intermediate 204 shown in Scheme 99 using 493A and 493B.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 204A


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(R) or (S) N′-(tert-butyldimethylsilyl)- 2-(1-((tert-butyldimethylsilypoxy)-2- hydroxypropan-2-yl)-4-(((tert- butyldimethylsilyl)oxy)methyl) thiazole-5-sulfonimidamide
610





Intermediate 204B


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(S) or (R) N′-(tert-butyldimethylsilyl)- 2-(1-((tert-butyldimethylsilypoxy)-2- hydroxypropan-2-yl)-4-(((tert- butyldimethylsilyl)oxy) methyl)thiazole- 5-sulfonimidamide
610











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Intermediate 205



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N′-(tert-butyldimethylsilyl)-2-ethylthiazole-5-sulfonimidamide
Step 1: 2-Ethylthiazole-5-sulfonamide

To a stirred solution of 2-acetylthiazole-5-sulfonamide (1.0 g, 4.8 mmol) in ethylene glycol (20 mL) in a 50 mL round-bottom flask was added NH2NH21120 (1.2 g, 24 mmol) dropwise at RT. The resulting mixture was stirred for 2 h at 150° C. under nitrogen. The mixture was allowed to cool down to RT. To the above mixture was added KOH (544 mg, 9.6 mmol) at RT. The resulting mixture was stirred for additional 1.5 h at 150° C. The residue was eluted from silica gel column with DCM/MeOH (15:1). This resulted in 430 mg (46%) of the title compound as a yellow solid. MS-ESI: 191 (M−1).


Steps 2-4 used similar procedures for converting compound 442 to Intermediate 195 shown in Scheme 91 to afford Intermediate 205 from compound 496. MS-ESI: 306 (M+1).




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Intermediate 206



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(6R)-N′-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide
Step 1: 1,2-Dihydropyrazol-5-one

To a 5 L 4-neck flask containing a solution of methyl (E)-3-methoxyacrylate (2000 g, 17.2 mol) in MeOH (2.0 L) was added hydrazine hydrate (921 g, 18.4 mol) dropwise at RT under nitrogen. The resulting mixture was stirred for 90 min at 60° C. under nitrogen. The resulting mixture was concentrated under reduced pressure. This resulted in the title compound (1467 g, 68% wt, yield 69%) as an off-white solid. MS-ESI: 85 (M+1).


Step 2: 2-Acetyl-1,2-dihydropyrazol-5-one

To a 10 L 4-neck flask containing a solution of 1,2-dihydropyrazol-5-one (1467 g, 68% wt, 11.9 mol) in pyridine (6.0 L) was added Ac2O (1214 g, 11.9 mol) at RT under nitrogen. The resulting mixture was stirred for 1.5 h at 95° C. under nitrogen. The resulting mixture was concentrated under reduced pressure. The residue was slurry with MeOH (1×3000 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (1×500 mL). The filter cake was dried under reduced pressure. This resulted in the title compound (1630 g, 78% wt, 85%) as an off-white solid. MS-ESI: 127 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J=3.0 Hz, 1H), 6.00 (d, J=3.0 Hz, 1H), 2.48 (s, 3H), 2.44 (s, 1H).


Step 3: (R)-2-acetyl-1-(oxiran-2-ylmethyl)-1,2-dihydropyrazol-5-one

To a 10 L 4-neck flask containing a solution of 2-acetyl-1,2-dihydropyrazol-5-one (400 g, 78% wt, 3.17 mol) and R-glycidol (246 g, 3.33 mol) in THF (4.0 L), to the stirred solution was added PPh3 (915 g, 3.49 mol). To the above mixture was added TMAD (705 g, 3488 mmol) in portions at 0° C. The resulting mixture was stirred for additional 1 h at RT. The resulting mixture was quenched with 1×4.0 L of water. The aqueous layer was extracted with EtOAc (3×1.0 L). The organic layers were combined and washes with brine (1 L), dried over Na2SO4 and concentrated under reduced pressure. The crude was slurry in PE/EtOAc (10:1) (16 L) for 4 h. The resulting mixture was filtered. The filter cake was washed with PE/EtOAc (10:1) (1×1000 mL). The filtrate was concentrated under reduced pressure. This resulted in the title compound (470 g, 84% wt, 87%) as an off-white solid. MS-ESI: 183 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.27 (d, J=3.0 Hz, 1H), 6.27 (d, J=3.0 Hz, 1H), 4.56 (dd, J=11.8, 2.7 Hz, 1H), 4.02 (dd, J=11.8, 6.8 Hz, 1H), 3.40-3.34 (m, 1H), 2.86 (dd, J=5.1, 4.3 Hz, 1H), 2.74 (dd, J=5.1, 2.6 Hz, 1H), 2.54 (s, 3H).


Step 4: (R)-2-acetyl-1-(3-chloro-2-hydroxypropyl)-1,2-dihydropyrazol-5-one

To a 10 L 3-neck flask was placed a solution of (R)-2-acetyl-1-(oxiran-2-ylmethyl)-1,2-dihydropyrazol-5-one (500 g, 84% wt, 2.74 mol) in THF (2.5 L), to the stirred solution was added AcOH (494 g, 8233 mmol) dropwise and LiCl (186 g, 4391 mmol) in portions at 0° C. under nitrogen. The resulting mixture was stirred for 16 h at RT under nitrogen. The reaction was quenched with water at RT. The aqueous layer was extracted with EtOAc (3×3.0 L). The organic layers were combined and washed with 2×3.0 L of sat. NaHCO3 and 5.0 L of brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. This resulted in the title compound (552 g, 82% wt, yield 90%) as an off-white solid. MS-ESI: 219 (M+1). 1H NMR (400 MHz, CDCl3) δ 8.10 (d, J=3.0 Hz, 1H), 6.02 (d, J=3.0 Hz, 1H), 4.44 (d, J=5.0 Hz, 2H), 4.29-4.23 (m, 1H), 3.81-3.67 (m, 2H), 2.61 (s, 3H).


Step 5: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol

To a 10 L 3-neck flask was placed a solution of (R)-2-acetyl-1-(3-chloro-2-hydroxypropyl)-1,2-dihydropyrazol-5-one (500 g, 82% wt, 2.29 mol) in DMF (5.0 L), to the stirred solution was added K2CO3 (948 g, 6.86 mol) under nitrogen. The resulting mixture was stirred for 16 h at 135° C. under nitrogen and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford (152 g, yield 58%) of the title compound as an off-white solid. MS-ESI: 141 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 7.11 (d, J=2.1 Hz, 1H), 5.31 (d, J=2.1 Hz, 1H), 4.19-4.12 (m, 1H), 4.12-3.98 (m, 3H), 3.90-3.81 (m, 1H).


Step 6: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl acetate

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (55.0 g, 392 mmol) in MeCN (825 mL) in a 2-L 3-necked round-bottom flask under nitrogen was added pyridine (93.1 g, 1.18 mol) and DMAP (4.79 g, 39.2 mmol). This was followed by the addition of acetyl chloride (43.1 g, 549 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. LCMS showed reaction was completed. The resulting mixture was concentrated directly. The residue was eluted from silica gel with EtOAc/PE (1:4). This resulted in 58 g (81%) of the title compound as a light yellow solid. MS-ESI: 183 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.39 (d, J=2.0 Hz, 1H), 5.57 (d, J=2.0 Hz, 1H), 5.45-5.36 (m, 1H), 4.49-4.41 (m, 1H), 4.40-4.27 (m, 2H), 4.24 (dd, J=12.1, 1.5 Hz, 1H), 2.14 (s, 3H).


Step 7: (R)-6-acetoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl acetate (58.0 g, 318 mmol) in DCM (120 mL) in a 2-L 3-necked round-bottom flask under nitrogen was added chlorosulfonic acid (81.3 g, 700 mmol) dropwise at 0° C. The resulting solution was stirred for 12 h at RT. LCMS showed the conversion was completed. The reaction mixture was used directly in the next step. MS-ESI: 263 (M+1).


Step 8: (R)-3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl acetate


To a stirred solution of (R)-6-acetoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonic acid in DCM (crude from step 7) in a 2-L 3-necked round-bottom flask under nitrogen was added pyridine (55.1 g, 696 mmol) dropwise at 0° C. To this was added PCl5 (144 g, 696 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 1 L of water/ice. The resulting solution was extracted with 3×300 mL of EtOAc. The resulting mixture was washed with 2 ×500 ml of NaHCO3 and 1 ×500 mL of H2O. The resulting mixture was washed with 1×500 mL of NaCl (aq.). The mixture was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in 76 g (crude) of the title compound as a light yellow solid. MS-ESI: 281/283 (M+1).


Step 9: (R)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

To a stirred solution of NH3 in THF (1 M, 730 ml) in a 3-L round-bottom flask was added (R)-3-(chloro-sulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-6-yl acetate (73.0 g, 260 mmol) in several batches. The flask was then filled with NH3 (balloon). The resulting solution was stirred overnight at 40° C. in an oil bath. After reaction completed, the solids were filtered out. The filtrate was concentrated. The residue was diluted with NH3 (7 M in MeOH, 730 mL). The resulting solution was stirred for 2 h at RT. LC showed the reaction was complete. The MeOH solution was concentrated under reduced pressure to a final volume of about 100 mL. Et2O (360 ml) was charged to the resulting solution and kept stirring for 30 min. The mixture was filtered, and the cake washed with Et2O (100 mL). The white solid was dried under vacuum. This resulted in 37 g (53% for 3 steps) of the title compound as a white solid. MS-ESI: 220 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 7.48 (s, 1H), 7.06 (s, 2H), 5.64 (d, J=2.3 Hz, 1H), 4.30 (s, 3H), 4.30-4.18 (m, 1H), 4.00-3.90 (m, 1H).


Step 10: (R)—N-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide

To a stirred solution of (R)-6-hydroxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonamide (500 mg, 2.28 mmol) in DMF (20 mL) in a 50-mL round-bottom flask was added DBU (2.08 g, 13.7 mmol) and TBDPSCl (5.02 g, 18.2 mmol) at 0° C. The resulting solution was stirred for 2 h at RT and then diluted with 30 mL of H2O. The resulting solution was extracted with 3×100 mL of EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 530 mg (33.3%) of the title compound as a solid. MS-ESI: 696 (M+1).


Step 11: (6R)—N′-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

To a stirred solution of PPH3Cl2 (759 mg, 2.28 mmol) in DCE (30 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added DIEA (492 mg, 3.81 mmol) at 0° C. The resulting solution was stirred for 10 min at RT. Then (R)-N-(tert-butyldiphenylsilyl)-6-((tert-butyldiphenylsilyl)oxy)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3] oxazine-3-sulfonamide (530 mg, 0.76 mmol) in CHCl3 (10 mL) was added at 0° C. The resulting solution was stirred for 30 min at 0° C. Then NH3 (g) was bubbled to the reaction mixture for 15 min at 0° C. The resulting solution was stirred for 2 h at RT. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 400 mg (75.6%) of the title compound as a white solid. MS-ESI: 695 (M+1).




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Intermediate 207



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(6R)-N′-(tert-butyldimethylsilyl)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide
Step 1: (R)-6-methoxy-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (40 g, 285 mmol) in DMF (400 mL) in a 1 L 4-neck round-bottom flask was added NaH (60% oil dispersion, 13.7 g, 342 mmol) in portions at 0° C. The resulting mixture was stirred for 1 h at RT. To the above mixture was added MeI (48.7 g, 343 mmol) dropwise at RT. The resulting mixture was stirred for additional 2 h at RT. The reaction was quenched with AcOH (3.66 g, 57.1 mmol) at 0° C. and concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (1:2) to afford the title compound (34.6 g, 79%) as a light yellow solid. MS-ESI: 155 (M+1).


Steps 2-4 used similar procedures for converting compound 505 to compound 508 shown in Scheme 101 to afford compound 513 from compound 510. MS-ESI: 232 (M−1).


Steps 5-6 used similar procedures for converting compound 442 to intermediate 195 shown in Scheme 91 to afford intermediate 207 from compound 513. MS-ESI: 347 (M+1).




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Intermediate 208



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Tert-butyl ((6R)-3-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate

Steps 1-5 used similar procedures for converting compound 499 to compound 504 shown in Scheme 101 to afford compound 517 from compound 499. MS-ESI: 141 (M+1).


Step 6: (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl methanesulfonate

To a stirred solution of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-ol (40 g, 285 mmol) in pyridine (280 mL) in a 500 mL 3-neck flask under nitrogen was added MSCl (39 g, 343 mmol) dropwise at RT. The resulting mixture was stirred for 30 min at RT. The resulting mixture was concentrated under reduced pressure. The crude was diluted with 500 mL of water. The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with water (3×200 mL) and brine 1×100 mL, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (57 g, 92%) as an off-white solid. MS-ESI: 219 (M+1).


Step 7: (R)-6-azido-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

To a stirred solution of (S)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl methanesulfonate (46 g, 211 mmol) in DMF (313 mL) in a 1 L 3-neck flask under nitrogen was added NaN3 (21 g, 316 mmol) at RT. The resulting mixture was stirred for 6 h at 80° C. LCMS showed reaction was complete. This was used directly in the next step. MS-ESI: 166 (M+1).


Step 8: (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine

To a stirred solution of (R)-6-azido-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine in DMF from the last step was added MeOH (313 mL) followed by Pd/C (10% wt., 10 g) under nitrogen. The mixture was hydrogenated at RT for 5 h under hydrogen atmosphere using a hydrogen balloon. LCMS showed reaction was complete. The mixture was filtered through a pad of Celite and concentrated under reduced pressure to remove low boiling solvent. This resulted in the title compound in DMF solution which was used directly in the next step. MS-ESI: 140 (M+1).


Step 9: Tert-butyl (R)-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

To a stirred solution of (R)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-amine in DMF from the last step was added MeOH (313 mL) followed by TEA (50 g, 496 mmol) and di-tert-butyl dicarbonate (79 g, 364 mmol) at RT under nitrogen. The resulting mixture was stirred for 16 h at RT. The resulting mixture was quenched with 500 mL of water. The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with H2O (2×600 mL) and brine (1×600 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (45.9 g, 91%, for 3 steps) as an off-white solid. MS-ESI: 240 (M+1).


Step 10: Tert-butyl (R)-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

To a stirred solution of tent-butyl (R)-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3] oxazin-6-yl)carbamate (140 g, 585 mmol) in MeCN (2.1 L) in a 3 L 3-neck flask under nitrogen was added NBS (115 g, 644 mmol) at 0° C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was diluted with 2000 mL of water. The resulting mixture was extracted with EtOAc (3×800 mL). The combined organic layers were washed with brine (1×800 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (167 g, 90%) as an off-white solid. MS-ESI: 318/320 (M+1).


Step 11: Tert-butyl (R)-(3-bromo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate

To a stirred solution of tert-butyl(R)-(3-bromo-6,7-dihydro-5H-pyrazolo -[5,1-b][1,3]oxazin-6-yl)carbamate (170 g, 534 mmol) in DMF (1.19 L) in a 3 L 3-neck flask under nitrogen was added sodium hydride (60% oil dispersion, 26 g, 650 mmol) in portions at 0° C. The mixture was stirred for 1 h at 0° C. Then MeI (379 g, 2.67 mol) was added and the mixture was allowed to warm to RT and stirred for 2 h. The reaction mixture was quenched by water and extracted with EtOAc (3*800 mL), the organic layers were washed with H2O (3×500 mL) and brine (1×800 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (8:1) to afford the title compound (153 g, 86%) as an off-white solid. MS-ESI: 332/334 (M+1).


Step 12: Tert-butyl(R)-(3-(benzylthio)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl) carbamate

To a stirred solution of tert-butyl(R)-(3-bromo-6,7-dihydro-5H-pyrazolo-[5,1-b][1,3] oxazin-6-yl)(methyl) carbamate (130 g, 391 mmol) in THF (1.3 L) in a 3 L 3-neck flask under nitrogen was added n-BuLi (188 mL, 470 mmol, 2.5 mol/L) dropwise at −78° C. The resulting mixture was stirred for 1 h at −78° C. To the above mixture was added bis(phenylmethyl) disulfide (145 g, 587 mmol) in THF (300 mL) dropwise at −78° C. The resulting mixture was stirred for additional 2 h at RT. The reaction was quenched by the addition of sat. NH4Cl (aq.) (500 mL) at RT. The resulting mixture was extracted with EtOAc (3×500 mL). The combined organic layers were washed with brine (1×800 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (6:1) to afford the title compound (106 g, 72%) as an off-white solid. MS-ESI: 376 (M+1).


Step 13: Tert-butyl (R)-(3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl) carbamate

To a stirred solution of tert-butyl (R)-(3-(benzylthio)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)- (methyl) carbamate (110 g, 293 mmol) in AcOH (3.67 L)/H2O (1.83 L) in a 10 L 3-neck flask under nitrogen was added NCS (155 g, 1.17 mol) in portions at 0° C. The resulting mixture was stirred for 1 h at RT. The reaction was quenched with water/ice at RT. The resulting mixture was extracted with MTBE (3×1 L). The combined organic layers were washed with water (2×1.0 L), NaHCO3 (2×1.0 L) and brine (1×1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (80 g, crude) as a yellow solid. MS-ESI: 374 (M+Na).


Step 14: Tert-butyl (R)-methyl(3-sulfamoyl-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

To a stirred solution of tert-butyl (R)-(3-(chlorosulfonyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (80 g, 227 mmol) in NH3 in THF (1 M, 800 mL, 800 mmol) in a 2 L 3-neck flask under nitrogen was filled with (balloon). The resulting mixture was stirred overnight at 60° C. The reaction mixture was quenched by adding water and extracted with MTBE (3*800 mL), the organic layers were washed with H2O (3×500 mL) and brine (1×800 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The precipitated solid was slurry with MTBE (1×100 mL). This resulted in the title compound (36 g, for 2 steps) as an off-white solid. MS-ESI: 333 (M+1).


Steps 15-16 used similar procedures for converting compound 442 to intermediate 195 shown in Scheme 91 to afford intermediate 208 from compound 526. MS-ESI: 446 (M+1).




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Intermediate 209



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N′-(tert-butyldimethylsilyl)-6-(2-hydroxypropan-2-yl)pyridine-2-sulfonimidamide
Step 1: Methyl 6-sulfamoylpicolinate

To a stirred solution of 6-bromopyridine-2-sulfonamide (5.0 g, 21 mmol) in MeOH (200 mL) in a 100 mL of pressure tank reactor was added Pd(dppf)Cl2 (1.5 g, 2.1 mmol), Pd(PPh3)4 (2.4 g, 2.1 mmol) and TEA (10.7 g, 105 mmol) under nitrogen. The pressure tank reactor was evacuated and refilled three times with carbon monoxide. The reaction mixture was stirred overnight at 80° C. under carbon monoxide atmosphere (10 atm). The resulting mixture was concentrated under reduced pressure. The residue was eluted from silica gel column with PE/EtOAc (1:2). This resulted 1.8 g (39%) of the title compound as a light yellow solid. MS-ESI: 215 (M−1).


Step 2: 6-(2-Hydroxypropan-2-yl)pyridine-2-sulfonamide

To a stirred solution of methyl 6-sulfamoylpyridine-2-carboxylate (1.8 g, 8.3 mmol) in THF (180 mL) under nitrogen was added MeMgBr (3 M in THF, 28 mL, 83 mmol) dropwise at 0° C. The solution was stirred overnight at RT under nitrogen. The reaction was quenched by adding 50 mL of water, then acidified to pH 6 with conc. HCl. The resulting mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EtOAc (5:1). This resulted in the title compound 0.90 g (50%) as an off-white solid. MS-ESI: 215 (M−1).


Steps 3-4 used similar procedures for converting compound 442 to intermediate 195 shown in Scheme 91 to afford intermediate 209 from compound 530. MS-ESI: 330 (M+1).




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Intermediate 210



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N′-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-ethyl-1H-pyrazole-3-sulfonimidamide
Step 1: Methyl 1-ethyl-3-nitro-1H-pyrazole-5-carboxylate

To a stirred solution of methyl 3-nitro-1H-pyrazole-5-carboxylate (300 mg, 1.75 mmol) in DMF (10 mL) in a 50-mL round-bottom flask were added K2CO3 (485 mg, 3.5 mmol) and bromoethane (382 mg, 3.5 mmol) in portions at RT. The resulting solution was stirred for 4 h at 30° C. The resulting solution was diluted with 10 mL of H2O. The resulting solution was extracted with 4×20 mL of EtOAc and the organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 305 mg (87%) of the title compound as a light yellow solid. MS-ESI: 200 (M+1).


Steps 2-7 used similar procedures for converting compound 445 to intermediate 196 shown in Scheme 92 to afford intermediate 210 from compound 532. MS-ESI: 433 (M+1).




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Intermediate 211



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Tert-butyl (S)-(amino(1-(fluoromethyl)-1H-pyrazol-3-yl)(oxo)-λ6-sulfaneylidene)carbamate
Step 1: 1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-pyrazole

To a stirred solution of 1H-pyrazole (10 g, 146.9 mmol) in dry THF (400 mL) under nitrogen was added NaH (60% wt., dispersion in mineral oil, 6.17 g, 154 mmol) in portions at 0° C. The reaction mixture was stirred for 15 min at RT. To the above mixture was added SEMCl (26.5 mL, 150 mmol) dropwise at 0° C. and the reaction mixture was stirred for 2 h at RT. The reaction was quenched with water (200 mL) and extracted with EtOAc (3×400 mL) and the organic layers were combined, washed with water (400 mL) and brine (400 mL), dried over MgSO4, filtered and concentrated under vacuum. The residue was eluted from silica gel with 5-50% EtOAc in hexane. This resulted in 23.5 g (81%) of the title compound as clear oil. MS-ESI: 199 (M+1).


Step 2: (5)-1-02-(trimethylsilyHethoxy)methyl)-1H-pyrazole-5-sulfinamide

To a solution of 1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (7.5 g, 37.8 mmol) in dry THF (200 mL) under nitrogen was added n-BuLi in hexane (2.5 M, 16 mL, 40 mmol) dropwise at −78 ° C. and the reaction mixture was stirred for 2 h at −78° C. To above solution was cannulated a solution of Mts-S,R,R-Aux (15 g, 39.7 mmol) in dry THF (200 mL) maintained at −78° C. The mixture was stirred for 3 h at −78° C. To above mixture was added KHMDS in THF (1 M, 75.6 mL, 75.6 mmol) dropwise at −78° C. The reaction was warmed to 0° C. The reaction mixture was quenched with formic acid in THF (1 M, 113 mL, 113 mmol) dropwise at 0° C. The mixture was concentrated under vacuum and the residue was dissolved in DCM and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/hexane (10%-100%). This resulted in 5.6 g (57%, 99% ee Chiralpak AD, hexane/EtOH 70:30+0.1% DEA) of the title compound as a beige waxy solid. MS-ESI: 262 (M+1).


Step 3: Tert-butyl (S)-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)sulfinyl)carbamate

To a solution of (S)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-sulfinamide (5.5 g, 21 mmol) in dry THF (200 mL) under nitrogen was added t-BuOLi in THF (1 M, 43.1 mL, 43.1 mmol) dropwise at 0° C. The reaction mixture was stirred for 20 min at 0° C. To above mixture was added Boc2O (4.59 g, 21 mmol) in portions and the reaction was stirred for 2 h at 0° C. The reaction was quenched with formic acid in THF (1 M, 44 mL, 44 mmol) at 0° C. The mixture was concentrated under vacuum. The residue was eluted from silica gel with 5-50% EtOAc in hexane. This resulted in 6.0 g (79%, 99% ee from Chiralpak IG, hexane/EtOH 70:30+0.1% DEA) of the title compound as a colorless oil. MS-ESI: 362 (M+1)


Step 4: Tert-butyl (S)-(amino(oxo)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-sulfaneylidene)carbamate

To a solution of tert-butyl (S)-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)sulfinyl)carbamate (5.75 g, 15.9 mmol) in dry DME (100 mL) was added TCCA (1.85 g, 7.95 mmol) in portions at 0° C. The mixture was stirred for 1 h at 0° C. This reaction solution was cannulated into a flask containing NH3 (7 M in MeOH, 22.7 mL, 160 mmol) at 0° C. and the mixture was stirred for 4 h at the same temperature. The reaction mixture was diluted with DCM, filtered through a silica plug washed with EtOAc and concentrated. The residue was eluted from silica gel with 1070% EtOAc in hexane. This resulted in 3.0 g (50%) of the title compound as a white solid. MS-ESI: 377 (M+1).


Step 5: Tert-butyl (S)-(amino(oxo)(1H-pyrazo1-5-yl)-sulfaneylidene)carbamate

To a solution of tert-butyl (S)-(amino(oxo)(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-λ6-sulfaneylidene)carbamate (2.8 g, 7.44 mmol) in EtOH (50 mL) was added aq. HCl (3 M, 24.8 mL, 74.4 mmol) dropwise at RT. The mixture was stirred for 2 h at RT. The reaction was cooled to 0° C. and quenched with sat. NaHCO3. The mixture was extracted with EtOAc (3×100 mL) and the organic layers were combined. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was eluted from silica gel with 0-20% MeOH in DCM. This resulted in 755 mg (41%, 97.5% ee from Chiralpak IG, hexane/EtOH 85:15+0.1% DEA) of the title compound as a white foam. MS-ESI: 247 (M+1).


Step 6: Tert-butyl (S)-(amino(1-(fluoromethyl)-1H-pyrazol-3-yl)(oxo)-λ6-sulfaneylidene)carbamate

To a solution of tert-butyl (S)-(amino(oxo)(1H-pyrazol-5-yl)-λ6-sulfaneylidene)carbamate (45 mg, 0.18 mmol) in dry THF (2 mL) under nitrogen was added t-BuOK in THF (1 M, 384 uL, 0.38 mmol) at RT. The mixture was stirred for 30 min at RT. To above mixture was added CH2FI (14 uL, 0.20 mmol). The mixture was stirred over-weekend. The reaction was quenched with formic acid in THF (1 M, 385 uL) and the mixture was concentrated under vacuum. The residue was eluted from silica gel with 0-25% MeOH in DCM. This resulted in 27 mg (54%, 98% ee from Chiralpak IG, hexane/EtOH 80:20+0.1% DEA) of the title compound as a white solid. MS-ESI: 279 (M+1).


Schemes for amino pyridines Intermediates: Schemes 107-115 illustrate the preparation of amino pyridines intermediates.




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Intermediate 212



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2-(Difluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 2-(Difluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 2-aminocyclopent-1-ene-1-carbonitrile (20 g, 185 mmol) in DCE (400 mL) in a 1 L round-bottom flask under nitrogen was added 1,1-difluoropropan-2-one (17.4 g, 185 mmol) and BF3.Et2O (47% wt., 25 g, 370 mmol) dropwise at 0° C. The resulting solution was stirred for 4 h at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 500 mL of water. The pH value of the solution was adjusted to 8 with K2CO3 (sat.). The resulting solution was extracted with 3×500 mL of EtOAc. The organic layers were dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.71 g (5.0%) of the title compound as a yellow solid. MS-ESI: 185 (M+1).




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Intermediate 213



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3-Ethyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

Step 1 used similar procedures for converting compound 544 to intermediate 212 shown in Scheme 107 to afford compound 546 from compound 545. MS-ESI: 217 (M+1).


Step 2: 3-Bromo-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (950 mg, 4.4 mmol) in MeCN (20 mL) was added NBS (1.56 g, 8.8 mmol). The resulting solution was stirred for 1 h at RT under nitrogen. The reaction was then quenched by the addition of 20 mL of sat. Na2S2O3 (aq). The resulting solution was extracted with 3×50 mL of EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and then concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/5). This resulted in 1.8 g (83%) of the title compound as a yellow solid. MS-ESI: 295, 297 (M+1).


Step 3: 2-(2,2,2-Trifluoroethyl)-3-vinyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 3-bromo-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (1.0 mg, 3.4 mmol) in dioxane (100 mL) and water (10 mL) were added Cs2CO3 (2.2 g, 6.8 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.0 g, 6.8 mmol) and Pd(dppf)Cl2 (250 mg, 0.34 mmol) under nitrogen. The resulting solution was stirred overnight at 90° C. under nitrogen. The reaction mixture was then diluted with 100 mL of water. The solids were filtered out. The filtrate was extracted with 3×200 mL of EtOAc, the combined organic layers were dried over Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/1). This resulted in 1.0 g (73%) of the title compound as a yellow solid. MS-ESI: 243 (M+1).


Step 4: 3-Ethyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 2-(2,2,2-trifluoroethyl)-3-vinyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (500 mg, 2.06 mmol) in MeOH (50 mL) was added Pd/C (10% wt., 50 mg) under nitrogen in portions. The flask was evacuated and refilled three times with hydrogen. The resulting solution was stirred overnight at RT under hydrogen with a balloon. The solids were filtered out. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1/1). This resulted in 400 mg (80%) of the title compound as a yellow solid. MS-ESI: 245 (M+1).




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Intermediate 214



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2-(1-Fluorocyclopropyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

Step 1-3 used similar procedures for converting compound 545 to compound 548 shown in Scheme 108 to afford intermediate 214 from compound 549. MS-ESI: 207 (M+1).




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Intermediate 215



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3-Cyclopropyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 3-Cyclopropyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 3-bromo-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (1.0 g, 3.4 mmol) in toluene (20 mL) and water (2.0 mL) were added cyclopropylboronic acid (1.2 g, 13.6 mmol) and Na2CO3 (1.1 g, 10.2 mmol) in portions at RT. To the above solution was added Pd(dppf)Cl2 (20 mg, 0.03 mmol) and Ruphos (20 mg, 0.03 mmol) under nitrogen. The mixture was stirred overnight at 90° C. under nitrogen; LCMS showed the starting material was consumed. The resulting mixture was concentrated under reduced pressure. The residue was eluted from silica gel with PE/EA (6:1). This resulted in 600 mg (69%) of the title compound as a yellow solid. MS-ESI: 257 (M+1).









TABLE 47







The Intermediates in the following Table were prepared using the similar procedures for


converting compound 547 to Intermediate 215 shown in Scheme 110 from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 216


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3-Cyclopropyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4-amine
243





Intermediate 217 (from 558)


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2-Methyl-3-phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
225











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Intermediate 218A and Intermediate 218B



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3,5-Dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine and 3,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 3-Methylhexanediamide

To a stirred solution of 3-methyladipic acid (10 g, 62.4 mmol) in DCM (300 mL) was added SOCl2 (100 mL, 841 mmol) dropwise with stirring at 0° C. under nitrogen. The resulting solution was stirred for 4 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 11 g (crude) of 3-methylhexanedioyl dichloride as a brown oil and it was dissolved in THF (50 mL). This solution was assigned as “A”. To stirred solution of NH3 in THF (0.5 M, 300 mL) was added solution A (50 mL prepared above) dropwise at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 20 mL of MeOH. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 9.72 g (98%) of the title compound as a white solid. MS-ESI: 159 (M+1).


Step 2: 3-Methylhexanedinitrile

To a stirred solution of 3-methylhexanediamide (10 g, 63.2 mmol) in MeCN (200 mL) was added POCl3 (48.5 g, 316 mmol) dropwise at 0° C. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of 20 mL of water/ice. The resulting solution was extracted with 3×200 mL of DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3.58 g (46%) of the title compound as a yellow oil. MS-ESI: 121 (M−1).


Step 3: Mixture of 2-amino-5-methylcyclopent-1-ene-1-carbonitrile and 2-amino-4-methylcyclopent-1-ene-1-carbonitrile

To a stirred solution of 3-methylhexanedinitrile (3 g, 24.6 mmol) in THF (100 mL) was added NaH (60% wt. dispersion in mineral oil, 2.95 g, 74 mmol) in portions at 0° C. under nitrogen. The resulting solution was stirred overnight at 80° C. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3×200 mL of EtOAc, the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.65 g (crude) mixture (1:1) of the title compound as a brown yellow solid. MS-ESI: 121 (M−1) for both.


Step 4 used similar procedures for converting compound 544 to intermediate 212 shown in Scheme 107 to afford intermediate 218A and 218B from compound 555A and 555B. MS-ESI: 231 (M+1) for both.




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Intermediate 219



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2-Methyl-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 2-Methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of acetone (34.8 g, 6.0 mol) in toluene (50 mL) was added 2-aminocyclopent-1-ene-1-carbonitrile (10.8 g, 100 mmol) and ZnCl2 (1.5 g, 110 mmol) at RT. The resulting solution was stirred for 16 h at 100° C. under nitrogen. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 2.2 g (14.9%) of the title compound as a yellow solid. MS-ESI: 149 (M+1).


Step 2: 3-Bromo-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (2.2 g, 14.8 mmol) in MeCN (30 mL) was added NBS (3.17 g, 18 mmol). The resulting solution was stirred for 2 h at RT. The resulting mixture was quenched with sat. Na2SO3 (aq., 5.0 mL), then diluted with water (50 mL), extracted with DCM (3×100 mL). The combined organic layers were dried over Na2SO4 and concentrated. The residue was eluted from silica gel with EtOAc/PE (1:1). This resulted in 1.3 g (39%) of the title compound as a dark brown solid. MS-ESI: 227/229 (M+1).


Step 3: 2-Methyl-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 3-bromo-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (100 mg, 0.44 mmol) in DMF (2.0 mL)/NMP (2.0 mL) in a sealed tube under nitrogen was added trimethyl-(trifluoro- methyl)silane (170 mg, 1.3 mmol), CuI (168 mg, 0.88 mmol) and KF (51.2 mg, 0.88 mmol). The resulting solution was stirred overnight at 80° C. The residue was eluted from a silica gel column with EtOAc/PE (1:1) and further purified by prep-TLC. This resulted in 3.0 mg (3.0%) of the title compound as an off-white solid. MS-ESI: 217 (M+1).




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Intermediate 220



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8-Amino-1,5,6,7-tetrahydrodicyclopenta[b,e]pyridin-3(2H)-one
Step 1: 2,2,2-Trichloroethyl (3-hydroxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate

To a stirred solution of HCl in 1,4-dioxane (4 M, 40 mL) was added 2,2,2-trichloroethyl (3-((tert-butyl-dimethylsilyl)oxy)-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (4.3 g, 9.0 mmol) in portions at RT. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with EtOAc/PE (1:2). This resulted in 2.45 g (75%) of the title compound as an off-white solid. MS-ESI: 365/367/369 (M+1).


Step 2: 2,2,2-Trichloroethyl (3-oxo-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate

To a stirred solution of 2,2,2-trichloroethyl (3-hydroxy-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl) carbamate (643 mg, 1.76 mmol) in DCM (25 mL) was added MnO2 (764 mg, 8.79 mmol) in portions at RT. The resulting solution was stirred for 2 h at RT. The solids were filtered out. The resulting mixture was concentrated. This resulted in 630 mg (crude) of the title compound as a light yellow solid. MS-ESI: 363/365/367 (M+1).




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Intermediate 221



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3-Methyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 3-Methyl-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 3-bromo-2-(2,2,2-trifluoroethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (500 mg, 1.69 mmol) in dioxane (15 mL) in a 40-mL sealed tube under nitrogen were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (1.06 g, 8.47 mmol), K2CO3 (706 mg, 5.08 mmol) and Pd(dtbpf)Cl2 (221 mg, 0.034 mmol). The reaction mixture was stirred overnight at 85° C. The reaction was quenched with H2O (15 mL). The mixture was extracted with 3×30 mL of EtOAc and the organic layers were combined. The organic layer was dried with anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (2/1). This resulted in 200 mg (51%) of the title compound as a brown solid. MS-ESI: 231 (M+1).




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Intermediate 222



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2,2,2-Trichloroethyl (2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate
Step 1: 2,2,2-Trichloroethyl (2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

To a stirred solution of 2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (500 mg, 2.48 mmol) in THF (30 mL) in a 100-mL round-bottom flask under nitrogen was added DIEA (639 mg, 4.96 mmol) at RT, followed by the addition of 2,2,2-trichloroethyl chloroformate (1.05 g, 4.96 mmol) dropwise at RT. The resulting solution was stirred overnight at RT. The reaction solution was quenched with H2O (10 mL). The mixture was extracted with 3×50 mL EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE(1:1). This resulted in 633 mg (68%) of the title compound as a brown yellow solid. MS-ESI: 376/378/380 (M+1).









TABLE 48







The Intermediates in the following Table were prepared using the similar procedures


for converting compound 354 to Intermediate 222 shown in Scheme 115 from appropriated starting


materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 223


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2,2,2-Trichloroethyl (2-(difluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamate
358/360/362





Intermediate 224


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2,2,2-Trichloroethyl (3-ethyl-2-(2,2,2- trifluoroethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
419/421/423





Intermediate 225


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2,2,2-Trichloroethyl (2-(1- fluorocyclopropyl)-3-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl)calbamate
381/383/385





Intermediate 226


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2,2,2-Trichloroethyl (3-cyclopropyl-2- (2,2,2-trifluoroethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
431/433/435





Intermediate 227


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2,2,2-Trichloroethyl (3-cyclopropyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
417/419/421





Intermediate 228


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2,2,2-Trichloroethyl (3,5-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate and 2,2,2-trichloroethyl (3,6-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
405/407/409








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Intermediate 229


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2,2,2-Trichloroethyl (2-methyl-3- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
391/393/395





Intermediate 230


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2,2,2-Trichloroethyl (3-oxo-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamate
363/365/367





Intermediate 231


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2,2,2-Trichloroethyl (2-methyl-3-phenyl- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamate
399/401/403





Intermediate 232


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2,2,2-Trichloroethyl (3-methyl-2-(2,2,2- trifluoroethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
405/407/409









Schemes of Sulfonimidamide and amino pyridines Intermediates: Schemes 116-122 illustrate the preparation of sulfonimidamide and amino pyridines intermediates.




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Intermediate 233



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N′-(tert-butyldimethylsilyl)-2-(2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)thiazole-5-sulfonimidamide
Step 1: 2-((Tert-butyldimethylsilyl)oxy)-1-(thiazol-2-yl)ethan-1-ol

To a stirred solution of 2-bromothiazole (10.0 g, 61.3 mmol) in THF (120 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 36.8 mL, 92.0 mmol) dropwise at −78° C. The resulting solution was stirred at −78° C. for 20 min, then to the above solution was added 2-((tert-butyldimethylsilyl)oxy)acetaldehyde (16.0 g, 92.0 mmol) in THF (10 mL) dropwise at −78° C. The resulting solution was stirred for 2 h at −50° C. The reaction was quenched with water (50 mL). The resulting mixture was concentrated to remove THF under vacuum. The aqueous phase was extracted with EtOAc (3×100 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:9). This resulted in 8.1 g (51.0%) of the title compound as yellow oil. MS-ESI: 260 (M+1).


Step 2: 2-(2,2,3,3,8,8,9,9-Octamethyl-4,7-dioxa-3,8-disiladecan-5-yl)thiazole

To a stirred solution of 2-((tert-butyldimethylsilyl)oxy)-1-(thiazol-2-yl)ethan-1-ol (8.0 g, 30.9 mmol) in THF (150 mL) under nitrogen was added NaH (60% wt, 3.09 g, 77.3 mmol) in portions at 0° C. The resulting solution was stirred for 10 min at 0° C. Then to the above solution was added TBSCl (18.6 g, 124 mmol) in THF (15 mL) dropwise at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was quenched with water (100 mL), the resulting mixture was concentrated to remove THF under vacuum. The aqueous phase was extracted with EtOAc (3×100 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (4:96). This resulted in 8 g (69.3%) of the title compound as yellow oil. MS-ESI: 374 (M+1).


Steps 3-6 used similar procedures for converting compound 485 to Intermediate 203 shown in Scheme 98 to afford Intermediate 233 from compound 561. MS-ESI: 566 (M+1).




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Intermediate 234



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5-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-N,N-dimethylthiazole-2-carboxamide
Step 1: Thiazole-2-carbonyl chloride

To a stirred solution of thiazole-2-carboxylic acid (2.0 g, 15.5 mmol) in DCM (100 mL) was added DMF (0.095 mL, 1.24 mmol) followed by oxalyl chloride (5.91 g, 46.5 mmol) dropwise at 0° C. The reaction mixture was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 2.4 g (crude) of the title compound as a yellow solid which was used for next step without further purification.


Step 2: N,N-dimethylthiazole-2-carboxamide

To a stirred solution of dimethylamine (2 M in THF, 38.8 mL, 77.5 mmol) was added thiazole-2-carbonyl chloride (2.30 g, crude from last step) in THF (60 mL) dropwise at 0° C. The resulting mixture was stirred for 16 h at RT. The reaction was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. This resulted in 2.18 g (90% over 2 steps) of the title compound as yellow oil. MS-ESI: 157 (M+1).


Steps 3-6 used similar procedures for converting compound 485 to Intermediate 203 shown in Scheme 98 to afford Intermediate 234 from compound 567. MS-ESI: 349 (M+1).




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Intermediate 235



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Tert-butyl (amino(1-ethyl-4-fluoro-1H-pyrazol-5-yl)(oxo)-16-sulfaneylidene)carbamate
Step 1: 1-Ethyl-4-fluoro-1H-pyrazole

To a stirred solution of 4-fluoro-1H-pyrazole (1.72 g, 20.0 mmol) in DMF (15 mL) under nitrogen was added Cs2CO3 (13.0 g, 40.0 mmol) and ethyl iodide (9.36 g, 60.0 mmol) at RT. The resulting mixture was stirred for 16 h at RT. The reaction was quenched with water (20 mL) and extracted with ether (2×50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. This resulted in 2.0 g (87.7%) of the title compound as brown oil. MS-ESI: 115 (M+1).


Step 2: 1-Ethyl-4-fluoro-1H-pyrazole-5-sulfinamide

To a stirred solution of 1-ethyl-4-fluoro-1H-pyrazole (1.5 g, 13.2 mmol) in THF (50 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 7.92 mL, 19.8 mmol) dropwise with stirring at −78° C. The resulting solution was stirred for 1.5 h at −78° C., then to the above solution was added (2S,3aS,8aR)-3-tosyl-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole 2-oxide (4.82 g, 13.8 mmol) in THF (15 mL) dropwise at −78° C. The resulting solution was stirred for 3 h at −78° C. To the above mixture was added KHMDS (1 M in THF, 26.3 mL, 26.3 mmol) dropwise at −78° C. The resulting solution was stirred for 1 h at −78° C. The solution was slowly warmed to RT and stirred for an additional 1 h at RT. The reaction mixture was quenched with MeOH (50 mL) and concentrated under vacuum. The residue was diluted with water (100 mL) and extracted with EtOAc (2×100 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel column with PE/EtOAc (1:1). This resulted in 790 mg (ee value=0) (33.8%) of the title compound as an orange solid. MS-ESI: 178 (M+1). The regiochemistry of compound 572 was confirmed by NOESY. 1H NMR (400 MHz, DMSO-d6) δ 7.59 (d, J=4.4 Hz, 1H), 6.91 (s, 2H), 4.35-4.16 (m, 2H), 1.33 (t, J=7.2, Hz, 3H). NOESY: NH2 at 6.91 (s, 2H) has correlations with N-Et's CH2 at 4.35-4.16 (m, 2H) and CH3 at 1.33 (t, J=7.2, Hz, 3H).


Step 3: Tert-butyl ((1-ethyl-4-fluoro-1H-pyrazol-5-yl)sulfinyl)carbamate

To a stirred solution of 1-ethyl-4-fluoro-1H-pyrazole-5-sulfinamide (696 mg, 3.93 mmol) in THF (25 mL) under nitrogen was added t-BuOLi (1 M in THF, 7.86 mL, 7.86 mmol) dropwise at 0° C. The resulting mixture was stirred for 1 h at 0° C. To the above mixture was added di-tert-butyl dicarbonate (3.42 g, 15.7 mmol) in THF (10 mL) dropwise at 0° C. The resulting mixture was stirred for 3 h at 0° C. and then quenched with MeOH (10 mL) and concentrated under vacuum. The residue was diluted with water (30 mL) and extracted with EtOAc (2×30 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel column with PE/EtOAc (5:1). This resulted in 717 mg (65.8%) of the title compound as light yellow oil. MS-ESI: 278 (M+1).


Step 4: Tert-butyl (amino(1-ethyl-4-fluoro-1H-pyrazol-5-yl)(oxo)-16-sulfaneylidene)carbamate

To a stirred solution of tert-butyl ((1-ethyl-4-fluoro-1H-pyrazol-5-yl)sulfinyl)carbamate (717 mg, 2.59 mmol) in ACN (25 mL) was introduced NH3 (g) bubble at 0° C. for 10 min. Then to the above solution was added NCS (3.45 g, 25.9 mmol) in portions at 0° C. The resulting solution was stirred for 3 h at 35° C. in an oil bath. The residue was quenched with water (100 mL) and extracted with EtOAc (3×150 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel column with PE/EtOAc (3:2). The product was further purified by Prep-HPLC with the following conditions: Column XSelect CSH Prep C18 OBD, 19*250 mm, 5 um Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 53% B over 7 min; 254/210 nm. This resulted in 163 mg (21.6%) of the title compound as a white solid. MS-ESI: 293 (M+1).




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Intermediate 236



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3,5-Dimethyl-2,6-bis(trifluoromethyl)pyridin-4-amine
Step 1: 1,1,1,7,7,7-Hexafluoroheptane-2,4,6-trione

To a stirred mixture of LiH (1.51 g, 189 mmol) in DME (100 mL) under nitrogen were added ethyl 2,2,2-trifluoroacetate (26.9 g, 189 mmol) and acetone (5.0 g, 86.2 mmol) dropwise at 0° C. The resulting mixture was stirred for 16 h at 80° C. under nitrogen. The mixture was allowed to cool down to RT and 50 mL of DME solvent was evaporated under vacuum. The residue was quenched with H2SO4 (15% wt. in water, 50 mL) dropwise at 0° C. The aqueous layer was extracted with DCM (3×50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was dissolved in toluene (50 mL) and heated to reflux with Dean-Stark trap for 4 h. After all water was separated, the resulting mixture was cooled and evaporated under vacuum to afford the title compound (26 g, crude) as a red solid. MS-ESI: 249 (M−1)


Step 2: 2,6-Bis(trifluoromethyl)pyridin-4-amine

To a stirred mixture of 1,1,1,7,7,7-hexafluoroheptane-2,4,6-trione (14.7 g crude from last step) in EtOH (300 mL) was added NH4OAc (36.3 g, 471 mmol) in portions at RT. The resulting mixture was heated to reflux with stirring for 16 h under nitrogen. The mixture was allowed to cool down to RT. The reaction was quenched with water (50 mL) and concentrated to remove EtOH under vacuum. The aqueous layer was extracted with EtOAc (3×30 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel column with PE/EtOAc (10:1) to afford the title compound (9.63 g, 85.9% over two steps) as a yellow solid. MS-ESI: 229 (M−1)


Step 3: 3,5-Dibromo-2,6-bis(trifluoromethyl)pyridin-4-amine

To a stirred solution of 2,6-bis(trifluoromethyl)pyridin-4-amine (4.80 g, 20.9 mmol) in ACN (150 mL) under nitrogen was added NBS (18.7 g, 105 mmol) in portions at 0° C. The resulting mixture was stirred for 16 h at 60° C. The reaction was quenched with sat. aq. Na2S2O3 (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel column with PE/EtOAc (20:1) to afford the title compound (5.69 g, 70.2%) as a yellow solid. MS-ESI: 385/387/389 (M−1).


Step 4: 3,5-Dimethyl-2,6-bis(trifluoromethyl)pyridin-4-amine

To a stirred mixture of 3,5-dibromo-2,6-bis(trifluoromethyl)pyridin-4-amine (5.50 g, 14.2 mmol) in dioxane (125 mL) and H2O (12.5 mL) in a sealed tube under nitrogen were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (50% wt. in THF, 17.9 g, 71.0 mmol), Pd(dppf)Cl2 (1.04 g, 1.42 mmol) and Cs2CO3 (13.9 g, 42.6 mmol) in portions at RT. The resulting mixture was stirred for 16 h at 90° C. The mixture was allowed to cool down to RT and then diluted with sat. aq. NaCl (100 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel column with PE/EtOAc (10:1) to afford the title compound (3.35 g, 91.3%) as a light yellow solid. MS-ESI: 259 (M+1).




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Intermediate 237



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N′-(tert-butyldimethylsilyl)-4-fluoro-1-phenyl-1H-pyrazole-3-sulfonimidamide
Step 1: N,N-dibenzyl-4-fluoro-1-phenyl-1H-pyrazole-3-sulfonamide

To a stirred solution of N,N-dibenzyl-4-fluoro-1H-pyrazole-3-sulfonamide (4.0 g, 11.6 mmol) in DMF (120 mL) was added phenylboronic acid (4.24 g, 34.8 mmol), pyridine (2.75 g, 34.7 mmol) and Cu2O (1.66 g, 44.6 mmol) in portions at RT. The resulting mixture was stirred for 16 hat 70° C. under air. The solids were filtered out. The resulting solution was diluted with 250 mL of water and extracted with 4×150 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel with EtOAc/PE (1:15). This resulted in 3.31 (67.8%) of the title compound as a white solid. LCMS-ESI: 422 (M+1).


Steps 2-5 used similar procedures for converting compound 458A to Intermediate 197 shown in Scheme 93 to afford Intermediate 237 from compound 578. MS-ESI: 355 (M+1).




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Intermediate 238



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3-(4-Fluorophenyl)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 3-(4-Fluorophenyl)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 3-bromo-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (500 mg, 1.78 mmol) in dioxane (10 mL) and H2O (1.0 mL) under nitrogen were added (4-fluorophenyl)boronic acid (498 mg, 3.56 mmol), K3PO4 (1132 mg, 5.34 mmol) and Pd(dtbpf)Cl2 (116 mg, 0.178 mmol) in portions at RT. The reaction mixture was stirred for 16 h at 100° C. The reaction was diluted with 10 mL of water and extracted with 3×10 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (1:2). This resulted in 230 mg (43.5%) of the title compound as a yellow solid. MS-ESI: 297 (M+1)









TABLE 60







The Intermediates in the following Table were prepared using the similar procedures


for converting compound 355 to Intermediate 238 shown in Scheme 121 from appropriate


reagents.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 239


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3-Phenyl-2-(trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-amine
279





Intermediate 240


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3-Cyclopropyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4-amine
243





Intermediate 241


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3-(2-Fluorophenyl)-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- amine
297





Intermediate 242


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3-(3-Fluorophenyl)-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- amine
297











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Intermediate 243



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3-Phenyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 2-aminocyclopent-1-ene-1-carbonitrile (20 g, 185 mmol) in DCE (400 mL) under nitrogen was added 2-phenylacetaldehyde (44.4 g, 370 mmol) and BF3Et2O (47% wt., 25 g, 370 mmol) dropwise at 0° C. The resulting solution was stirred for 16 h at 110° C. The resulting mixture was concentrated under vacuum. The resulting residue was diluted with 500 mL of water then extracted with 3×500 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:3). This resulted in 250 mg (0.64%) of the title compound as a yellow solid. MS-ESI: 211 (M+1).









TABLE 61







The Intermediate in the following table were prepared using the similar procedures for


converting compound 451 to Intermediate 197 shown in Scheme 93.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 244


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N′-(tert-butyldimethylsilyl)-4-fluoro-1- isopropyl-1H-pyrazole-3-sulfonimidamide
321
















TABLE 62







The Intermediate in the following table were prepared using the similar procedures for


converting Intermediate 45 to Intermediate 161 shown in Scheme 82 from Intermediate 45 and


(S)-(+)-Mandelic acid.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 245


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(S)-3-Methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- amine
189
















TABLE 63







The Intermediates in the following Table were prepared using the similar procedures


for converting compound 354 to Intermediate 222 shown in Scheme 115 from appropriated


starting materials.










Intermediate #
Structure
IUPAC Name
Exact Mass [M − H]





Intermediate 246


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2,2,2-Trichloroethyl (3-(4-fluorophenyl)- 2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
471/473/475





Intermediate 247


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2,2,2-Trichloroethyl (3-phenyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
453/455/457





Intermediate 248


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2,2,2-Trichloroethyl (3-cyclopropyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
417/419/421





Intermediate 249


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2,2,2-Trichloroethyl (3-(3-fluorophenyl)- 2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
471/473/475





Intermediate 250


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2,2,2-Trichloroethyl (3-(2-fluorophenyl)- 2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamate
471/473/475





Intermediate 251


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2,2,2-Trichloroethyl (3-phenyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamate
385/387/389





Intermdiate 252


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2,2,2-Trichloroethyl (S)-(3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamate
363/365/367











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Intermediate 253



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N′-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide
Step 1: N-(tert-butyl)-5-chlorothiophene-2-sulfonamide

To a stirred solution of tBuNH2 (20.2 g, 276 mmol) in DCM (180 mL) under nitrogen was added TEA (42.0 g, 415 mmol), followed by the addition of 5-chlorothiophene-2-sulfonyl chloride (10.0 g, 46.3 mmol) in DCM (20 mL) dropwise at 0° C. The resulting solution was stirred for 16 h at 35° C. The reaction was quenched with water/ice (200 mL) and extracted with DCM (2×200 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:10). This resulted in 11.0 g (93.9%) of the title compound as a yellow solid. MS-ESI: 252/254 (M−1). 1H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 1H), 7.46 (d, J=4.0 Hz, 1H), 7.21 (d, J=4.1 Hz, 1H), 1.17 (s, 9H).


Step 2: N-(tert-butyl)-5-chloro-3-fluorothiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-chlorothiophene-2-sulfonamide (11.0 g, 43.5 mmol) in THF (200 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 52.4 mL, 131 mmol) dropwise at −78° C. The resulting solution was stirred at −78° C. for 1 h. To the above solution was added NFSI (41.6 g, 131 mmol) in THF (100 mL) dropwise at −78° C. The resulting solution was slowly warmed to RT, and stirred at RT for another 1 h. The reaction mixture was then quenched with water/ice (250 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:20). This resulted in 6.2 g (43.3%) of the title compound as a yellow solid. MS-ESI: 270/272 (M−1).


Step 3: N-(tert-butyl)-5-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-chloro-3-fluorothiophene-2-sulfonamide (6.2 g, 22.8 mmol) in THF (200 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 91.2 mL, 228 mmol) dropwise at −78° C. The resulting solution was stirred for 50 min at −78° C. To this was added acetone (53.0 g, 913 mmol) dropwise with stirring at −78° C. The resulting solution was stirred for additional 1.5 h at −60° C. The reaction was then quenched with water/ice (200 mL) and extracted with EtOAc (2×300 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:5). This resulted in 4.4 g (65.4%) of the title compound as yellow oil. MS-ESI: 328/330 (M−1).


Step 4: N-(tert-butyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-5-chloro-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (4.3 g, 13.1 mmol) in MeOH (80 mL) under nitrogen was added Pd/C (10% wt, 470 mg) in portions at RT. The flask was evacuated and refilled with hydrogen three times. The resulting mixture was stirred for 16 h at RT under hydrogen with a balloon. The solids were filtered out and the filtrate was concentrated under vacuum. This resulted in 3.88 g (crude) of the title compound as a white solid. MS-ESI: 294 (M−1).


Step 5: 3-Fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of N-(tert-butyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (3.88 g, 13.1 mmol) in DCM (78 mL) under nitrogen was added BCl3 (1 M in DCM, 39 mL, 39 mmol) dropwise at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched with water/ice (80 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (2:3). This resulted in 1.9 g (60.7% over 2 steps) of the title compound as yellow oil. MS-ESI: 238 (M−1).


Step 6: N-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide

To a stirred solution of 3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonamide (1.89 g, 7.91 mmol) in THF (40 mL) under nitrogen was added NaH (60% wt., 630 mg, 15.9 mmol) in portions at 0° C., followed by the addition of TBSCl (2.39 g, 15.9 mmol) in THF (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with water/ice (50 mL). The resulting solution was extracted with EtOAc (2×50 mL). The organic layers were combined and dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl EtOAc/PE (1:3). This resulted in 2.1 g (75.2%) of the title compound as a white solid. MS-ESI: 352 (M−1). 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.56 (d, J=5.1 Hz, 1H), 5.38 (s, 1H), 1.43 (s, 6H), 0.89 (s, 9H), 0.16 (s, 6H).


Step 7: N′-(tert-butyldimethylsilyl)-3-fluoro-4-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide

To a stirred solution of PPH3Cl2 (1.41 g, 4.24 mmol) in CHCl3 (15 mL) under nitrogen was added DIEA (1.83 g, 14.1 mmol) dropwise at 0° C. The resulting solution was stirred for 15 min at 0° C. To the above solution was added N-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazole-5-sulfonamide (1.0 g, 2.83 mmol) in CHCl3 (10 mL) dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. NH3 (g) was bubbled into the reaction solution for 10 min at 0° C. Then the solution was stirred for another 30 min at RT. The solids were filtered out, the filtrate was diluted with water (20 mL). The resulting solution was extracted with DCM (3×20 mL). The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 800 mg (80.1%) of the title compound as an off-white solid. MS-ESI: 351 (M−1).




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Intermediate 254



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N′-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazole-5-sulfonimidamide
Step 1: 2-(Difluoromethyl)thiazole

To a stirred solution of thiazole-2-carbaldehyde (10 g, 88.5 mmol) in DCM (150 mL) under nitrogen atmosphere was added DAST (28.6 g, 178 mmol) dropwise at −78° C. The resulting mixture was stirred for 16 h at RT. The reaction was quenched with 100 mL of water/ice at 0° C. The mixture was neutralized to pH=8 with sat. NaHCO3 (aq.). The resulting mixture was extracted with DCM (2×100 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum below 5° C. This resulted in the title compound (5.8 g, 48.5%) as a yellow oil which was used for next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.94 (dt, J=3.0, 1.4 Hz, 1H), 7.58 (d, J=3.1 Hz, 1H), 6.91 (t, J=54.8 Hz, 1H).


Step 2: Lithium 2-(difluoromethyl)thiazole-5-sulfinate

To a stirred solution of 2-(difluoromethyl)thiazole (5.8 g, 43.0 mmol) in THF (50 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 21.0 mL, 52.5 mmol) dropwise at −78° C. The resulting solution was stirred for 20 min at −78° C. To the above solution was introduced SO2 bubbled at −78° C. for 5 min. The resulting mixture was stirred for 2 h at RT and concentrated under vacuum. This resulted in 16.5 g (crude) title compound as a dark yellow solid which was used for next step without further purification. MS-ESI: 198 (M−1).


Step 3: 2-(Difluoromethyl)thiazole-5-sulfonamide

To a stirred solution of lithium 2-(difluoromethyl)thiazole-5-sulfinate (16.5 g, crude from last step) in ACN (50 mL) was added NCS (17.1 g, 128 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT. To the above solution was introduced NH3 bubbled at 0° C. for 10 min. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 2.87 g (15.2% over two steps) of the title compound as a yellow solid. MS-ESI: 213 (M−1). 1H NMR (400 MHz, CDCl3) δ 8.33 (t, J=1.5 Hz, 1H), 6.87 (t, J=54.3 Hz, 1H), 5.55 (s, 2H).


Step 4: N-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazole-5-sulfonamide

To a stirred solution of 2-(difluoromethyl)thiazole-5-sulfonamide (2.87 g, 13.4 mmol) in THF (50 mL) under nitrogen was added NaH (60% wt, 2.05 g, 51.2 mmol) in portions at 0° C., followed by the addition of TBSCl (4.59 g, 30.6 mmol) in THF (5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with 50 mL of water/ice. The resulting solution was extracted with EtOAc (2×50 mL). The organic layers were combined and dried over anhydrous Na2SO4. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with ethyl EtOAc/PE (1:4). This resulted in 2.48 g (56.4%) of the title compound as a yellow solid. MS-ESI: 327 (M−1).


Step 5: N′-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazole-5-sulfonimidamide

To a stirred solution of PPH3Cl2 (2.43 g, 7.31 mmol) in CHCl3 (30 mL) under nitrogen was added DIEA (2.40 g, 18.6 mmol) dropwise at 0° C. The resulting solution was stirred for 15 min at 0° C. To the above solution was added N-(tert-butyldimethylsilyl)-2-(difluoromethyl)thiazole-5-sulfonamide (1.20 g, 3.66 mmol) in CHCl3 (5 mL) dropwise at 0° C. The resulting solution was stirred for 2 h at 0° C. NH3 (g) was bubbled into the reaction solution for 15 min at 0° C. Then the solution was stirred for another 2 h at RT. The solids were filtered out, the filtrate was diluted with water (20 mL). The resulting solution was extracted with DCM (3×20 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 670 mg (56.0%) of the title compound as yellow oil. MS-ESI: 328 (M+1).




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Intermediate 255



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N′-(tert-butyldimethylsilyl)-1-(1,1-difluoroethyl)-4-fluoro-1H-pyrazole-3-sulfonimidamide
Step 1: 4-Fluoro-1-(tetrahydro-211-pyran-2-yl)-1H-pyrazole

To a stirred solution of 4-fluoro-1H-pyrazole (5.00 g, 58.1 mmol) in 3,4-dihydro-2H-pyran (9.77 g, 116 mmol) under nitrogen was added a catalytic amount of TFA (260 mg, 2.32 mmol). The resulting solution was stirred for 16 h at 100° C. The reaction was then quenched with 200 mg of NaH (60% wt.) at 0° C. The resulting solution was diluted with water (100 mL). The resulting solution was extracted with EtOAc (3×100 mL). The organic layers were combined and dried over anhydrous Na2SO4. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 12.0 g (crude) of the title compound as a light brown oil. MS-ESI: 171 (M+1).


Step 2: Lithium 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate

To a stirred solution of 4-fluoro-1-(oxan-2-yl)pyrazole (12.0 g, crude from last step) in THF (250 mL) was added n-BuLi (2.5 M in hexane, 20.0 mL, 50 mmol) dropwise at −78° C. The resulting solution was stirred for 40 min at −78° C. To the above solution was introduced SO2 (g) bubbled at −78° C. for 5 min. Then, the temperature was warmed to RT. The resulting solution was stirred for an additional 1 h at RT. The resulting mixture was concentrated under vacuum. This resulted in 28.0 g (crude) of the title compound as a light yellow semi-solid. MS-ESI: 233 (M−1).


Step 3: N-(tert-butyl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide

To a solution of lithium 4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfinate (28.0 g, crude from last step) in ACN (200 mL) was added NCS (19.9 g, 149 mmol) in ACN (50 mL) dropwise at 0° C. The resulting solution was stirred for 1 h at RT. To the reaction mixture above was added tBuNH2 (49.8 g, 683 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for an additional 30 min at RT. The resulting mixture was concentrated under vacuum and diluted with 200 mL of water. The resulting solution was extracted with 3×150 mL of EtOAc, and the organic layers were combined. The residue after evaporation was purified by Prep-TLC with EtOAc/PE (1:4). This resulted in 13.3 g (75.0% over three steps) of the title compound as a yellow solid. MS-ESI: 304 (M−1). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=4.6 Hz, 1H), 5.90 (dd, J=8.6, 2.9 Hz, 1H), 5.17 (s, 1H), 3.98-3.86 (m, 1H), 3.80-3.68 (m, 1H), 2.48-2.32 (m, 1H), 2.21-2.02 (m, 2H), 1.85-1.55 (m, 3H), 1.31 (s, 9H).


Step 4: N-(tert-butyl)-4-fluoro-1H-pyrazole-5-sulfonamide

To a solution of N-(tert-butyl)-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-sulfonamide (13.3 g, 43.6 mmol) in MeOH (220 mL) was added HCl (conc., 20 mL) dropwise at 0° C. The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated under vacuum. This resulted in 9.7 g (crude) of the title compound as a yellow green solid. MS-ESI: 222 (M+1).


Step 5: 1-(2-Bromo-1,1-difluoroethyl)-N-(tert-butyl)-4-fluoro-1H-pyrazole-3-sulfonamide

To a solution of N-(tert-butyl)-4-fluoro-1H-pyrazole-5-sulfonamide (9.70 g, 43.8 mmol) in THF (200 mL) was added DBU (33.4 g, 219 mmol) at −20° C. The resulting solution was stirred for 5 min at −20° C. Then 2-bromo-1,1-difluoroethene was bubbled to this reaction mixture at −20° C. for 10 min. The resulting solution was stirred for 1 h at −20° C. The resulting mixture was concentrated and diluted with 150 mL of water. The resulting solution was extracted with EtOAc (3×100 mL). The organic layers were combined and dried over anhydrous Na2SO4. The residue was purified by Prep-TLC with EtOAc/PE (1:2). This resulted in 8.5 g (53.7% over 2 steps) of the title compound as a yellow solid. MS-ESI: 364/366 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J=4.5 Hz, 1H), 8.21 (s, 1H), 4.58 (t, J=12.1 Hz, 2H), 1.19 (s, 9H). NOESY: Ar—H at 8.80 (d, J=4.5 Hz, 1H) correlated with CH2 at 4.58 (t, J=12.1 Hz, 2H).


This also resulted in 2.0 g (13.4%) of by product (E)-1-(2-bromo-1-fluorovinyl)-N-(tert-butyl)-4-fluoro-1H-pyrazole-3-sulfonamide (599BP″) as a yellow solid which eluted after 599″. MS-ESI: 344/346 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=5.0 Hz, 1H), 6.27 (d, J=5.3 Hz, 1H), 5.00 (br s, 1H), 1.36 (s, 9H).


Step 6: N-(tert-butyl)-1-(1,1-difluoroethyl)-4-fluoro-1H-pyrazole-3-sulfonamide

To a stirred solution of 1-(2-bromo-1,1-difluoroethyl)-N-tert-butyl-4-fluoropyrazole-3-sulfonamide (8.0 g, 22.0 mmol) in EtOH (250 mL) in a stainless steel pressure reactor under nitrogen was added Pd/C (10% wt., 3.50 g) and AcOH (0.5 mL). The mixture was stirred at 100° C. for 16 h under hydrogen (10 atm), filtered through a Celite pad and concentrated under vacuum. The residue was purified by Prep-TLC (EA/PE 1:1) to afford 5.0 g of the title compound (79.7%) as a light yellow solid. MS-ESI: 286 (M+1).


Step 7: 1-(1,1-Difluoroethyl)-4-fluoro-1H-pyrazole-3-sulfonamide

N-tert-butyl-1-(1,1-difluoroethyl)-4-fluoropyrazole-3-sulfonamide (5.0 g, 17.5 mmol) was added HCl (conc. 50 mL) in portions with stirring at 0° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:1). This resulted in 3.90 g (97.3%) of the title compound as a yellow solid. MS-ESI: 230 (M+1).


Steps 8-9 used similar procedures for converting compound 588″ to Intermediate 253 shown in Scheme 123 to afford Intermediate 255 from compound 601″. MS-ESI: 343 (M+1).









TABLE 63A







The Intermediate in the following Table were prepared using similar procedures for


converting compound 355″ to Intermediate 238 shown in Scheme 121 from appropriate reagents.










Intermediate #
Structure
IUPAC Name
Exact Mass [M + H]+





Intermediate 256


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3-(3,4-Difluorophenyl)-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-amine
315











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Intermediate 257



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3-(3,4-Difluorophenyl)-4-isocyanato-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine

To a solution of 3-(3,4-difluorophenyl)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (200 mg, 0.637 mmol) in THF (4 mL) under nitrogen was added TEA (129 mg, 1.28 mmol) and BTC (151 mg, 0.508 mmol) at 0° C. The resulting solution was stirred for 2 h at 70° C. This resulted in the title compound in a brown solution which was used for next step directly.




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Intermediate 258



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N′-(tert-butyldimethylsilyl)-2-(2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)thiazole-5-sulfonimidamide


Step 1: Diethyl 2-(thiazol-2-yl)malonate

To a stirred solution of ethyl 2-(thiazol-2-yl)acetate (2.0 g, 11.7 mmol) in THF (20 mL) under nitrogen was added NaH (60% wt. dispersion in mineral oil, 1.0 g, 25.0 mmol) in portions at 0° C. The resulting solution was stirred for 30 min at 0° C. Then diethyl carbonate (23.0 g, 195 mmol) was added dropwise to the above solution. The resulting solution was stirred for 8 h at 65° C. The reaction was then quenched with 30 mL of water, then extracted with 3×50 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was eluted from silica gel with EtOAc/PE (1/2). This resulted in 2.44 g (85.8%) of the title compound as a light yellow solid. MS-ESI: 242 (M−1).


Step 2: Diethyl 2-methyl-2-(thiazol-2-yl)malonate

To a stirred solution of diethyl 2-(thiazol-2-yl)malonate (2.0 g, 8.22 mmol) in THF (30 mL) was added DBU (2.50 g, 16.4 mmol) at 0° C. Then MeI (4.67 g, 32.9 mmol) was added dropwise to the above solution. The resulting solution was stirred for 2 h at RT. The reaction was then quenched with 20 mL of water/ice, and then extracted with 3×50 mL of EtOAc. The organic layers were combined and dried over anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by Prep-TLC with EtOAc/PE (1/2). This resulted in 1.3 g (61.5%) of the title compound as light yellow oil. MS-ESI: 258 (M+1).


Step 3: 2-Methyl-2-(thiazol-2-yl)propane-1,3-diol

To a stirred solution of diethyl 2-methyl-2-(thiazol-2-yl)malonate (1.0 g, 3.89 mmol) in THF (30 mL) was added DIBAL-H (1 M in hexane, 7.82 mL, 7.82 mmol) dropwise at 0° C. over 5 min. The resulting solution was stirred for 24 h at RT. The reaction was then quenched with 10 mL of MeOH. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase column with ACN/water (15/75). This resulted in 290 mg (43.1%) of the title compound as light yellow oil. MS-ESI: 174 (M+1).


Step 4: 2-(2,2,3,3,6,9,9,10,10-Nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)thiazole

To a stirred solution of 2-methyl-2-(thiazol-2-yl)propane-1,3-diol (72.0 mg, 0.416 mmol) in THF (10 mL) under nitrogen was added NaH (60% wt., 66.6 mg, 1.66 mmol) in portions at 0° C. The resulting solution was stirred for 30 min at 0° C. Then TBSCl (190 mg, 1.25 mmol) was added to the above solution at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched with 10 mL of water/ice, and extracted with 3×30 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated. This resulted in 300 mg (crude) of the title compound as light yellow crude oil. MS-ESI: 402 (M+1).


Steps 5-8 used similar procedures for converting compound 485″ to intermediate 203 shown in Scheme 98 to afford Intermediate 258 from compound 607″. MS-ESI: 594 (M+1)




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Intermediate 259



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N′-(tert-butyldimethylsilyl)-2-(1-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)thiazole-5-sulfonimidamide
Step 1: Ethyl 2-methyl-2-(thiazol-2-yl)propanoate

To a stirred solution of ethyl 2-(thiazol-2-yl)acetate (2.50 g, 14.6 mmol) in THF (30 mL) under nitrogen was added NaH (60% wt., 1.75 g, 43.8 mmol) in portions at 0° C., followed the dropwise addition of methyl iodide (20.7 g, 146 mmol) at 0° C. The resulting solution was stirred for 16 h at RT. The reaction was quenched with water/ice (30 mL). The resulting mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (2×30 mL), dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (10:1). This resulted in 1.4 g (48.2%) of the title compound as a yellow solid. MS-ESI: 200 (M+1).


Step 2: 2-Methyl-2-(thiazol-2-yl)propan-1-ol

To a stirred solution of ethyl 2-methyl-2-(thiazol-2-yl)propanoate (1.30 g, 6.53 mmol) in THF (50 mL) was added NaBH4 (1.44 g, 39.1 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was quenched with water/ice (15 mL). The resulting solution was extracted with 3×50 mL of EtOAc. The combined organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 600 mg (58.5%) of the title compound as a yellow solid. MS-ESI: 158 (M+1).


Steps 3-7 used similar procedures for converting compound 606″ to Intermediate 258 shown in Scheme 127 to afford Intermediate 259 from compound 613″. MS-ESI: 464 (M+1).




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Intermediate 219



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2-Methyl-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 3-Iodo-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (2.50 g, 16.9 mmol) in TFA (100 mL) at 0° C. was added NIS (7.61 g, 33.8 mmol) in portions at 0° C. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum and then diluted with 250 mL of water. The resulting solution was extracted with 2×300 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (9:1). This resulted in 1.70 g (36.7%) of the title compound as a white solid. MS-ESI: 275 (M+1)


Step 2: 2-Methyl-3-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 3-iodo-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (500 mg, 1.82 mmol) in DMF (10 mL) in a sealed tube under nitrogen was added (1,10-phenanthroline)(trifluoromethyl)copper(I) (2.27 g, 7.28 mmol). The resulting solution was stirred for 16 h at 80° C. The solids were filtered out. The filtrate was purified by Prep-HPLC using the following conditions: Column:)(Bridge Shield RP18 OBD Column, 30*150 mm, 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 35% B over 10 min; 254 nm; Rt: 9.27 min. This resulted in 140 mg (35.5%) of the title compound as a white solid. MS-ESI: 217 (M+1)




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Intermediate 260



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N′-(tert-butyldimethylsilyl)-1-cyclopropyl-4-fluoro-1H-pyrazole-3-sulfonimidamide
Step 1: N-(tert-butyl)-1-cyclopropyl-4-fluoro-1H-pyrazole-3-sulfonamide

To a stirred solution of N-(tert-butyl)-4-fluoro-1H-pyrazole-3-sulfonamide (3.0 g, 13.6 mmol) in DMF (100 mL) was added cyclopropylboronic acid (3.51 g, 40.8 mmol) and Cu2O (1.93 g, 13.6 mmol) in portions at RT. To the above mixture was added pyridine (3.22 g, 40.8 mmol) dropwise at RT. The resulting mixture was stirred for 16 h at 70° C. under air. The resulting solution was filtered, the filter cake was washed with EtOAc (50 mL).The wash and filtrate was diluted with water (100 mL), and then extracted with EtOAc (3×100 mL). The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (1:6). This resulted in the title compound (1.4 g, 39.5%) as a yellow solid. MS-ESI: 262 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J=4.7 Hz, 1H), 7.77 (s, 1H), 3.86-3.76 (m, 1H), 1.15 (s, 9H), 1.09-0.96 (m, 4H). Ar-H at 8.14 (d, J=4.7 Hz, 1H) has correlations with cyclopropyl's CH2 at 1.09-0.96 (m, 4H) and CH at 3.86-3.76 (m, 1H) in NOESY.


Step 2: 1-Cyclopropyl-4-fluoro-1H-pyrazole-3-sulfonamide

To HCl (30 mL, conc.) was added N-(tert-butyl)-1-cyclopropyl-4-fluoro-1H-pyrazole-3-sulfonamide (1.40 g, 5.36 mmol) in portions at RT. The resulting solution was stirred for 1 h at RT. The resulting solution was concentrated under vacuum. This resulted in the title comopound (1.1 g, crude) as a brown solid. MS-ESI: 206 (M+1).


Steps 3-4 used similar procedures for converting compound 588″ to Intermediate 253 shown in Scheme 123 to afford Intermediate 260 from compound 619″. MS-ESI: 319 (M+1).




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Intermediate 261



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N′-(tert-butyldimethylsilyl)-2-(trifluoromethyl)thiazole-5-sulfonimidamide
Step 1: Lithium 2-(trifluoromethyl)thiazole-5-sulfinate

To a stirred solution of 2-(trifluoromethyl)thiazole (500 mg, 3.27 mmol) in THF (10 mL) under nitrogen was added n-BuLi (2.5 M in hexane, 3.3 mL, 8.17 mmol) dropwise at −78° C. The resulting solution was stirred for 20 min at −78° C. To the above solution was introduced SO2 (g) bubbled at −78° C. for 5 min. The resulting mixture was stirred for 2 h at RT and concentrated under vacuum. This resulted in 1.5 g (crude) of the title compound as a yellow solid which was used for next step without further purification. MS-ESI: 216 (M−1).


Step 2: 2-(Trifluoromethyl)thiazole-5-sulfonamide

To a stirred solution of lithium 2-(trifluoromethyl)thiazole-5-sulfinate (1.5 g, crude from last step) in ACN (10 mL) was added NCS (4.38 g, 32.7 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT. To the above solution was introduced NH3 (g) bubbled at 0° C. for 5 min. The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The mixture was dissolved EtOAc (200 mL) then washed with water (2×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-TLC with EtOAc/PE (1:1). This resulted in 160 mg (21.1% over two steps) of the title compound as a light yellow solid. MS-ESI: 231 (M−1). 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 5.32 (s, 2H).


Steps 3-4 used similar procedures for converting compound 593″ to Intermediate 254 shown in Scheme 124 to afford Intermediate 261 from compound 623″. MS-ESI: 346 (M+1).




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Intermediate 262



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N′-(tert-butyldimethylsilyl)-4-fluoro-1-((R)-2-hydroxypropyl)-1H-pyrazole-3-sulfonimidamide
Step 1: (R)-N-(tert-butyl)-4-fluoro-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide

To a stirred solution of N-(tert-butyl)-4-fluoro-1H-pyrazole-5-sulfonamide (1.0 g, 4.52 mmol) in DMF (20 mL) under nitrogen was added K2CO3 (1.87 g, 13.56 mmol) and (R)-2-methyloxirane (524 mg, 9.04 mmol). The resulting solution was stirred for 16 h at 100° C. The reaction was quenched with 25 mL of water, and extracted with 3×30 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:3). This resulted in 820 mg (65.0%) of the title compound as a yellow solid. MS-ESI: 280 (M+1).


Step 2: (R)-4-fluoro-1-(2-hydroxypropyl)-1H-pyrazole-3-sulfonamide

To stirred concentrated HCl (10 mL) was added (R)-N-(tert-butyl)-4-fluoro-1-(2-hydroxypropyl)-1H- pyrazole-3-sulfonamide (820 mg, 2.94 mmol) in portions at 0° C. The resulting solution was stirred for 2 h at RT and then concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc (100%). This resulted in 600 mg (91.5%) of the title compound as yellow oil. MS-ESI: 224 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.98 (d, J=4.7 Hz, 1H), 7.68 (s, 2H), 5.03 (d, J=4.3 Hz, 1H), 4.09-3.90 (m, 3H), 1.07 (d, J=5.8 Hz, 3H). Ar—H at 7.98 (d, J=4.7 Hz, 1H) has correlation with CH2 at 4.09-3.90 (m, 3H) in NOESY.


Steps 3-4 used similar procedures for converting compound 588″ to Intermediate 253 shown in Scheme 123 to afford Intermediate 262 from compound 626″. MS-ESI: 337 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 7.87 (d, J=4.8 Hz, 1H), 6.86 (s, 2H), 5.00 (br s, 1H), 4.07-3.89 (m, 3H), 1.10-1.02 (m, 3H), 0.86 (s, 9H), 0.04 (s, 6H).




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Intermediate 263



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N′-(tert-butyldimethylsilyl)-1-cyclopropyl-1H-pyrazole-3-sulfonimidamide
Step 1: 1-Cyclopropyl-3-nitro-1H-pyrazole

To a stirred solution of 3-nitro-1H-pyrazole (20.0 g, 177 mmol) and cyclopropylboronic acid (30.4 g, 353 mmol) in DCE (500 mL) was added 2,2′-bipyridine (27.6 g, 177 mmol) dropwise at RT. To the above solution were added Na2CO3 (18.8 g, 177 mmol) and Cu(OAc)2 (32.1 g, 177 mmol) in portions at RT. The resulting mixture was stirred for 16 h at 70° C. under air. The mixture was allowed to cool down to RT then filtered. The filter cake was washed with EtOAc (100 mL). The filtrate and wash were combined and concentrated under vacuum. The residue was diluted with water (500 mL), extracted with EtOAc (3×500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (1:10). This resulted in the title compound (12.0 g, 44.3%) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (d, J=2.5 Hz, 1H), 7.05 (d, J=2.6 Hz, 1H), 3.96 (tt, J=7.5, 3.9 Hz, 1H), 1.21-1.13 (m, 2H), 1.13-1.03 (m, 2H). Cyclopropane's CH at 3.96 (tt, J=7.5, 3.9 Hz, 1H) has correlation with Ar—H at 8.13 (d, J=2.5 Hz, 1H) in NOESY.


Step 2: 1-Cyclopropyl-1H-pyrazol-3-amine

To a stirred solution of 1-cyclopropyl-3-nitro-1H-pyrazole (12.0 g, 78.4 mmol) in MeOH (50 mL) was added Pd/C (10% wt., 120 mg) in portions at RT under nitrogen. The mixture was stirred for 16 h at RT under hydrogen with a hydrogen balloon, then filtered through a Celite pad and concentrated under vacuum. This resulted in the title compound (8.68 g, 90%) as a light yellow solid. MS-ESI: 124 (M+1).


Step 3: 1-Cyclopropyl-1H-pyrazole-3-sulfonyl chloride

To a stirred solution of 1-cyclopropyl-1H-pyrazol-3-amine (1.0 g, 8.13 mmol) in ACN (10 mL) under nitrogen was added HBF4 (40% wt. in water, 2.68 g, 12.2 mmol) dropwise at 0° C. To the above solution was added tert-butyl nitrite (1.26 g, 12.2 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at 0° C. This solution was assigned as solution A. To a stirred solution of CuCl (2.41 g, 24.4 mmol) in ACN (5 mL) was introduced SO2 (g) bubbled for 10 min at 0° C., this solution was assigned as solution B. To solution B was added solution A dropwise with stirring at 0° C. over 5 min. The resulting solution was stirred for 10 min at 0° C., then allowed to react, with stirring, for an additional 3 h at RT. The reaction was quenched with water/ice (10 mL), and then extracted with DCM (2×30 mL). The organic layers were combined and washed with brine (30 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum. This resulted in the title compound (1.5 g, crude) as yellow oil which was used in next step without further purification.


Step 4: 1-Cyclopropyl-1H-pyrazole-3-sulfonamide

To a stirred DCM (25 mL) was bubbled NH3 (g) for 15 min at 0° C., this was followed by the addition of 1-cyclopropyl-1H-pyrazole-3-sulfonyl chloride (1.50 g, crude from last step) in DCM (10 mL) dropwise at 0° C. The resulting solution was stirred for 1 h at RT and then concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (1:1). This resulted in the title compound (250 mg, 16.4% over two steps) as a white solid. MS-ESI: 186 (M−1).


Steps 5-6 used similar procedures for converting compound 588″ to Intermediate 253 shown in Scheme 123 to afford Intermediate 263 from compound 631″. MS-ESI: 301 (M+1).




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Intermediate 264



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2,3 -Bis(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine
Step 1: 3-Iodo-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (2.0 g, 9.89 mmol) in TFA (20 mL) under nitrogen was added NIS (3.34 g, 14.8 mmol) in portions at 0° C. The resulting solution was stirred for 16 h at RT. The resulting mixture was concentrated under vacuum. The residue was diluted with 50 mL of water, and then extracted with 3×80 mL of EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from silica gel column with EtOAc/PE (9:1). This resulted in 2 g (61.6%) of the title compound as a brown solid. MS-ESI: 329 (M+1).


Step 2: 2,3-Bis(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

To a stirred solution of 3-iodo-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (450 mg, 1.37 mmol) in DMF (5 mL) in a sealed tube under nitrogen was added (1,10-phenanthroline) (trifluoromethyl)copper(I) (1.72 g, 5.48 mmol). The resulting solution was stirred for 16 h at 45° C. The solids were filtered out. The filtrate was purified by Prep-HPLC using the following conditions: Column:)(Bridge Shield RP18 OBD Column, 30*150 mm, 5 um; Mobile Phase A: Water (10 mM NH4HCO3+0.1% NH3E2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 35% B over 10 min; UV 254 nm; RT: 9.14 min. This resulted in 150 mg (40.4%) of the title compound as a dark yellow solid. MS-ESI: 271 (M+1).




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Intermediate 265



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(2,3-Bis(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate

To a stirred solution of 2,3-bis(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (125 mg, 0.46 mmol) in THF (15 mL) under nitrogen was added NaH (60% wt., 56 mg, 1.39 mmol) in portions at 0° C. To this was added DMAP (28 mg, 0.23 mmol) at 0° C. The resulting solution was stirred for 20 min at 35° C. To the above solution was added 2,2,2-trichloroethyl carbonochloridate (1.96 g, 9.25 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 3 days at 35° C. The reaction was then quenched with 30 mL of water/ice. The resulting solution was extracted with 3×40 mL of EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was eluted from a silica gel column with EtOAc/PE (1:9). This resulted in 13 mg (6.2%) of the title compound as a yellow solid. MS-ESI: 445/447/449 (M+1).


Example 1
Compound 165



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N′-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (Scheme 1)
Examples 2 and 3
Compounds 165a and 165b



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(R)- and (S)- N′-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide



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Step 1: N-(tert-butyldimethylsilyl)-N′-(5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-5-(2-hydroxy-propan-2-yl)thiazole-2-sulfonimidamide

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (206 mg, 0.61 mmol) in THF (10 mL). To the above solution was added NaH (60% wt. oil dispersion, 73.6 mg, 1.84 mmol). The resulting solution was stirred for 10 min at RT. Then a solution of phenyl (5-fluoro-2,4-diisopropylpyridin-3-yl)carbamate (194 mg, 0.61 mmol) in THF (10 mL) was added to the above solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at RT. The reaction was then quenched by the addition of 10 mL of water. The resulting solution was extracted with 5×20 ml of EtOAc. The organic phases were combined and concentrated. This resulted in 360 mg crude title compound as light yellow oil. MS-ESI: 558(M+1).


Step 2: N′-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiazole-2- sulfonimidamide

Into a 50-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-N′-((5-fluoro-2,4-diiso-propyl-pyridin-3 -yl)carbamoyl)-5 -(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (360 mg, crude) in THF (5 mL) and HF pyridine (0.10 mL). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge BEH130 Prep C18 OBD, 19*150 mm 5 um; mobile phase, water (10 mM NH4HCO3) and ACN (30% to 60% gradient over 7 min); Detector, 254/210 nm. This resulted in 70 mg of Example 1 as an off-white solid. MS-ESI: 444 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.27 (s, 1H), 7.76 (br s, 3H), 5.82 (s, 1H), 3.25-3.05 (m, 2H), 1.53 (s, 6H), 1.18 (d, J=6.9 Hz, 6H), 1.08 (d, J=6.8 Hz, 6H).


Step 3: Chiral Resolution

The product (100 mg, Example 1) was separated with the followed condition: Column: CHIRALPAK ID, 2*25 cm (5 um); Mobile Phase A: HPLC grade Hex (0.1% FA), Phase B: HPLC grade EtOH; Flow rate: 20 mL/min; Gradient: 15% B to 15% B in 18 min; 220/254 nm; Rt1: 9.555 min; Rt2: 14.358 min. This resulted in 24.6 mg (97.9% ee, 49.2%) of Example 2 (fast-eluting) as a white solid and 22.8 mg (98.9% ee, 45.6%) of Example 3 as a white solid. The absolute stereochemistry was unconfirmed.


Example 2

MS-ESI: 444 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.27 (s, 1H), 7.76 (br s, 3H), 5.82 (s, 1H), 3.25-3.05 (m, 2H), 1.53 (s, 6H), 1.18 (d, J=6.9 Hz, 6H), 1.08 (d, J=6.8 Hz, 6H).


Example 3

MS-ESI: 444 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.27 (s, 1H), 7.76 (br s, 3H), 5.82 (s, 1H), 3.25-3.05 (m, 2H), 1.53 (s, 6H), 1.18 (d, J=6.9 Hz, 6H), 1.08 (d, J=6.8 Hz, 6H).









TABLE 15







Examples in the following table were prepared using similar conditions as described in


Example 1 and Scheme 1 from appropriate starting materials.











Example
Compound


Exact Mass


#
Number
Structure
IUPAC Name
[M + H]+





4
163


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N′-((5-fluoro-2,4- diisopropylpyridin-3- yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiazole- 2-sulfonimidamide
444





5
128


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N-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]py- ridin-8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
422





6
110


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N′-((2,4-diisopropylpyridin-3- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
426









Example 7
Compound 164



embedded image


N′-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme 1A)



embedded image


Step 1: Tert-butyl (N-((5-fluoro-2,4-diisopropylpyridin-3-yl) carbamoyl)-2-(2-hydroxypropan-2-yl) thiazole-5-sulfonimidoyl)carbamate

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl (amino(2-(2-hydroxypropan-2-yl)thiazol-5 -yl)(oxo)-λ6-sulfaneylidene)carbamate (327 mg, 1.02 mmol) in THF (10 mL). To the stirred solution was added NaH (60% wt. oil dispersion, 122 mg, 3.05 mmol). The resulting solution was stirred for 10 min at RT. Then a solution of phenyl N-[5-fluoro-2,4-bis(propan-2-yl)pyridin-3-yl]carbamate (322 mg, 1.02 mmol) in THF (10 mL) was added. The resulting solution was allowed to react, with stirring, for an additional 2 h at RT. The reaction was then quenched by the addition of 3 mL of water. The resulting mixture was concentrated. This resulted in 500 mg crude title compound as yellow oil. MS-ESI: 544 (M+1).


Step 2: N′-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 50-mL round-bottom flask, was placed tert-butyl (N-((5-fluoro-2,4-diisopropylpyridin-3-yl)-carba-moyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoyl)carbamate (500 mg crude) in HCl (4M)/dioxane (20 mL). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column,)(Bridge Prep C18 OBD, 5 um, 19*150 mm; mobile phase, water (10 mM NH4HCO3) and ACN (5% to 41% gradient in 6 min); Detector, 254/210 nm. This resulted in 90 mg of Example 7 as an off-white solid. MS-ESI: 444 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.60 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.86 (s, 2H), 6.26 (s, 1H), 3.29-3.05 (m, 2H), 1.49 (s, 6H), 1.20-0.99 (m, 12H).









TABLE 16







Examples in the following table were prepared using similar conditions as described in


Example 7 and Scheme 1A from appropriate starting materials.












Final Target


Exact Mass


Example #
Number
Structure
IUPAC Name
[M + H]+





8
167


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide
422









Example 9
Compound 159



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N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide (scheme 2)



embedded image


Step 1: N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonoimidamide (160 mg, 0.41 mmol) in THF (10 mL). To the stirred solution was added NaH (60% wt. oil dispersion, 48.7 mg, 1.22 mmol) at 0° C. The resulting solution was stirred for 10 min at RT. Then 2,2,2-trichloroethyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (142 mg, 0.41 mmol) was added to the reaction solution. The resulting solution was allowed to react with stirring for an additional 2 h while the temperature was maintained at 40° C. in an oil bath. The reaction was then quenched by the addition of 10 mL of H2O. The resulting solution was extracted with 5×20 mL of EtOAc and the organic layers was combined and concentrated. The residue was purified using TLC with DCM/MeOH=10:1. This resulted in 230 mg (95.4%) of the title compound as a light yellow solid. MS-ESI: 595 (M+1).


Step 2: N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl) -1-phenyl-1H-pyrazole-3-sulfonimidamide

Into a 50-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-N′-hexahydrodicyclopenta[b, e]pyridin-8-yl)carbamoyl)-5 -(2-hydroxypropan-2-yl)-1-phenyl-1H-pyrazole-3-sulfonimidamide (230 mg, 0.39 mmol) in THF (8 mL). To the above solution was added HF-Pyridine (0.1 mL) dropwise. The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD, 19*150 mm 5 um; mobile phase, water (10 mM NH4HCO3+0.1% NH3.H2O) and ACN (10% to 54% gradient over 6 min); Detector, UV, 210/254 nm. This resulted in 102 mg (53.8%) of Example 9 as an off-white solid. MS-ESI: 481 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.58 (s, 2H), 7.52 (s, 5H), 6.75 (s, 1H), 5.43 (s, 1H), 2.79 (t, J=7.6 Hz, 4H), 2.71 (t, J=7.5 Hz, 4H), 2.00-1.80 (m, 4H), 1.34 (s, 6H).









TABLE 17







Examples in the following table were prepared using similar conditions as described in


Example 9 and Scheme 2 from appropriate starting materials.












Compound


Exact Mass


Example #
Number
Structure
IUPAC Name
[M + H]+





10
135


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4- propionylthiophene-2- sulfonimidamide
419





11
119


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1-isopropyl-1H- pyrazole-3-sulfonimidamide
389





12
122


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1-(difluoromethyl)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
425





13
125


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4- ((dimethylamino)methyl)benzenesul- fonimidamide
442





14
126


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1-isopropyl-1H- pyrazole-3-sulfonimidamide
417





15
101


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3-fluoro-5-(2-hydroxypropan-2- yl)-N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
465





16
114


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4-(2-hydroxypropan-2-yl)-N′- ((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e!pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
447





17
117


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N′-((3-ethyl-2-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide
424





18
116


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2-(2-hydroxypropan-2-yl)-N′-((3- isopropyl-2-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
438





19
130


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4-((dimethylamino)methyl)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8- yl)carbamoyl)benzenesulfonimida- mide
414





20
170


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)-4- (methoxymethyl)thiazole-5- sulfonimidamide
494





21
171


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1-isopropyl-N′-((3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole-4- sulfonimidamide
403





22
172


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1-isopropyl-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
415





23
173


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4- isopropylthiophene-2- sulfonimidamide
405





24
174


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N′-((2-cyclopropyl-3-methyl-6,7- dihydro-5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-3-fluoro-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
453





25
175


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N′-((2-cyclopropyl-3-methyl-6,7- dihydro-5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
435





26
176


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N′-((2-cyclopropyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
421





27
177


embedded image


4-fluoro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
439





33
111


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N′-((2,3-dihydro-1H- cyclopenta[c]quinolin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide
432









Example 28
Compound 118



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N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxyethyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (scheme 2A)



embedded image


Step 1: N-(tert-butyldimethylsilyl)-4-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N′-((1,2,3,5,6,7-hexahy drodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-4-(2-((tert-butyldimethyl-silyl)oxy)ethyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (200 mg, 0.41 mmol) in THF (15 mL). To the above solution was added NaH (60% wt. oil dispersion, 32.8 mg, 0.82 mmol), then 2,2,2-trichloroethyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (142 mg, 0.41 mmol) was added into the reaction solution. The resulting solution was stirred for 30 min at RT. The reaction was then quenched by the addition of 5.0 mL of water. The resulting solution was extracted with 3×15 mL of EtOAc, and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 210 mg (75%) of the title compound as yellow oil. MS-ESI: 694 (M+1).


Step 2: N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxyethyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-4-(2-((tert-butyldimethyl-silyl)oxy)ethyl)-N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (200 mg, 0.29 mmol) in HCl in dioxane (10 mL, 4 M). The resulting solution was stirred for 30 min at RT. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column,)(Bridge Prep OBD C18, 30.150 mm 5 um; mobile phase, water (10 mM NH4HCO3) and ACN (4% to 28% gradient in 5 min); Detector, UV 254/220nm. This resulted in 90 mg (67%) of Example 28 as a white solid. MS-ESI: 466 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.76 (br s, 2H), 6.19 (s, 1H), 4.90-4.70 (br s, 1H), 3.80-3.60 (m, 2H), 3.20-3.00 (m, 2H), 2.90-2.60 (m, 8H), 2.10-1.80 (m, 4H), 1.48 (d, J=6.0 Hz, 6H).









TABLE 18







Examples in the following table were prepared using similar conditions as described in


Example 28 and Scheme 2A from appropriate starting materials.











Example
Compound


Exact Mass


#
Number
Structure
IUPAC Name
[M + H]+





29
150


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-4-(hydroxymethyl)-2- (2-hydroxypropan-2-yl)thiazole-3- sulfonimidamide
452





30
121


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-4-(hydroxymethyl)-2- (2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide
480





31
178


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N′-((3-hydroxy-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide
438





32
179


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N′-((4,6-diisopropyl-2- (trifluoromethyl)pyrimidin-5- yl)carbamoyl)-4-(hydroxymethyl)-2- (2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide
525









Example 34
Compound 107



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N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2-sulfonimidamide (scheme 2B)



embedded image


Step 1: N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2-sulfonimidamide

N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2-sulfonoimidamide (250 mg, 0.72 mmol) in THF (10 mL). To the above solution was added NaH (60% wt. oil dispersion, 57.2 mg, 1.43 mmol). The resulting solution was stirred for 10 min at RT. Then 2,2,2-trichloroethyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (251 mg, 0.72 mmol) was added to the reaction solution. The resulting solution was allowed to react, with stirring, for an additional 16 h at 30° C. The reaction was then quenched by the addition of 10 mL of water. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 270 mg (68.6%) of the title compound as a white solid. MS-ESI: 549 (M+1).


Step 2: N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl) -5-methylthiophene-2-sulfonimidamide

Into a 50-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydrodicyclo-penta[b,e]pyridin-8-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)-5-methylthiophene-2-sulfonimidamide (270 mg, 0.49 mmol) in CH3OH (10 mL). To the above solution was added silica gel (5.0 g). The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (8:1). The crude product was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep C18 OBD, 10 um, 19*250 mm; mobile phase, water (0.1% FA) and ACN (10% to 40% gradient over 7 min); Detector, UV. This resulted in 100 mg (46.78%) of Example 34 as a white solid. MS-ESI: 435 (M+1). 1HNMR (400 MHz, DMSO-d6) δ: 8.72 (s, 1H), 8.14 (s, 1H), 7.64 (br s, 2H), 7.48 (s, 1H), 5.11 (br s, 1H), 2.81-2.74 (m, 4H), 2.73-2.71 (m, 4H), 2.54 (s, 3H), 1.99-1.92 (m, 4H), 1.44 (s, 6H).









TABLE 19







Examples in the following table were prepared using similar conditions as described in


Example 34 and Scheme 2B from appropriate starting materials.











Example
Compound


Exact Mass


#
Number
Structure
IUPAC Name
[M + H]+





35
155


embedded image


N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
421





36
166


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-3-(2- hydroxypropan-2-yl)-1-methyl-1H- pyrazole-5-sulfonimidamide
419





37
149


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
421





38
105


embedded image


3-fluoro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
439





39
141


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4-(2-hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
435





40
103


embedded image


3-fluoro-5-(2-hydroxypropan-2-yl)- N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
453





41
127


embedded image


N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
449





42
102


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-3-fluoro-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
467





43
131


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N′-((3,5-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
449





44
123


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N′-((3,5-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4- isopropylthiophene-2- sulfonimidamide
433





45
180


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1-(difluoromethyl)-N′-((1′,5′,6′,7′- tetrahydro-2′H-spiro[cyclopropane- 1,3′-dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
423





46
113


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tert-butyl (4- ((dimethylamino)methyl)-N- ((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8- yl)carbamoyl)phenylsulfonimidoyl) carbamate
514





47
181


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N′-((2-cyclopropyl-3-ethyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)thiophene-2-sulfonimidamide
449





48
182


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4-(2-hydroxypropan-2-yl)-N′-((2- isopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
423









Example 49
Compound 183



embedded image


N′-((3-fluoro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (scheme 3)



embedded image


Step 1: 2-(2-Hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)-1,3-thiazole-5-sulfonoimidamide (2.0 g, 5.96 mmol) in dioxane (50 mL) and aq. HCl (10 mL, 12 M). The resulting solution was stirred for 2 h at RT. The resulting mixture was concentrated. This resulted in 2.0 g crude title compound as a white solid. MS-ESI: 222 (M+1).


Step 2: N′-((3-fluoro-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxy-propan-2-yl)thiazole-5-sulfonimidamide

Into a 25-mL round-bottom flask, was placed a solution of 2,2,2-trichloroethyl (3-fluoro-1,2,3,5,6,7-hexa- hydrodicyclopenta[b,e]pyridin-8-yl)carbamate (66 mg, 0.18 mmol) in THF (2.0 mL). This was followed by the addition of NaH (60% wt. oil dispersion, 14.4 mg, 0.36 mmol) at 0° C. The resulting solution was stirred for 10 min at RT. To this was added 2-(2-hydroxypropan-2-yl)-1,3-thiazole-5-sulfonoimidamide (40 mg, 0.18 mmol). The resulting solution was stirred overnight at 45° C. The reaction was then quenched by the addition of 0.5 mL of water. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep C18 OBD, 10 um, 19*250 mm; mobile phase, water (0.05% FA) and ACN (5% to 30% gradient over 7 min); Detector, UV. This resulted in 5.4 mg (6.8%) of Example 49 as a white solid. MS-ESI: 440 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.10 (s, 1H), 5.99-5.60 (m, 1H), 3.00-2.60 (m, 8H), 2.10-1.90 (m, 2H), 1.51 (s, 6H).









TABLE 20







Examples in the following table were prepared using similar conditions as described in


Example 49 and Scheme 3 from appropriate starting materials.











Example
Compound


Exact Mass


#
Number
Structure
IUPAC Name
[M + H]+





50
154


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-2-(2-hydroxypropan-2- yl)thiazole-4-sulfonimidamide
422









Example 51
Compound 120



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4-((Dimethylamino)methyl)-N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-N-methylbenzenesulfonimidamide (scheme 3A)



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Step 1: 4-((Dimethylamino)methyl)-N′-methylbenzenesulfonimidamide

Into a 50 mL round-bottom flask was added N-(tert-butyldimethylsilyl)-4-((dimethylamino)methyl)-N′-methylbenzenesulfonimidamide (600 mg, 1.76 mmol) in DCM (3.0 mL) at RT. To this stirred solution was added TFA (3 mL, 40 mmol) dropwise. The resulting mixture was stirred for 30 min and concentrated under reduced pressure. The crude product (500 mg) was purified by Prep-HPLC with the following conditions (Column:)(Bridge Prep OBD C18, 30×150 mm, 5 um; Mobile phase A: water (10 mM, NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 45% B in 8 min; 254/210 nm; Rt: 6.13 min) to afford the title compound (250 mg, 62.6%) as a white solid. MS-ESI: 228 (M+1).


Step 2: 4-((Dimethylamino)methyl)-N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-N-methylbenzenesulfonimidamide

Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, were placed 4-((dimethylamino)methyl)-N′-methylbenzenesulfonimidamide (180 mg, 0.79 mmol) in THF (10 mL) at 0° C. To a stirred solution was added NaH (60% wt. oil dispersion, 63.2 mg, 1.58 mmol) in portions at 0° C. The resulting mixture was stirred for 15min at 0° C. To the above mixture was added 2,2,2-trichloroethyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (277 mg, 0.79 mmol) in THF (3 mL) dropwise at 0° C. The resulting mixture was stirred for additional 2 h at RT. The reaction was quenched by the addition of water/ice (0.5 mL) at 0° C. The resulting mixture was concentrated under reduced pressure. The crude product (300 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 30×150 mm 5 um; Mobile phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN (5% to 50% gradient over 7 min), Flow rate: 60 mL/min; 254/210 nm UV detector; Rt 6.37 min) to afford Example 51 as a white solid (80 mg, 23%). MS-ESI: 428(M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 7.80 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 3.48 (s, 2H), 2.85-2.73 (m, 4H), 2.73-2.65 (m, 4H), 2.44 (s, 3H), 2.17 (s, 6H), 2.00-1.80 (m, 4H).


Example 52
Compound 162



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2-(2-hydroxypropan-2-yl)-N′-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazole-5-sulfonimidamide (scheme 4)



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Step 1: Tert-butyl (2-(2-hydroxypropan-2-yl)-N-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]-pyridin-8-yl)carbamoyl)thiazole-5-sulfonimidoyl)carbamate

Into a 1-L round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl (amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene)carbamate (12.8 g, 40 mmol) in THF (300 mL). This was followed by the addition of NaH (60% wt. oil dispersion, 2.66 g, 66.4 mmol) in several batches at 0° C. The resulting solution was stirred for 20 min at RT. To this was added a solution of N-(3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)-1H-imidazole-1-carboxamide (7.5 g, 27 mmol) in DMF (50 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. The resulting mixture was quenched by the addition of 10 mL of H2O. The resulting solution was extracted with 2×300 mL of EtOAc. The combined organic layer was washed with 3×200 mL H2O, dried over anhydrous sodium sulfate and concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 3.5 g (24.6%) of the title compound as a white solid. MS-ESI: 536 (M+1).


Step 2: 2-(2-hydroxypropan-2-yl)-N′-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)- carbamoyl)thiazole-5-sulfonimidamide

Into a 500-mL round-bottom flask, was placed a solution of tert-butyl (2-(2-hydroxypropan-2-yl)-N-((3- methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazole-5-sulfonimidoyl)carbamate (3.5 g, 6.53 mmol) in dioxane (210 mL). This was followed by the addition of HCl (52.5 mL, 12 M) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT. The pH value of the solution was adjusted to 7-8 with Na2CO3 (1.6 M). The resulting solution was extracted with 4×500 mL of EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column,)(Bridge Prep C18 OBD, 19*150 mm 5 um; mobile phase, water (10 mM NH4HCO3) and ACN (4% to 22% gradient over 6 min); Detector, 220/254 nm UV. This resulted in 2 g (71%) of Example 52 as a white solid. MS-ESI: 436 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 8.08 (s, 1H), 7.89 (br s, 2H), 6.28 (s, 1H), 3.03-2.98 (m, 1H), 2.83-2.79 (t, J=7.2 Hz, 2H), 2.72-2.61 (m, 4H), 2.27-2.20 (m, 1H), 2.07-1.92 (m, 2H), 1.51-1.45 (m, 7H), 1.21-1.19 (d, J=8.0 Hz, 3H).


Example 53
Compound 104



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4-(2-Hydroxypropan-2-yl)-5-methyl-N′-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazole-2-sulfonimidamide (scheme 4A)



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Step 1: N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methyl-N′-((3-methyl-1,2,3,5,6,7-hexa-hydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazole-2-sulfonimidamide

Into a 100-mL round-bottom flask, was placed N-(3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)-1H-imidazole-1-carboxamide (150 mg, 0.43 mmol) in DMF (15 mL). To the stirred solution was added NaH (60% wt. oil dispersion, 56.1 mg, 1.29 mmol). This was followed by the addition of the solution of N′-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methylthiazole-2-sulfonimidamide (120 mg, 0.43 mmol) in DMF (5.0 mL). The resulting solution was stirred for 16 h at 30° C. in an oil bath. The reaction was then quenched by the addition of 15 mL of water. The resulting solution was extracted with 2×30 mL of EtOAc. The combined extracts were dried over anhydrous sodium sulfate and concentrated. This resulted in 180 mg (74.4%) of the title compound as a yellow solid. MS-ESI: 564 (M+1).


2: 4-(2-Hydroxypropan-2-yl)-5-methyl-N′-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazole-2-sulfonimidamide

Into a 50-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-4-(2-hydroxypropan-2-yl)-5-methyl-N′-((3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazole-2-sulfonimidamide (180 mg, 0.32 mmol) in THF (15 mL), to the stirred solution was added TBAF (250 mg, 0.96 mmol). The resulting solution was stirred for 5 h at RT. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). The crude product was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18 OBD, 19*150 mm 5 um; mobile phase, water (0.1% FA) and ACN (12% to 22% gradient over 10 min); Detector, UV 254 nm. This resulted in 40 mg (27.87%) of Example 53 as a white solid. MS-ESI: 450 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 5.96 (s, 1H), 2.91-3.04 (m, 1H), 2.85-2.80 (m, 2H), 2.75-2.62 (m, 4H), 2.44 (s, 3H), 2.25-2.15 (m, 1H), 2.00-1.90 (m, 2H), 1.58(s, 6H), 1.42-1.40 (m, 1H), 1.20(d, J=7.8Hz, 3H)









TABLE 21







Examples in the following table were prepared using similar conditions as described in


Example 53 and Scheme 4A from appropriate starting materials.












Final Target


Exact Mass


Example #
Number
Structure
IUPAC Name
[M + H]+





54
168


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4-(hydroxymethyl)-2-(2- hydroxypropan-2-yl)-N′-((3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide
466









Example 55
Compound 158



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N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonimidamide (scheme 5)



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Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed N-(1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)-1H-imidazole-1-carboxamide (246 mg, 0.92 mmol) in DMF (5 mL). To the above solution was added 5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazole-3-sulfonimidamide (200 mg, 0.92 mmol) and NaH (60% wt. oil dispersion, 73.6 mg, 1.84 mmol). The resulting solution was stirred for 1 h at RT. The resulting mixture was quenched with 3 mL of H2O and concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD, 19*150 mm, 5 um; mobile phase, water (10 mM NH4HCO3+0.1% NH3.H2O) and ACN (5% to 38% gradient in 6 min); Detector, UV 210/254 nm. This resulted in 8.2 mg (2.14%) of Example 55 as a white solid. MS-ESI: 419 (M+1). 1H NMR (400 MHz, DMSO-d6) 8.70 (s, 1H), 7.47 (s, 2H), 6.49 (s, 1H), 5.51 (s, 1H), 4.04 (s, 3H), 2.90-2.60 (m, 8H), 2.00-1.80 (m, 4H), 1.48 (s, 6H).









TABLE 22







Examples in the following table were prepared using similar conditions as described in


Example 55 and Scheme 5 from appropriate starting materials.















Exact



Final Target


Mass


Example #
Number
Structure
IUPAC Name
[M + H]+





56
157


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-6-(2- hydroxypropan-2-yl)-2- methylpyridine-3-sulfonimidamide
430





57
156


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-6-(2- hydroxypropan-2-yl)pyridine-3- sulfonimidamide
416





58
160


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N′-((3,5-diisopropylpyridin-4- yl)carbamoyl)-2-(2-hydroxypropan- 2-yl)thiazole-5-sulfonimidamide
426





59
129


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1-isopropyl-N′-((3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
403





60
161


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N′-((2,3,5,6,7,8-hexahydro-1H- cyclopenta[b]quinolin-9- yl)carbamoyl)-2-(2-hydroxypropan- 2-yl)thiazole-5-sulfonimidamide
436





61
153


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide
450





62
152


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2-(2-hydroxypropan-2-yl)-N′-((2- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide
436





63
151


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2-(2-hydroxypropan-2-yl)-N′-((1- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide
436





64
147


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N′-((2,2-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide
450





65
146


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8-(3-(amino(2-(2-hydroxypropan-2- yl)thiazol-5-yl)(oxo)-λ6- sulfaneylidene)ureido)-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridine 4-oxide
438





66
133


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2-(2-hydroxypropan-2-yl)-N′- ((2,3,5,6,-tetramethylpyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
398





67
112


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2-(2-hydroxypropan-2-yl)-N′-((2- propyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
424









Example 68
Compound 115



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N′-((2-fluoro-3,5-diisopropylpyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (scheme 6)



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Step 1: N-(tert-butyldimethylsilyl)-N′-((2-fluoro-3,5-diisopropylpyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

Into a 100-mL round-bottom flask, was placed 2-fluoro-4-isocyanato-3,5-diisopropylpyridine (240 mg, 1.22 mmol) in THF (10 mL), to the stirred solution was added NaH (60% wt. oil dispersion, 59 mg, 2.45 mmol) and N′-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (410 mg, 1.22 mmol). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 mL of EtOAc and the organic layers combined and dried and concentrated. This resulted in 400 mg (59%) of the title compound as a yellow solid. MS-ESI: 558 (M+1).


Step 2: N′-((2-fluoro-3,5-diisopropylpyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide

Into a 100-mL round-bottom flask, was placed N-(tert-butyldimethylsilyl)-N′-((2-fluoro-3,5-diisopropyl-pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (400 mg, 0.72 mmol) in THF (10 mL) and HF-pyridine (31 mg, 1.08 mmol, 70% wt.). The resulting solution was stirred for 2 h at 25° C. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column,)(Bridge Prep OBD C18, 30*150 mm 5 um; mobile phase, water (10 mM NH4HCO3) and ACN (5% to 35% gradient over 6 min); Detector, UV 220/254 nm. This resulted in 200 mg (63%) of Example 68 as a white solid. MS-ESI: 443 (M+1). 1H NMR (400 MHz, CD3OD-d4) δ 8.14 (s, 1H), 7.92 (s, 1H), 3.30-3.00 (m, 2H), 1.59 (s, 6H), 1.50-1.10 (m, 12H).


Example 69
Compound 106



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3-Fluoro-N′-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide (scheme 7)



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Into a 50-mL round-bottom flask, was placed 5-fluoro-3-isocyanato-2,4-diisopropylpyridine (120 mg, 0.50 mmol) in THF (15 mL). To the stirred solution was added NaH (60% wt. oil dispersion, 60.4 mg, 1.51 mmol). The resulting solution was stirred for 10 min at RT. Then 3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide (150 mg, crude) was added . The resulting solution was allowed to react, with stirring, for an additional 1 h at RT. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 5×30 mL of EtOAc and the combined extract was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD, 5 um,19*150 mm ; mobile phase, water (10 mM NH4HCO3) and ACN (5% to 50% gradient over 6 min); Detector, UV (254/210 nm). This resulted in 75 mg (32%) of Example 69 as an off-white solid. MS-ESI: 461 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 8.29 (s, 1H), 7.68 (br s, 2H), 6.96 (s, 1H), 5.83 (s, 1H), 3.38-3.17 (m, 2H), 1.45 (s, 6H), 1.22 (d, J=7.1 Hz, 6H), 1.10 (d, J=6.7 Hz, 6H).









TABLE 23







Examples in the following table were prepared using similar conditions as described in


Example 69 and Scheme 7 from appropriate starting materials.












Final





Example
Target


Exact Mass


#
Number
Structure
IUPAC Name
[M + H]+





70
148


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N′-((5-fluoro-2,4- diisopropylpyridin-3- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
443





71
132


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4-((dimethylamino)methyl)- N′-((5-fluoro-2,4- diisopropylpyridin-3- yl)carbamoyl)benzenesulfon- imidamide
436





72
140


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5-(2-hydroxypropan-2-yl)- N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8- yl)carbamoyl)thiazole-2- sulfonimidamide
436





73
139


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4-((dimethylamino)methyl)- 2-fluoro-N′-((3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8- yl)carbamoyl)benzenesulfon- imidamide
446





74
134


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4-((dimethylamino)methyl)- N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8- yl)carbamoyl)benzenesulfon- imidamide
428





75
145


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2-(2-hydroxypropan-2-yl)- N′-((3-isopropyl-2-phenyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
500





76
144


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N′-((3-ethyl-2-phenyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide
486





77
143


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2-(2-hydroxypropan-2-yl)- N′-((3-methyl-2-phenyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
472





78
142


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2-(2-hydroxypropan-2-yl)- N′-((2-phenyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
458





79
138


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N′-((2,3-dimethyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide
410





80
137


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N′-((2-ethyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide
410





81
136


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2-(2-hydroxypropan-2-yl)- N′-((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane- 1,3′- dicyclopenta[b,e]pyridin]- 8′-yl)carbamoyl)thiazole-5- sulfonimidamide
448





82
124


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N′-((2-cyclopropyl-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide
436
















TABLE 24







Examples in the following table were obtained from chiral HPLC resolutions of racemic


examples described above. The chiral column and eluents are listed in the table. As a convention,


the faster-eluting enantiomer is always listed first in the table followed by the slower-eluting


enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been


resolved and the absolute stereochemistry at that center has not been determined. For mixtures


contained two chiral centers and if two columns are used for separating the four diastereomers, the


individual isomers are listed in the order of faster column 1/faster column 2; faster column 1/slower


column 2; slower column 1/faster column 2; followed by slower column 1/slower columne 2.













Ex-
Com-




LC-


am-
pound




MS


ple
Num-




[M +


#
ber
Structure
IUPAC Name
Column
Eluents
H]+
















83
128a


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(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK, IG, 2*25 cm (5 um)
EtOH in Hex (0.1% FA)
422





84
128b


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(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in Hex (0.1% FA)
422





85
150a


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(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
452





86
150b


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-l)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
452





87
163a


embedded image


(R) or (S)-N′-((5-fluoro-2,4- diisopropylpyridin-3- yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiazole- 2-sulfonimidamide
CHIRALPAK ID, 2*25, cm (5 um)
EtOH in Hex (0.1% FA)
444





88
163b


embedded image


(S) or (R)-N′-((5-fluoro-2,4- diisopropylpyridin-3- yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiazole- 2-sulfonimidamide
CHIRALPAK ID, 2*25 cm (5 um)
EtOH in Hex (0.1% FA)
444





91
167a


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)thiazole- 2-sulfonimidamide
Chiralpak AD, 2*25 cm (5 um)
30% MeOH in CO2
422





92
167b


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)thiazole- 2-sulfonimidamide
Chiralpak AD, 2*25 cm (5 um)
30% MeOH in CO2
422





93
164b


embedded image


(S) or (R)-N′-((5-fluoro-2,4- diisopropylpyridin-3- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK ID, 2*25 cm (5 um)
EtOH in Hex (0.1% FA)
444





94
164a


embedded image


(R) or (S)-N′-((5-fluoro-2,4- diisopropylpyridin-3- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK ID, 2*25 cm (5 um)
EtOH in Hex (0.1% FA)
444





95
161a


embedded image


(S) or (R)-N′-((2,3,5,6,7,8- hexahydro-1H- cyclopenta[b]quinolin-9- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB S-5 um, 250*20 mm
EtOH in Hex (0.1% FA)
436





96
161b


embedded image


(R) or (S)-N′-((2,3,5,6,7,8- hexahydro-1H- cyclopenta[b]quinolin-9- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB S-5 um, 250*20 mm
EtOH in Hex (0.1% FA)
436





97
159a


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1- phenyl-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
481





98
195b


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1- phenyl-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
481





99
158a


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1- methyl-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)#
419





100
158b


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)- 1-methyl-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
419





101
157a


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-6-(2- hydroxypropan-2-yl)-2- methylpyridine-3- sulfonimidamide
CHIRAL ART Cellulose-SB S-5 um, 2*25 cm
EtOH in Hex (8 mM NH3•MeOH)
430





102
157b


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-6-(2- hydroxypropan-2-yl)-2- methylpyridine-3- sulfonimidamide
CHIRAL ART Cellulose-SB S-5 um, 2*25 cm
EtOH in Hex (8 mM NH3•MeOH)
430





103
160a


embedded image


(R) or (S)-N′-((3,5- diisopropylpyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
426





104
160b


embedded image


(S) or (R)-N′-((3,5- diisopropylpyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
426















105
162ab


embedded image


(S,R) or (S,S)-2-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide
These two isomers are faster- eluting on CHIRAL ART Cellulose-SB, 2*25 cm, 5 um, EtOH in Hex (8 mM NH3•MeOH); separated to single isomer on CHIRALPAK IG, 20*250 mm, 5 um EtOH in MTBE (10 mM NH3—MeOH)
436





106
162aa


embedded image


(S,S) or (S,R)-2-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide

436





107
162bb


embedded image


(R,R)-2-(2-hydroxypropan-2- yl)-N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide
These two isomers are slower-eluting on CHIRAL ART Cellulose-SB, 2*25 cm, 5 um, EtOH in Hex (8 mM NH3•MeOH); separated to single isomer on CHIRALPAK IG, 20*250 mm, 5 um EtOH in MTBE (10 mM NH3—MeOH)
436





108
162ba


embedded image


(R,S)-2-(2-hydroxypropan-2- yl)-N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide

436
















109
156a


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-6-(2- hydroxypropan-2-yl)pyridine- 3-sulfonimidamide
CHIRAL ART Cellulose-SB S, 2*25 cm, 5 um
EtOH in MTBE (10 mM NH3—MeOH)
416





110
156b


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-6-(2- hydroxypropan-2-yl)pyridine- 3-sulfonimidamide
CHIRAL ART Cellulose-SB S, 2*25 cm, 5 um
EtOH in MTBE (10 mM NH3—MeOH)
416





111
155a


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in Hex (8 mM NH3•MeOH)
421





112
155b


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in Hex (8 NH3•MeOH)
421





113
149a


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in Hex (8 mM NH3•MeOH)
421





114
149b


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in Hex (8 mM NH3•MeOH)
421





115
106a


embedded image


(R) or (S)-3-fluoro-N′-((5- fluoro-2,4-diisopropylpyridin- 3-yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
CHIRALPAK ID, 2*25 cm (5 um)
EtOH in Hex (8 mM NH3•MeOH)
461





116
106b


embedded image


(S) or (R)-3-fluoro-N′-((5- fluoro-2,4-diisopropylpyridin- 3-yl)carbamoyl)-5-(2-hy- droxypropan-2-yl)thiophene- 2-sulfonimidamide
CHIRALPAK ID, 2*25 cm (5 um)
EtOH in Hex (8 mM NH3•MeOH)
461





117
148a


embedded image


(R) or (S)-N′-((5-fluoro-2,4- diisopropylpyridin-3- yl)carbamoyl)-4-(2-hy- droxypropan-2-yl)thiophene- 2-sulfonimidamide
CHIRALPAK IF, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
443





118
148b


embedded image


(S) or (R)-N′-((5-fluoro-2,4- diisopropylpyridin-3- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
CHIRALPAK IF, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
443





119
147a


embedded image


(S) or (R)-N′-((2,2-dimethyl- 1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
450





120
147b


embedded image


(R) or (S)-N′-((2,2-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
450





121
107a


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-5- methylthiophene-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
435





122
107b


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-5- methylthiophene-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
435





123
145a


embedded image


(R) or (S)-2-(2-hydroxy- propan- 2-yl)-N′-((3-isopropyl-2- phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
500





124
145b


embedded image


(S) or (R)-2-(2-hydroxy- propan- 2-yl)-N′-((3-isopropyl-2- phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
500





125
105a


embedded image


(R) or (S)-3-fluoro-N′- ((1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)thio- phene-2-sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
439





126
105b


embedded image


(S) or (R)-3-fluoro-N′- ((1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)thio- phene-2-sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
439





127
153a


embedded image


(S) or (R)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
450





128
153b


embedded image


(R) or (S)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
450





129
133a


embedded image


(R) or (S)-2-(2- hydroxypropan- 2-yl)-N′-((2,3,5,6- tetramethylpyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB S-5 um, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
398





130
133b


embedded image


(S) or (R)-2-(2- hydroxypropan- 2-yl)-N′-((2,3,5,6- tetramethylpyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB S-5 um, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
398





131
137a


embedded image


(R) or (S)-N′-((2-ethyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
IPA in Hex:DM = 5:1 (0.1% FA)
410





132
137b


embedded image


(S) or (R)-N′-((2-ethyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
IPA in Hex:DCM = 5:1 (0.1% FA)
410





133
136a


embedded image


(S) or (R)-2-(2-hydroxy- propan- 2-yl)-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
448





134
136b


embedded image


(R) or (S)-2-(2-hydroxy- propan- 2-yl)-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiazole-5- sulfonimidamide
CHRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
448





135
140a


embedded image


(R,R/S) or (S,R/S)-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
436





136
140b


embedded image


(S,R/S) or (R,R/S)-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
436





137
140aa


embedded image


(R,R) or (R,S)-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-2- sulfonimidamide
Chiralpak AD- H, 2*25 cm (5 um); from Ex. 135
40% MeOH (8 mM NH3•MeOH) in CO2
436





138
140ab


embedded image


(R,S) or (R,R)-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-2- sulfonimidamide
Chiralpak AD- H, 2*25 cm (5 um); from Ex. 135
40% MeOH (8 mM NH3•MeOH) in CO2
436





139
140ba


embedded image


(S,S) or (S,R)-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-2- sulfonimidamide
Chiralpak AD- H, 2*25 cm (5 um); from Ex. 136
40% MeOH (8 mM NH3•MeOH) in CO2
436





140
140bb


embedded image


(S,R) or (S,S)-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-2- sulfonimidamide
Chiralpak AD- H, 2*25 cm (5 um); from Ex. 136
40% MeOH (8 mM NH3•MeOH) in CO2
436





141
129aa


embedded image


(R,R) or (R,S)-1-isopropyl-N′- ((3-methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in MTBE (10 mM NH3—MeOH)
403





142
129ab


embedded image


(S,S) or (S,R)-1-isopropyl-N′- ((3-methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in MTBE (10 mM NH3—MeOH)
403





143
129ba


embedded image


(R,S) or (R,R)-1-isopropyl-N′- ((3-methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in MTBE (10 mM NH3—MeOH)
403





144
129bb


embedded image


(S,R) or (S,S)-1-isopropyl-N′- ((3-methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in MTBE (10 mM NH3—MeOH)
403





145
127a


embedded image


(S) or (R)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
449





146
127b


embedded image


(R) or (S)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thio- phene-2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
449





147
130a


embedded image


(S) or (R)-4- ((dimethylamino)methyl)-N′- ((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin-8- yl)carbamoyl)benzene- sulfonamidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
414





148
130b


embedded image


(R) or (S)-4- ((dimethylamino)methyl)-N′- ((1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8- yl)carbamoyl)benzene- sulfonamidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
414





149
126a


embedded image


(R) or (S)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1-isopropyl- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
417





150
126b


embedded image


(S) or (R)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1-isopropyl- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
417





151
168a


embedded image


(S,R/S) or (R,R/S)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
466





152
168b


embedded image


(R,R/S) or (S,R/S)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexa- hydrodicyclopenta[b,e]py- ridin-8-yl)carbamoyl)thia- zole-5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
466





153
141b


embedded image


(R,R/S) or (S,R/S)-4-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
435





154
141a


embedded image


(S,R/S) or (R,R/S)-4-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
435





155
141aa


embedded image


(R,R) or (R,S)-4-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexahy- drodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um); from Ex. 153
EtOH in MTBE (10 mM NH3—MeOH)
435





156
141ab


embedded image


(R,S) or (R,R)-4-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um); from Ex. 153
EtOH in MTBE (10 mM NH3—MeOH)
435





157
141ba


embedded image


(S,S) or (S,R)-4-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexahy- drodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um); from Ex. 154
EtOH in MTBE (10 mM NH3—MeOH)
435





158
141bb


embedded image


(S,R) or (S,S)-4-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7-hexahy- drodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um); from Ex. 154
EtOH in MTBE (10 mM NH3—MeOH)
435





159
104a


embedded image


(R,R/S) or (S,R/S)-4-(2- hydroxypropan-2-yl)-5- methyl- N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin-8-yl)carba- moyl)thiazole-2- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
EtOH in Hex (0.1% FA)
450





160
104b


embedded image


(S,R/S) or (R,R/S)-4-(2- hydroxypropan-2-yl)-5- methyl- N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-2- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
EtOH in Hex (0.1% FA)
450





161
168aa


embedded image


(S,S) or (S,R)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in MTBE (10 mM NH3—MeOH)
466





162
168ab


embedded image


(S,R) or (S,S)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in MTBE (10 mM NH3—MeOH)
466





163
168ab


embedded image


(R,S) or (R,R)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in MTBE (10 mM NH3—MeOH)
466





164
168bb


embedded image


(R,R) or (R,S)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,c]pyridin- 8-yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in MTBE (10 mM NH3—MeOH)
466





165
122a


embedded image


(R) or (S)-1-(difluoromethyl)- N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
425





166
122b


embedded image


(S) or (R)-1-(difluoromethyl)- N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
425















167
103aa


embedded image


(S,R) or (S,S)-3-fluoro-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
1st and 2nd peaks on CHIRAL ART Cellulose-SB S, 2*25 cm, 5 um, EtOH in Hex (8 mM NH3•MeOH); separated to individual isomers on CHIRALPAK IG, 2*25 cm, 5 um, EtOH in MTBE (10 mM NH3•MeOH)
453





168
103ab


embedded image


(S,S) or (S,R)-3-fluoro-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide

453





169
103ba


embedded image


(R,R) or (R,S)-3-fluoro-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
3ed and 4th peaks on CHIRAL ART Cellulose-SB S, 2*25 cm, 5 um, EtOH in Hex (8 mM NH3•MeOH); separated to individual isomers on CHIRALPAK IG, 2*25 cm, 5 um, EtOH in MTBE (10 mM NH3—MeOH)
453





170
103bb


embedded image


(R,S) or (R,R)-3-fluoro-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide

453
















171
102a


embedded image


(S) or (R)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-3- fluoro-5-(2-hydroxy- propan-2-yl)thiophene- 2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
467





172
102b


embedded image


(R) or (S)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-3- fluoro-5-(2-hydroxy- propan-2-yl)thiophene- 2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
467





173
101a


embedded image


(S) or (R)-3-fluoro-5-(2- hydroxypropan-2-yl)-N′- ((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
465





174
101b


embedded image


(R) or (S)-3-fluoro-5-(2- hydroxypropan-2-yl)-N′- ((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
465





175
125a


embedded image


(S) or (R)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4- ((dimethylamino)meth- yl)benzene- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
442





176
125b


embedded image


(R) or (S)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4- ((dimethylamino)meth- yl)benzene- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
442





177
132a


embedded image


(R) or (S)-4-((dimethyl- amino)methyl)-N′-((5-fluoro- 2,4-diisopropylpyridin- 3-yl)carbamoyl)benzene- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
Hex (0.1% DEA):EtOH = 70:30
436





178
132b


embedded image


(S) or (R)-4-((dimethyl- amino)methyl)-N′-((5- fluoro-2,4-diisopropylpyridin- 3-yl)carbamoyl)benzene- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
Hex (0.1% DEA):EtOH = 70:30
436





179
131b


embedded image


(S) and (S,R,R) and (S,S,S)- N′-((3,5-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]py- ridin-8-yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
1st, 2nd, 3ed peak (three isomers) CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
449





180
131a


embedded image


(R,S,S) and (R,R,R)-N′-((3,5- dimethyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2-hy- droxypropan-2-yl)thiophene- 2-sulfonimidamide
4th, 5th peaks (two isomers) CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
449





181
131aab


embedded image


(R,R,S) and (R,S,R)-N′-((3,5- dimethyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
6th peak CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
449





182
131c


embedded image


(S,R,S) and (S,S,R) or (S,R,R) or (S,S,S)-N′-((3,5- dimethyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2-hy- droxypropan-2-yl)thiophene- 2-sulfonimidamide
1st perk from Ex. 179; CHIRALPAK IE, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
449





183
131d


embedded image


(S,R,R) or (S,S,S) or (S,R,S) and (S,S,R)-N′-((3,5-dimethyl- 1,2,3,5,6,7-hexa- hydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thio- phene-2-sulfonimidamide
2nd perk from Ex. 179; CHIRALPAK IE, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
449





184
131e


embedded image


(S,S,S) or (S,R,S) and (S,S,R) or (S,R,R)-N′-((3,5-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thio- phene-2-sulfonimidamide
3ed perk from Ex. 179; CHIRALPAK IE, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
449





185
131f


embedded image


(R,S,S) or (R,R,R)-N′-((3,5- dimethyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2-hy- droxypropan-2-yl)thiophene- 2-sulfonimidamide
1st perk from Ex. 180; CHIRALPAK AD-H-TC001 SFC, 2*25 cm, 5 um
MeOH (2 mM NH3—MeOH) in CO2
449





186
131g


embedded image


(R,R,R) or (R,S,S)-N′-((3,5- dimethyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thio- phene-2-sulfonimidamide
2nd perk resulted from Ex. 180 CHIRALPAK AD-H-TC001 SFC, 2*25 cm, 5 um
MeOH (2 mM NH3—MeOH) in CO2
449





187
121a


embedded image


(R) or (S)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
30% MeOH and 70% CO2
480





188
121b


embedded image


(S) or (R)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4- (hydroxymethyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IG, 28%250 mm, 5 um
30% MeOH and 70% CO2
480





189
169a


embedded image


(S) or (R)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-5- methylthiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3, MeOH)
463





190
169b


embedded image


(R) or (S)-N′-((3,3-dimethyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)-5- mehtylthiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM MH3•MeOH)
463





191
119a


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-1-isopropyl- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
389





192
119b


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-1-isopropyl- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
389





193
118a


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxyethyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IF, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
466





194
118b


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4-(2- hydroxyethyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IF, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
466





195
134aa


embedded image


(S,S) or (S,R)-4-((di- methylamino)methyl)-N′-((3- methyl-1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin-8- yl)carbamoyl)benzene- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in Hex (8 mM NH3•MeOH)
428





196
134ab


embedded image


(S,R) or (S,S)-4-((di- methylamino)methyl)-N′-((3- methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)benzene- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in Hex (8 mM NH3•MeOH)
428





197
134a


embedded image


(R,R) or (R,S)-4-((dimethyl- amino)methyl)-N′-((3- methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)benzene- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
428





198
134bb


embedded image


(R,S) or (R,R)-4-((dimethyl- amino)methyl)-N′-((3- methyl-1,2,3,5,6,7-hexa- hydrodicyclo- penta[b,e]pyridin-8- yl)carbamoyl)benzene- sulfonamidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
428





199
117a


embedded image


(S) or (R)-N′-((3-ethyl- 2-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
424





200
117b


embedded image


(R) or (S)-N′-((3-ethyl-2- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
424





201
172a


embedded image


(S) or (R)-1-Isopropyl-N′- ((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK AS-H, 2*25 cm (5 um)
EtOH (2 mM NH3—MeOH) in CO2
415





202
172b


embedded image


(R) or (S)-1-Isopropyl-N′- ((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK AS-H, 2*25 cm (5 um)
EtOH (2 mM NH3—MeOH) in CO2
415





203
173a


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4- isopropylthiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in Hex (8 mM NH3•MeOH)
405





204
173b


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-4- isopropylthiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in Hex (8 mM NH3•MeOH)
405





205
183a


embedded image


(R,R) or (R,S)-N′-((3-fluoro- 1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
440





206
183b


embedded image


(S,S) or (S,R)-N′-((3-fluoro- 1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
440





207
183c


embedded image


(R,S) or (R,R)-N′-((3-fluoro- 1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
440





208
183d


embedded image


(S,R) or (S,S)-N′-((3-fluoro- 1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
440





209
116a


embedded image


(S) or (R)-2-(2- hydroxypropan- 2-yl)-N′-((3-isopropyl-2- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
EtOH in MTBE (0.1% FA)
438





210
116b


embedded image


(R) or (S)-2-(2- hydroxypropan- 2-yl)-N′-((3-isopropyl-2- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
EtOH in MTBE (0.1% FA)
438





211
114a


embedded image


(R) or (S)-4-(2-hydroxy- propan-2-yl)-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, (5 um)
EtOH in Hex (8 mM (NH3•MeOH)
447





212
114b


embedded image


(S) or (R)-4-(2-hydroxy- propan-2-yl)-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm (5 um)
EtOH in Hex (8 mM NH3•MeOH)
447





213
124a


embedded image


(S) or (R)-N′-((2- cyclopropyl- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
436





214
124b


embedded image


(R) or (S)-N′-((2- cyclopropyl- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
436





215
154a


embedded image


(R) or (S)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 4-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
422





216
154b


embedded image


(S) or (R)-N′-((1,2,3,5,6,7- hexahydrodicyclo- penta[b,e]pyridin- 8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 4-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (8 mM NH3•MeOH)
422





217
120a


embedded image


(R) or (S)-4- ((dimethylamino)methyl)-N′- ((1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-N- methylbenzene- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
EtOH in MTBE (10 mM NH3—MeOH)
428





218
120b


embedded image


(S) or (R)-4- ((dimethylamino)methyl)-N′- ((1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pryidin- 8-yl)carbamoyl)-N- methylbenzene- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
EtOH in MTBE (10 mM NH3—MeOH)
428





219
142a


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(R) or (S)-2-(2-hydroxy- propan-2-yl)- N′-((2-phenyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IF, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
458





220
142b


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(S) or (R)-2-(2-hydroxy- propan-2-yl)- N′-((2-phenyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IF, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
458





221
143a


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(S) or (R)-2-(2-hydroxy- propan-2-yl)-N′-((3-methyl-2- phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB S-5 um, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
472





222
143b


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(R) or (S)-2-(2-hydroxy- propan-2-yl)-N′-((3-methyl-2- phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB S-5 um, 2*25 cm, 5 um
EtOH in Hex (0.1% FA)
472





223
184a


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(R,R) or (R,S)-1-(difluoro- methyl)-N′-((3-methyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
1st peak Column, CHIRALPAK IG, 20*250 mm, 5 um
EtOH in MTBE (10 mM NH3—MeOH)
411















224
184b


embedded image


(S,S) or (S,R)-1-(difluoro- methyl)-N′-((3-methyl- 1,2,3,5,67-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
Eluted as a mixture of 2nd and 3rd peaks CHIRAPAK IG, 20*250 mm, 5 um, EtOH in MTBE (10 mM NH3—MeOH). Separated to individual isomers on CHIRALPAK IG, 2*25 cm (5 um), EtOH in Hex (8 mM NH3—MeOH)
411





225
184c


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(R,S) or (R,R)-1-(difluoro- methyl)-N′-((3-methyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide

411
















226
184d


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(S,R) or (S,S)-1-(difluoro- methyl)-N′-((3-methyl- 1,2,3,5,6,7-hexahydro- dicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
Column, CHIRALPAK IG, 28*250 mm, 5 um
EtOH in MTBE (10 mM NH3—MeOH)
411





227
174a


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(R) or (S)-N′-((2-cyclopropyl- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-3-fluoro-5-(2- hydroxypropan-2-yl)thio- phene-2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
IPA in Hex (8 mM NH3•MeOH)
453





228
174b


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(S) or (R)-N′-((2-cyclopropyl- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-3-fluoro-5-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
IPA in Hex (8 mM NH3•MeOH)
453





229
175a


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(R) or (S)-N′-((2-cyclopropyl- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene- 2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
IPA in Hex (8 mM NH3•MeOH)
435





230
175b


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(S) or (R)-N′-((2-cyclopropyl- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2-hydroxy- propan-2-yl)thiophene- 2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
IPA in Hex (8 mM NH3•MeOH)
435





231
180a


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(R) or (S)-1-(difluoromethyl)- N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
MeOH (2 mM NH3—MeOH) in CO2
423





232
180b


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(S) or (R)-1-(difluoromethyl)- N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pryidin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
MeOH (2 mM NH3—MeOH) in CO2
423






#The amount of NH3 in this chiral chromatographic solvent and similar solvents were adjusted by adding 2 M NH3 in methanol to the desired NH3 concentration. In this case, the resulting concentration of NH3 in methanol is 8 mM.







Single crystal X-ray crystallographic analysis was performed on compound 162bb (Example 107 shown in Table 23 above). FIG. 1 shows ball and stick models of the asymmetrical unit containing two crystallographically independent molecules of compound 162bb, with hydrogen atoms omitted for clarity. Table M below shows fractional atomic coordinates of compound 162bb. The X-ray crystal structure data of compound 162bb shows (R) configuration at both the sulfur and carbon stereocenters.









TABLE 25







Fractional Atomic Coordinates (×104) and Equivalent Isotropic


Displacement Parameters (Å2 × 103) for Example 107. Ueq is defined as ⅓


of the trace of the orthogonalised UIJ tensor.













Atom
x
y
z
U(eq)







S4
5075(6) 
4544(8) 
4537(3) 
36.8(19) 



S2
4781(6) 
4698(9) 
−473(3) 
43(2)



S1
7558(7) 
5846(10)
−529(3) 
50(2)



S3
2293(7) 
5663(9) 
4517(3) 
46(2)



O2
4520(16)
6060(20)
−694(8) 
39(5)



O5
5510(15)
3200(20)
4347(7) 
31(4)



O3
4619(17)
5920(20)
674(8)
45(5)



N3
4140(18)
4020(20)
 66(9)
25(5)



O6
5356(18)
3350(20)
5721(9) 
50(5)



N9
5338(18)
5480(30)
6075(9) 
36(6)



N8
5550(20)
5180(30)
5117(11)
48(7)



N4
4450(20)
3850(30)
1039(11)
51(7)



O4
−270(20)
6350(30)
4492(10)
57(6)



N7
5257(19)
5700(30)
4048(10)
37(6)



O1
10130(20) 
6580(30)
−616(10)
66(7)



N2
4410(20)
3530(30)
−970(9) 
32(5)



C00H
5460(20)
4710(30)
5620(11)
31(6)



C20
1070(20)
4520(30)
4713(11)
35(7)



N10
5083(19)
4460(20)
7857(6) 
75(9)



C32
6064(18)
3890(20)
7545(8) 
 66(10)



C33
6147(16)
4230(20)
6957(8) 
46(8)



C26
5250(17)
5130(20)
6679(6) 
41(7)



C27
4269(16)
5700(20)
6991(8) 
46(8)



C31
4186(16)
5360(20)
7579(8) 
47(8)



N1
8450(20)
3680(30)
 38(10)
40(6)



C2
6540(30)
4700(40)
−317(13)
47(7)



N6
1480(20)
3260(30)
4781(10)
43(6)



C7
4370(30)
4560(40)
 561(14)
54(8)



C4
10220(20) 
5300(30)
−295(12)
38(7)



C16
7300(30)
5850(40)
2595(15)
59(9)



C21
3350(30)
4350(40)
4584(13)
46(8)



C14
5804(16)
4870(20)
1845(8) 
45(8)



C8
4666(18)
4160(20)
1669(7) 
43(8)



C9
3784(16)
3830(30)
2079(9) 
 66(10)



C13
4039(19)
4200(30)
2665(8) 
 81(12)



N5
5180(20)
4910(30)
2841(7) 
78(9)



C15
6059(17)
5240(30)
2431(9) 
 83(12)



C18
7080(30)
5340(40)
1585(13)
46(8)



C22
2820(20)
3160(40)
4759(12)
37(7)



C25
−750(30)
4770(50)
5293(15)
63(9)



C6
10910(30) 
5480(50)
 336(16)
 69(10)



C34
7230(30)
3470(50)
6749(15)
 66(10)



C5
10840(30) 
4200(50)
−671(17)
 74(11)



C30
3160(40)
6000(50)
7827(19)
 92(13)



C28
3190(30)
6640(50)
6797(16)
 70(11)



C23
−290(30)
4940(40)
4703(13)
49(8)



C3
7110(30)
3580(40)
 −17(12)
43(8)



C17
7830(40)
6370(50)
2016(18)
 88(13)



C36
7060(30)
2850(50)
7758(16)
 70(11)



C35
7990(40)
2950(50)
7343(17)
 82(12)



C1
8870(20)
4850(30)
−219(12)
39(7)



C24
−1130(30) 
4170(50)
4203(16)
 71(11)



C12
2860(40)
3740(60)
3000(20)
 92(14)



C29
2320(40)
6600(50)
7354(17)
 79(12)



C10
2690(40)
2920(50)
1935(19)
 89(13)



C37
7650(60)
2820(80)
8380(30)
160(30)



C11
2050(50)
3380(70)
2530(20)
112(17)



C19
7290(50)
7110(60)
3030(20)
113(17)










Example 233
Compound 652



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N′-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(hydroxymethyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide (Scheme I)
Examples 234
Compound 652b) and 235 (Compound 652a



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(R)- and (S)—N′-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(hydroxymethyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide




embedded image


Step 1: N-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-N′-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide (1.0 g, 2.2 mmol) in THF (50 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added t-BuOK (493 mg, 4.4 mmol) in portions at 0° C. The resulting solution was stirred for 15 min at 0° C. To the above mixture was added 2,2,2-trichloroethyl (3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (830 mg, 2.2 mmol) in THF (5 mL) dropwise at 0° C. The resulting mixture was stirred overnight at RT. The resulting solution was then quenched with water (5 mL). The mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (20:1). This resulted in 400 mg (27%) of the title compound as an off-white solid. MS-ESI: 675 (M+1).


Step 2: N′-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(hydroxymethyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-N′-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide (400 mg, 0.59 mmol) in THF (20 mL) in a 100-mL round-bottom flask was added HF-pyridine (70% wt., 50 mg, 1.77 mmol) dropwise at 0° C. The reaction solution was stirred for 2 h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: XBridge Prep C18 OBD Column 19×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 9% B to 36% B over 7 min; UV 254/210 nm; Rt: 7.13 min. This resulted in 200 mg (75.6%) of Example 233 as a white solid. MS-ESI: 447 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 6.70 (s, 1H), 4.79-4.74 (m, 1H), 4.66 (s, 2H), 2.95 (t, J=7.6 Hz, 2H), 2.86-2.76 (m, 4H), 2.16-2.03 (m, 2H), 1.96 (t, J=7.2 Hz, 2H), 1.52 (d, J=6.6 Hz, 3H), 1.51 (d, J=6.6 Hz, 3H), 1.27 (s, 6H).


Step 3: Chiral resolution
Example 233

(200 mg) was resolved by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK AS, 2*25 cm (5 um); Mobile Phase A: CO2, Mobile Phase B: EtOH (2 mM NH3MeOH); Flow rate: 40 mL/min; Gradient: 20% B; 220 nm; RT1:4.54; RT2:6.29; Injection Volume: 2.5 ml; Number of Runs: 10. This resulted in 81 mg of Example 234 followed by 75 mg of Example 235, both as white solids.


Example 234

MS-ESI: 447 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 6.70 (s, 1H), 4.79-4.72 (m, 1H), 4.66 (s, 2H), 2.95 (t, J=7.6 Hz, 2H), 2.84-2.73 (m, 4H), 2.16-2.03 (m, 2H), 1.96 (t, J=7.3 Hz, 2H), 1.52 (d, J=6.6 Hz, 3H), 1.51 (d, J=6.6 Hz, 3H), 1.27 (s, 6H).


Example 235

MS-ESI: 447 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 6.70 (s, 1H), 4.81-4.74 (m, 1H), 4.66 (s, 2H), 2.95 (t, J=7.6 Hz, 2H), 2.86-2.75 (m, 4H), 2.14-2.05 (m, 2H), 1.96 (t, J=7.3 Hz, 2H), 1.52 (d, J=6.6 Hz, 3H), 1.51 (d, J=6.6 Hz, 3H), 1.27 (s, 6H).


Example 236
Compound 695



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N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide (Scheme II)



embedded image


Step 1: N-(tert-butyldimethylsilyl)-N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine-8-yl) carbamoyl)-5-(2-hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)-3-methylthiophene-2- sulfonimidamide (150 mg, 0.43 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt., dispersion in mineral oil, 34.4 mg, 0.86 mmol) at 0° C. The resulting solution was stirred for 10 min at RT. Then 2,2,2-trichloroethyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamate (150 mg, 0.43 mmol) in THF (5 mL) was added dropwise at 0° C. into the mixture. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 1.0 mL water. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 230 mg (97.4%) of the title compound as a yellow solid. MS-ESI: 549 (M+1).


Step 2: N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-5-(2-hydroxypropan-2-yl) -3-methylthiophene-2-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl) carbamoyl)-5-(2-hydroxypropan-2-yl)-3-methylthiophene-2-sulfonimidamide (230 mg, 0.42 mmol) in THF (10 mL) in a 50-mL round-bottom flask was added TBAF (110 mg, 0.42 mmol) in portions at RT. The resulting solution was stirred for 1 h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions:)(Bridge Prep OBD C18 Column, 30×150 mm 5 um; mobile phase, water (10 mM NH4HCO3) and ACN (20% to 60% in 7 min); 254/210 nm; RT: 6.13 min. This resulted in 100 mg (55%) of Example 236 as a white solid. MS-ESI: 435 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.56 (br, s, 2H), 6.81 (s, 1H), 5.67 (s, 1H), 2.82-2.68 (m, 8H), 2.37 (s, 3H), 2.00-1.92 (m, 4H), 1.48 (s, 3H), 1.47 (s, 3H)









TABLE 33







Examples in the following table were prepared using similar conditions as described in


Example 236 and Scheme II from appropriate starting materials.












Final


Exact


Example
Target


Mass


#
Number
Structure
IUPAC Name
[M + H]+





237
643


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N-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)- 4-(1-hydroxyethyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide
466





238
201


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2-(1,2-Dihydroxypropan- 2-yl)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)thiazole-5- sulfonimidamide
466





239
640


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5-(1,2-Dihydroxypropan- 2-yl)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)- 3-fluorothiophene-2- sulfonimidamide
483





240
605


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2-(1,2-Dihydroxypropan- 2-yl)-N′-((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)cabamoyl)thiazole-5- sulfonimidamide
480





241
605f


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(R, RS) or (S, RS) 2-(-1,2- dihydroxypropan-2-yl)-N′- ((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)cabamoyl)thiazole-5- sulfonimidamide (from Intermediate 117A)
480





242
605a


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(S, RS) or (R, RS) 2-(-1,2- dihydroxypropan-2-yl)-N′- ((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide (from Intermediate 117B)
480





243
691


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3-Chloro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b, e]pyridin-8-yl)carbamoyl)- 5-(2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
455





244
688


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4-Chloro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b, e]pyridin-8-yl)carbamoyl)- 5-(2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
455





245
676


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N′-((2-cyclopropyl-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1- (difluoromethyl)-1H- pyrazole-3- sulfonimidamide
411





246
669


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4-(2-Hydroxypropan-2- yl)-N′-((3-methyl-2-(1- methylcyclopropyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
449





247
612


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N′-((2,6-dicyclopropyl- 3,5-dimethylpyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
449





248
627


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2-(1,2-Dihydroxypropan- 2-yl)-N′-((3-isopropyl-2- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
454





249
607


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4-(2-Hydroxypropan-2- yl)-N′-((2-(2,2,2- trifluoroethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
463









Example 250
Compound 665



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N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-4-((methylamino)methyl)thiazole-5-sulfonimidamide (Scheme III)



embedded image


Step 1: 4-(Bromomethyl)-N′-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl) carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

To a stirred solution of N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-4- (hydroxymethyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (800 mg, 1.68 mmol) in THF (20 mL) in a 100-mL 3-necked round-bottom flask under nitrogen was added phosphorus tribromide (676 mg, 2.52 mmol) dropwise at 0° C. The resulting solution was stirred for 4 h at RT. The solution was slowly poured into water/ice (20 mL). The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 540 mg (60%) of crude title compound as an off-white solid. MS-ESI: 542/544 (M+1).


Step 2: N′-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)-4-((methylamino)methyl)thiazole-5-sulfonimidamide

To a stirred solution of 4-(bromomethyl)-N′-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine -8-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (500 mg, 0.92 mmol) in THF (10 mL) in a 50-mL round-bottom flask was added methanamine in THF (2 M, 2.31 mL, 4.62 mmol) dropwise at RT. The resulting solution was stirred for 4 h at 50° C. The reaction was quenched with water (10 mL). The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers were combined and dried with anhydrous Na2SO4. Then the organic phase was concentrated under vacuum. The residue was eluted from silica gel with EtOAc/PE (1:1). The crude product was further purified by Prep-HPLC with the following conditions: XBridge Prep C18 OBD Column 19×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 10% B to 24% B over 7 min; 254/210 nm; Rt: 6.52 min. This resulted in 200 mg (44%) of Example 250 as a yellow solid. MS-ESI: 493 (M+1).


Example 251
Compound 693



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N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-methoxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme IV)




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Step 1: Tert-butyl (N-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-methoxypropan-2-yl)thiazole-5-sulfonimidoyl)carbamate

To a stirred solution of tert-butyl (amino(2-(2-methoxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene) carbamate (500 mg, 1.49 mmol) in THF (10 mL) in a 100-mL round-bottom flask under nitrogen was added NaH (60% wt., dispersion in mineral oil, 71.5 mg, 1.79 mmol) at 0° C. The resulting solution was stirred for 10 min at RT. Then 2,2,2-trichloroethyl (1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl) carbamate (521 mg, 1.49 mmol) in THF (5 mL) was added dropwise into the solution at 0° C. The resulting solution was stirred for 2 h at RT. The reaction was then quenched by the addition of 5 mL water. The resulting solution was extracted with 3×50 mL of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. This resulted in 400 mg (50%) of the title compound as a yellow solid. MS-ESI: 536 (M+1).


Step 2: N′-((1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(2-methoxypropan-2-yl) thiazole-5-sulfonimidamide

A stirred solution of tert-butyl (N-((1,2,3,5,6,7-hexahydrodicyclopenta [b,e]pyridin-8-yl)carbamoyl)-2- (2-methoxypropan-2-yl)thiazole-5-sulfonimidoyl)carbamate (300 mg, 0.56 mmol) in HCl/dioxane (4 M, 20 mL) was stirred for 15 h at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC under the following conditions: XBridge Prep OBD C18 Column 30×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 20% B over 9.5 min; 254/210 nm; Rt: 7.32. This resulted in 130 mg (54%) of Example 251 as a white solid. MS-ESI: 436 (M+1). 1H NMR (300 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.14 (s, 1H), 7.97 (br s, 2H), 3.25 (s, 3H), 2.87-2.78 (m, 4H), 2.73-2.68 (m, 4H), 1.98-1.93 (m, 4H), 1.56 (s, 6H).


Example 252
Compound 645



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3 -Fluoro-5 -(2-hydroxypropan-2-yl)-N′-((2-isopropyl-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme V)




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Step 1: N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)-N′-((2-isopropyl-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)thiophene-2-sulfonimidamide (300 mg, 0.85 mmol) in THF (20 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt., dispersion in mineral oil, 102 mg, 2.56 mmol) at 0° C. The resulting solution was stirred for 15 min at RT. 2,2,2-trichloroethyl (2-isopropyl-3-methyl-6,7-dihydro-5H-cyclopenta[b]-pyridin-4-yl)carbamate (310 mg, 0.85 mmol) in THF (5 mL) was added dropwise to the solution. The resulting solution was stirred overnight at RT and quenched with water (2.0 mL). The resulting solution was concentrated under vacuum to get 580 mg of the title compound as an off-white crude solid which was used in the next step without further purification. MS-ESI: 569 (M+1).


Step 2: 3-Fluoro-5-(2-hydroxypropan-2-yl)-N′-((2-isopropyl-3-methyl-6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)thiophene-2-sulfonimidamide

The crude product (580 mg) of N-(tert-butyldimethylsilyl)-3-fluoro-5-(2-hydroxypropan-2-yl)-N′-((2- isopropyl-3-methyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)thiophene-2-sulfonimidamide was applied on a TLC and using DCM/MeOH=10:1 to keep Rf=0.3˜0.6, then left the product on TLC overnight at RT. The TBS group was removed on TLC to give the final product which was then eluted from TLC with DCM/MeOH=10:1. The final product was further purified by Prep-HPLC with the following conditions:)(Bridge Shield RP18 OBD Column, 19*250 mm,10 um; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 22% B to 23% B over 15 min; UV 210/254 nm; Rt: 16.03 min. This resulted in 130 mg (34%) of Example 252 as a white solid. MS-ESI: 455 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.80 (br, s, 2H), 6.98 (s, 1H), 5.86 (s, 1H), 3.24-3.17 (m, 1H), 2.84-2.80 (m, 2H), 2.77-2.66 (m, 2H), 2.09 (s, 3H), 1.98-1.90 (m, 2H), 1.48 (s, 3H), 1.47 (s, 3H), 1.15 (d, J=6.7 Hz, 6H).









TABLE 34







Examples in the following table were prepared using similar conditions as described in


Example 252 and Scheme V from appropriate starting materials.












Final


Exact


Example
Target


Mass


#
Number
Structure
IUPAC Name
[M + H]+





253
672


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2-(2-Hydroxypropan-2-yl)-N′- ((2,4,5,6-tetrahydro-1H- cyclobuta[b]cyclopenta[e] pyridin-7-yl)carbamoyl)thiazole- 5-sulfonimidamide
408





254
702


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N′-((3-(fluoromethyl)- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
454





255
692


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-4- methylthiophene-2- sulfonimidamide
435





256
656


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N′-((2-cyclopropyl-3,7- dimethyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
449





257
681


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4-(2-Hydroxypropan-2-yl)-N′- ((2-isopropyl-3-methyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
437





258
668


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1-(Difluoromethyl)-N′-((3- ethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
425





259
658


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N′-((2-cyclobutyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
449





260
667


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N′-((2-cyclopropyl-3- isopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
463





261
703


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8-(3-(Amino(2-(2- hydroxypropan-2-yl)thiazol- 5-yl)(oxo)-λ6- sulfanylidene)ureido)- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridine-3-carboxylic acid
466





262
664


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1-Isopropyl-N′-((2-isopropyl- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
405





263
632


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3-Fluoro-5-(2- hydroxypropan-2-yl)-N′-((3- methyl-2-(trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
481





264
624


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4-(2-Hydroxypropan-2-yl)-N′- ((3-methyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
463





265
631


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N′-((3-cyclopropyl-2-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-3-fluoro-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
467





266
630


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N′-((3-cyclopropyl-2-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
450





267
623


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N′-((3-cyclopropyl-2-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
435





268
621


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1-(Difluoromethyl)-N′-((3- methyl-2-(trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
439





269
629


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N′-((3-cyclopropyl-2-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1- (difluoromethyl)-1H- pyrazole-3-sulfonimidamide
425





270
610


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N′-((3-ethyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
478





271
611


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N′-((3-ethyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-3-fluoro-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
495





272
609


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N′-((3-ethyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
477





273
608


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N′-((3,7-dimethyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
478





274
616


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4-Fluoro-5-(2- hydroxypropan-2-yl)-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8- yl)carbamoyl)thiophene-2- sulfonimidamide
453





275
604


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1-Ethyl-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
401





276
603


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1-ethyl- 1H-pyrazole-3- sulfonimidamide
403





277
304


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-6,7- dihydro-5H-pyrazolo[5,1- b][1,3]oxazine-3- sulfonimidamide
431





278
306


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N′-((2-cyclopropyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1- b][1,3]oxazine-3- sulfonimidamide
417





279
677


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,d] pyridin-5-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
422





280
661


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2-(2-Hydroxypropan-2-yl)-N′- ((3-methyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
464





281
647


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N′-((2-(difluoromethyl)-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide
446









Example 282
Compound 619



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N-((2-(hydroxymethyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme VI)



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Step 1: Sodium 4-(3-(((tert-butyldimethylsilyl)amino)(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene)ureido)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate

To a stirred solution of N-(tert-butyldimethylsilyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (270 mg, 0.76 mmol) in THF (20 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt., dispersion in mineral oil, 91.2 mg, 2.28 mmol) at 0° C. The resulting solution was stirred for 5 min at RT. To the above solution was added ethyl 3-methyl-4-(((2,2,2-trichloroethoxy)carbonyl)amino)-6,7- dihydro-5H-cyclopenta[b]pyridine-2-carboxylate (300 mg, 0.76 mmol) in THF (5 mL) dropwise at 0° C. The resulting solution was stirred overnight at RT. Then the resulting solution was quenched by addition of 2 mL water. The resulting mixture was stirred for 1 h at RT. The resulting solution was concentrated under vacuum. This resulted in 440 mg (crude) title compound as a white solid which was used in the next step without further purification. MS-ESI: 576 (M+1).


Step 2: 4-(3-(Amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxosulfaneylidene)ureido)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylic acid

To a stirred solution of sodium 4-(3-(((tert-butyldimethylsilyl)amino)(2-(2-hydroxypropan-2-yl)thiazol-5-yl) (oxo)-λ6-sulfaneylidene)ureido)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylate (440 mg, crude) in dioxane (10 mL) in a 50-mL round-bottom flask was added conc. HCl (2 mL) dropwise at 0° C. The resulting solution was stirred for 30 min at RT. The resulting solution was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 174 mg (52%, over two steps) of the title compound as an off-white solid. MS-ESI: 440 (M+1).


Step 3: N′-((2-(hydroxymethyl)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole-5-sulfonimidamide

To a stirred solution of 4-(3-(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene)ureido)-3-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-2-carboxylic acid (150 mg, 0.34 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added BH3/THF (1M, 1.0 mL, 1.0 mmol) dropwise at 0° C. The resulting solution was stirred overnight at RT. The solution was quenched with MeOH (5 mL) and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following condition:)(Bridge Prep OBD C18 Column, 30×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 17% B over 7 min; UV 254/210 nm; Rt: 6.63. This resulted in 100 mg (71%) of Example 282 as a white solid. MS-ESI: 426 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 7.82 (s, 1H), 4.48 (s, 2H), 2.84-2.81 (m, 2H), 2.71-2.69 (m, 2H), 2.07 (s, 3H), 1.96-1.93 (m, 2H), 1.49 (s, 6H).


Example 283
Compound 618



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N′-((3 -cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-5 -(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (Scheme VII)




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Step 1: 5-(2-Hydroxypropan-2-yl)thiazole-2-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (1.0 g, 2.98 mmol) in THF (10 mL) in a 100-mL round-bottom flask was added HF/pyridine (70% wt., 255 mg, 8.94 mmol) dropwise at 0° C. The resulting solution was stirred overnight at RT. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (20:1). This resulted in 630 mg (95.5%) of the title compound as an off-white solid. MS-ESI: 222(M+1).


Step 2: N′-((3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-5-(2- hydroxypropan-2-yl)thiazole-2-sulfonimidamide

To a stirred solution of 5-(2-hydroxypropan-2-yl)thiazole-2-sulfonimidamide (500 mg, 2.26 mmol) in THF (20 mL) in a 100-mL round-bottom flask was added DBU (687 mg, 4.52 mmol) at RT. Then 2,2,2-trichloroethyl (3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (818 mg, 2.26 mmol) in THF (5 mL) was added to the stirred solution at RT. The resulting solution was stirred overnight at RT, quenched by addition of water (2.0 mL) and concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 um; mobile phase, water (10 mM NH4HCO3+0.1% NH3.H2O) and ACN (10% to 22% over 7 min); 254/210 nm; Rt: 5.88 min. This resulted in 310 mg (32%) of Example 283 as an off-white solid. MS-ESI: 436(M+1). 1H NMR (400 MHz, MeOH-d4) δ 7.68 (s, 1H), 2.89-2.86 (m, 4H), 2.54 (s, 3H), 2.08-1.99 (m, 2H), 1.62 (s, 6H), 1.62-1.50 (m, 1H) 1.02-1.00 (m, 2H), 0.42-0.40 (m, 2H).









TABLE 35







Examples in the following table were prepared using similar conditions as described in


Example 283 and Scheme VII from appropriate starting materials.












Final


Exact


Example
Target


Mass


#
Number
Structure
IUPAC Name
[M + H]+





284
626


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N′-((2-cyclopropyl-3- methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)- 4-(2-hydroxypropan- 2-yl)thiazole-2- sulfonimidamide
436
















TABLE 36







Examples in the following table were prepared using similar conditions as described in


Example 28 and Scheme 2A from appropriate starting materials.















Exact


Example
Final Target


Mass


#
Number
Structure
IUPAC Name
[M + H]+





285
696


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N-((6-cyano-2,4- diisopropylpyridin-3- yl)carbamoyl)-4- (hydroxymethyl)-2-(2- hydroxypropan- 2-yl)thiazole-5- sulfonimidamide
481





286
682


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N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- (hydroxymethyl)-1- isopropyl-1H-pyrazole- 3-sulfonimidamide
447





287
653


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N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-3- (hydroxymethyl)-1- isopropyl-1H-pyrazole- 4-sulfonimidamide
447





288
641


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2-(2-Hydroxypropan-2- yl)-N′-((3-methyl- 2-(1-methylcyclopropyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole- 5-sulfonimidamide
450
















TABLE 37







Examples in the following table were prepared using similar conditions as described in


Example 9 and Scheme 2 from appropriate starting materials.












Final


Exact


Example
Target


Mass


#
Number
Structure
IUPAC Name
[M + H]+





289
694


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4-Chloro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- isopropyl-1H-pyrazole-3- sulfonimidamide
423/ 425





290
687


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- isopropyl-4-methyl-1H- pyrazole-3- sulfonimidamide
403





291
660


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1-Isopropyl-N′-((3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)- 1H-imidazole-4- sulfonimidamide
403





292
140c


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5-(2-Hydroxypropan-2-yl)- N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8- yl)carbamoyl)thiazole-2- sulfonimidamide
436





293
635


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2-(2-Hydroxypropan-2-yl)- N′-((3-methoxy-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8- yl)carbamoyl)thiazole-5- sulfonimidamide
452





294
689


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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-2- (2-hydroxypropan-2-yl)-4- (methoxymethyl)thiazole-5- sulfonimidamide
466





295
642


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N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-4- (hydroxymethyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide
480





296
686


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N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)thiazole-2- sulfonimidamide
450





297
680


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N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-4- (hydroxymethyl)-2- isopropylthiazole-5- sulfonimidamide
464





298
674


embedded image


3-Cyano-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)benzenesulfonimidamide
468





299
684


embedded image


N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)pyridine-3- sulfonimidamide
444





300
683


embedded image


5-(2-Hydroxypropan-2-yl)- N′-((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane- 1,3′- dicyclopenta[b,e]pyridin]- 8′-yl)carbamoyl)thiazole-2- sulfonimidamide
448





301
679


embedded image


N′-((2-cyclopropyl-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4- (hydroxymethyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide
466





302
673


embedded image


N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-6- (2-hydroxypropan-2- yl)pyridine-3- sulfonimidamide
444





303
704


embedded image


N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- (4-fluorophenyl)-5-(2- hydroxypropan-2-yl)-1H- pyrazole-3- sulfonimidamide
527





304
664


embedded image


5-(2-Hydroxypropan-2-yl)- N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- phenyl-1H-pyrazole-3- sulfonimidamide
495





305
663


embedded image


N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-5- (2-hydroxypropan-2-yl)-1- phenyl-1H-pyrazole-3- sulfonimidamide
509





306
651


embedded image


N′-((2-cyclopropyl-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-5-(2- hydroxypropan-2-yl)-1- phenyl-1H-pyrazole-3- sulfonimidamide
495





307
659


embedded image


N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- phenyl-1H-pyrazole-3- sulfonimidamide
451





308
662


embedded image


N′-((3-ethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
450





309
649


embedded image


N′-((2-cyclobutyl-3-methyl- 6,7-dihydo-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide
450





310
650


embedded image


2-(2-Hydroxypropan-2-yl)- N′-((2-isopropyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5- sulfonimidamide
438





311
648


embedded image


N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-4- (hydroxymethyl)-2-(2- methoxypropan-2- yl)thiazole-5- sulfonimidamide
494





312
615


embedded image


N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-5- (2-hydroxypropan-2-yl)-1- isopropyl-1H-pyrazole-3- sulfonimidamide
475





313
620


embedded image


N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)pyridine-2- sulfonimidamide
444





314
185


embedded image


N′-((4-cyclopropyl-6- methylpyrimidin-2- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide
397





315
690


embedded image


3-Bromo-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
499





316
675


embedded image


N′-((2-cyclopropyl-3-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)thiazole-5- sulfonimidamide
450





317
678


embedded image


4-Fluoro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
439





318
671


embedded image


N′-((3-ethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-3- fluoro-5-(2-hydroxypropan- 2-yl)thiophene-2- sulfonimidamide
467





319
657


embedded image


N′-((2-(tert-butyl)-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
451





320
670


embedded image


N′-((2,3-dicyclopropyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
461





321
655


embedded image


N′-((2-(cyclopropylmethyl)- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
449





322
654


embedded image


N′-((3-cyclopropyl-2-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
449





323
634


embedded image


1-Ethyl-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
389





324
639


embedded image


1-Methyl-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
375





325
646a


embedded image


N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- phenyl)-1H-pyrazole-3- sulfonimidamide
437





326
638


embedded image


1-(Difluoromethyl)-N′- ((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]- 8′-yl)carbamoyl)-1H- pyrazole-4- sulfonimidamide
423





327
637


embedded image


1-(Difluoromethyl)-N′- ((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)- 1H-pyrazole-4- sulfonimidamide
425





328
633


embedded image


N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-3- (2-hydroxypropan-2- yl)benzenesulfonimidamide
415





329
625


embedded image


N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-3- (2-hydroxypropan-2- yl)benzenesulfonimidamide
415





330
622


embedded image


4-(2-Hydroxypropan-2-yl)- N′-((3-isopropyl-2-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
437





331
628


embedded image


1-Isopropyl-N′-((3-methyl- 2-(trifluoromethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
431





332
617


embedded image


1-(Difluoromethyl)-N′-((3- methyl-2-(trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole- 4-sulfonimidamide
439





333
614


embedded image


4-Fluoro-5-(2- hydroxypropan-2-yl)-N′- ((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]- 8′-yl)carbamoyl)thiophene- 2-sulfonimidamide
465





334
613


embedded image


N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-4- fluoro-5-(2-hydroxypropan- 2-yl)thiophene-2- sulfonimidamide
467





335
602


embedded image


3-Fluoro-5-(2- hydroxypropan-2-yl)-N′- ((2-(2,2,2-trifluoroethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
481





336
636c


embedded image


5- ((Dimethylamino)methyl)- 3-fluoro-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8- yl)carbamoyl)thiophene-2- sulfonimidamide
452





337
601


embedded image


2-(2-Hydroxypropan-2-yl)- N′-((2-isopropyl-6,7- dihydro-5H- cyclopenta[b]pyridin-3- yl)carbamoyl)thiazole-5- sulfonimidamide
424





338
685


embedded image


N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- (2,2,2-trifluoroethyl)-1H- pyrazole-3- sulfonimidamide
429
















TABLE 38







Examples in the following table were obtained from chiral HPLC resolutions of


racemic and diastereomeric mixture examples descibed above. The chiral column and eluents


are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the


table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center


denotes that this chiral center has been resolved and the absolute stereochemistry at that center


has not been determined. Assigned stereochemistry in compound names are tentative.














Final







Ex.
Target




LC-MS


#
Number
Structure
IUPAC Name
Column
Eluents
[M + H]+





339
685b


embedded image


(R) or (S)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- (2,2,2- trifluoroethyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
20% EtOH in MTBE (10 mM NH3—MeOH)
429





340
685b


embedded image


(S) or (R)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl) carbamoyl)-1- (2,2,2- trifluoroethyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
20% EtOH in MTBE (10 mM NH3-—MeOH)
429





341
694b


embedded image


(R) or (S)-4-Chloro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- isopropyl-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
423/425





342
694a


embedded image


(S) or (R)-4-Chloro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- isopropyl-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
423/425





343
687b


embedded image


(R) or (S)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- isopropyl-4-methyl- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
403





344
687a


embedded image


(S) or (R)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- isopropyl-4-methyl- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
403





345
689b


embedded image


(R) or (S)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)-4- (methoxymethyl) thiazole-5- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
466





346
689a


embedded image


(S) or (R)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)-4- (methoxymethyl) thiazole-5- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
466





347
642b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- (hydroxymethyl)-5- (2-hydroxypropan-2- yl)thiazole-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% IPA in Hex (0.1% FA)
480





348
642a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- (hydroxymethyl)-5- (2-hydroxypropan-2- yl)thiazole-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% IPA in Hex (0.1% FA)
480





349
686b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide
CHIRALPAK ID, 2*25 cm, 5 um
30% MeOH:ACN = 4:1 in CO2
450





350
686a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide
CHIRALPAK ID, 2*25 cm, 5 um
30% MeOH:ACN = 4:1 in CO2
450





351
170b


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)-4- (methoxymethyl) thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 5 um, 250*20 mm
30% EtOH Hex (8 mM NH3•MeOH)
494





352
170a


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-2-(2- hydroxypropan-2- yl)-4- (methoxymethyl) thiazole-5- carboxamide
CHIRAL ART Cellulose-SB, 5 um, 250*20 mm
30% EtOH in Hex (8 mm NH3•MeOH)
494





353
680b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- (hydroxymethyl)-2- isopropylthiazole-5- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
50% EtOH (0.1% NH3•H2O) in Hex
464





354
680a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- (hydroxymethyl)-2- isopropylthiazole-5- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
50% EtOH (0.1% NH3•H2O) in Hex
464





355
682b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- (hydroxymethyl)-1- isopropyl-1H- pyrazole-3- sulfonimidamide
Chiralpak AD, 2*25 cm, 5 um
40% IPA (2 mM NH3) in CO2
447





356
682a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- (hydroxymethyl)-1- isopropyl-1H- pyrazole-3- sulfonimidamide
Chiralpak AD, 2*25 cm, 5 um
40% IPA (2 mM NH3) in CO2
447





357
653b


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-3- (hydroxymethyl)-1- isopropyl-1H- pyrazole-4- sulfonimidamide
CHIRALPAK AD, 2*25 cm, 5 um
30% EtOH (2 mM NH3—MeOH) in CO2
447





358
653a


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-3- (hydroxymethyl)-1- isopropyl-1H- pyrazole-4- sulfonimidamide
CHIRALPAK AD, 2*25 cm, 5 um
30% EtOH (2 mM NH3—MeOH) in CO2
447





359
674b


embedded image


(R) or (S)-3-Cyano- N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzene- sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
35% MeOH (2 mM NH3—MeOH) in CO2
468





360
674a


embedded image


(S) or (R)-3-Cyano- N′-((3,3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)benzene- sulfonimidamide
Chiralpak IC 2*25 cm, 5 um
35% MeOH (2 mM NH3—MeOH) CO2
468





361
684b


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)pyridine-3- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
25% EtOH in Hex
444





362
684a


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)pyridine-3- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
25% EtOH in Hex
444





363
683b


embedded image


(S) or (R)-5-(2- Hydroxypropan-2- yl)-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane- 1,3′- dicyclopenta[b,e] pyridin]-8′- yl)carbamoyl)thiazole- 2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
40% IPA in EtOH (0.1% DEA)
448





364
683a


embedded image


(R) or (S)-5-(2- Hydroxypropan-2- yl)-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane- 1,3′- dicyclopenta[b,e] pyridin]-8′- yl)carbamoyl) thiazole-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
40% IPA in EtOH (0.1% DEA)
448





365
673b


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-6-(2- hydroxypropan-2- yl)pyridine-3- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex
444





366
673a


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-6-(2- hydroxypropan-2- yl)pyridine-3- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex
444





367
705b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1-(4- fluorophenyl)-5-(2- hydroxypropan-2- yl)-1H-pyrazole-3- sulfonimidamide
Lux 5 um Cellulose-4, AXIA packed, 2.12*25 cm
50% MeOH (2 mM NH3—MeOH) in CO2
527





368
705a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1-(4- fluorophenyl)-5-(2- hydroxypropan-2- yl)-1H-pyrazole-3- sulfonimidamide
Lux 5 um Cellulose-4, AXIA packed, 2.12*25 cm
50% MeOH (2 mM NH3—MeOH) in CO2
527





369
664b


embedded image


(R) or (S)-5-(2- Hydroxypropan-2- yl)-N′-((3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- phenyl-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
495





370
664a


embedded image


(S) or (R)-5-(2- Hydroxypropan-2- yl)-N′-((3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- phenyl)-1-pyrazole- 3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
495





371
663b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)-1-phenyl-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
509





372
663a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)-1-phenyl-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
509





373
651b


embedded image


(R) or (S)-N′-((2- cyclopropyl-3- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)-1-phenyl-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
30% EtOH in Hex (0.1% FA)
495





374
651a


embedded image


(S) or (R)-N′-((2- cyclopropyl-3- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)-1-phenyl-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
30% EtOH in Hex (0.1% FA)
495





375
659b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- phenyl-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IG, 5*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
451





376
659a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- phenyl-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IG, 5*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
451





377
649b


embedded image


(S) or (R)-N′-((2- cyclobutyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
450





378
649a


embedded image


(R) or (S)-N′-((2- cyclobutyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
450





379
650b


embedded image


(S) or (R)-2-(2- Hydroxypropan-2- yl)-N′-((2-isopropyl- 3-methyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
438





380
650a


embedded image


(R) or (S)-2-(2- Hydroxypropan-2- yl)-N′-((2-isopropyl- 3-methyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
438





381
648b


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- (hydroxymethyl)-2- (2-methoxypropan- 2-yl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
20% EtOH in Hex (8 mM NH3•MeOH)
494





382
648a


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- (hydroxymethyl)-2- (2-methoxypropan- 2-yl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
20% EtOH in Hex (8 mM NH3•MeOH)
494





383
615b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)-1-isopropyl-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
40% IPA in Hex (0.1% FA)
475





384
615a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)-1-isopropyl-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
40% IPA in Hex (0.1% FA)
475





385
620b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)pyridine-2- sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
444





386
620a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)pyridine-2- sulfonimidamide
Chiral IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
444





387
185a


embedded image


(R) or (S)-N′-((4- cyclopropyl-6- methylpyrimidin-2- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
397





388
185b


embedded image


(S) or (R)-N′-((4- cyclopropyl-6- methylpyrimidin-2- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
397





389
115b


embedded image


(R) or (S)-N′-((2- fluoro-3,5- diisopropylpyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
Chiralpak IA, 2*25 cm, 5 um
20% IPA in Hex (0.1% FA)
444





390
115a


embedded image


(S) or (R)-N′-((2- fluoro-3,5- diisopropylpyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
Chiralpak IA, 2*25 cm, 5 um
20% IPA in Hex (0.1% FA)
444





391
701b


embedded image


(S) or (R)-4-Fluoro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-3- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
439





392
701a


embedded image


(R) or (S)-4-Fluoro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-3- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH Hex (8 mM NH3•MeOH)
439





393
692b


embedded image


(R) or (S)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)-4- methylthiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
20% EtOH in MTBE (10 mM NH3—MeOH)
435





394
692a


embedded image


(S) or (R)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)-4- methylthiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
20% EtOH in MTBE (10 mM NH3—MeOH)
435





395
695b


embedded image


(R) or (S)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)-3- methylthiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
35% EtOH in Hex (8 mM NH3•MeOH)
435





396
695a


embedded image


(S) or (R)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)-3- methylthiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
35% EtOH in Hex (8 mM NH3•MeOH)
435





397
691b


embedded image


(R) or (S)-3-Chloro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
455





398
691b


embedded image


(S) or (R)-3-Chloro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 22*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
455





399
688b


embedded image


(S) or (R)-4-Chloro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
40% EtOH in Hex (8 mM NH3•MeOH)
455





400
688a


embedded image


(R) or (S)-4-Chloro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
40% EtOH in Hex (8 mM NH3•MeOH)
455





401
690b


embedded image


(R) or (S)-3-Bromo- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
499





402
690a


embedded image


(S) or (R)-3-Bromo- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonamidamide
CHIRALPAK IG, 2.0*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
499





403
661b


embedded image


(S) or (R)-2-(2- Hydroxypropan-2- yl)-N′-((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
464





404
661a


embedded image


(R) or (S)-2-(2- Hydroxypropan-2- yl)-N′-((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl)thiazole- 5-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
464





405
647b


embedded image


(S) or (R)-N′-((2- (difluoromethyl)-3- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in CO2
446





406
647a


embedded image


(R) or (S)-N′-((2- (difluoromethyl)-3- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in CO2
446





407
676b


embedded image


(R) or (S)-N′-((2- cyclopropyl-3- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-1- (difluoromethyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
10% EtOH in MTBE (10 mM NH3—MeOH)
411





408
676a


embedded image


(S) or (R)-N′-((2- cyclopropyl-3- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-1- (difluoromethyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
10% EtOH in MTBE (10 mM NH3—MeOH)
411





409
181b


embedded image


(R) or (S)-N′((2- cyclopropyl-3-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
Chiralpak AD, 2*25 cm 5 um
30% IPA in Hex (8 mM NH3•MeOH)
449





410
181a


embedded image


(S) or (R)-N′-((2- cyclopropyl-3-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
Chiralpak AD, 2*25 cm 5 um
30% IPA in Hex (8 mM NH3•MeOH)
449





411
675b


embedded image


(S) or (R)-N′-((2- cyclopropyl-3-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
25% MeOH (2 mM NH3—MeOH) in CO2
450





412
675a


embedded image


(R) or (S)-N′-((2- cyclopropyl-3-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
25% MeOH (2 mM NH3—MeOH) in CO2
450





413
681b


embedded image


(R) or (S)-4-(2- Hydroxypropan-2- yl)-N′-((2-isopropyl- 3-methyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
10% EtOH in Hex:DCM (3:1, 10 mM NH3—MeOH)
437





414
681a


embedded image


(S) or (R)-4-(2- Hydroxypropan-2- yl)-N′-((2-isopropyl- 3-methyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
10% EtOH in Hex:DCM (3:1, 10 mM NH3—MeOH)
437





415
669b


embedded image


(R) or (S)-4-(2- Hydroxypropan-2- yl)-N′-((3-methyl-2- (1- methylcyclopropyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
449





416
669a


embedded image


(S) or (R)-4-(2- Hydroxypropan-2- yl)-N′-((3-methyl-2- (1- methylcyclopropyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
449





417
176b


embedded image


(R) or (S)-N′-((2- cyclopropyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
Lux 5 um Cellulose-4 AXIA packed, 2.12*25 cm
40% EtOH in MeOH (2 mM NH3—MeOH)
421





418
176a


embedded image


(S) or (R)-N′-((2- cyclopropyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
Lux 5 um Cellulose-4 AXIA packed, 2.12*25 cm
40% EtOH in MeOH (2 mM NH3—MeOH)
421





419
182b


embedded image


(R) or (S)-4-(2- Hydroxypropan-2- yl)-N′-((2-isopropyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
Lux 5 um Cellulose-4 AXIA packed, 2.12*25 cm
40% MeOH (2 mM NH3—MeOH) in CO2
423





420
182a


embedded image


(S) or (R)-4-(2- Hydroxypropan-2- yl)-N′-((2-isopropyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
Lux 5 um Cellulose-4 AXIA packed, 2.12*25 cm
40% MeOH (2 mM NH3—MeOH) in CO2
423





421
678b


embedded image


(S) or (R)-4-Fluoro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
439





422
678a


embedded image


(R) or (S)-4-Fluoro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in HEx (8 mM NH3•MeOH)
439





423
658b


embedded image


(R) or (S)-N′-((2- cyclobutyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 5*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
449





424
658a


embedded image


(S) or (R)-N′-((2- cyclobutyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 5*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
449





425
667b


embedded image


(R) or (S)-N′-((2- cyclopropyl-3- isopropyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK ID, 2*25 cm, 5 um
30% MeOH (2 mM NH3—MeOH) in CO2
463





426
667a


embedded image


(S) or (R)-N′-((2- cyclopropyl-3- isopropyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK ID, 2*25 cm, 5 um
30% MeOH (2 mM NH3—MeOH) in CO2
463





427
657b


embedded image


(R) or (S)-N′-((2- (tert-butyl)-3- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IF, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
451





428
657a


embedded image


(S) or (R)-N′-((2- (tert-butyl)-3- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IF, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
451





429
670b


embedded image


(R) or (S)-N′-((2,3- dicyclopropyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
461





430
670a


embedded image


(S) or (R)-N′-((2,3- dicyclopropyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
461





431
612b


embedded image


(R) or (S)-N′-((2,6- dicyclopropyl-3,5- dimethylpyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
10% IPA in Hex:DCM (3:1, 10 mM NH3—MeOH)
449





432
612a


embedded image


(S) or (R)-N′-((2,6- dicyclopropyl-3,5- dimethylpyridin-4- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
10% IPA in Hex:DCM (3:1, 10 mM NH3—MeOH)
449





433
626b


embedded image


(R) or (S)-N′-((2- cyclopropyl-3- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiazole-2- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
10% EtOH in MTBE (0.1% FA)
436





434
626a


embedded image


(S) or (R)-N′-((2- cyclopropyl-3- methyl-6,7-dihydro- 5H- cyclopenta[c]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiazole-2- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
10% EtOH in MTBE (0.1% FA)
436





435
665b


embedded image


(R) or (S)-N′-((2- (cyclopropylmethyl)- 3-methyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
449





436
665a


embedded image


(S) or (R)-N′-((2- (cyclopropylmethyl)- 3-methyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
449





437
654b


embedded image


(R) or (S)-N′-((3- cyclopropyl-2-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfinimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
449





438
654a


embedded image


(S) or (R)-N′-((3- cyclopropyl-2-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
449





439
634b


embedded image


(R) or (S)-1-Ethyl- N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
389





440
634a


embedded image


(S) or (R)-1-Ethyl- N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
389





441
639b


embedded image


(R) or (S)-1-Methyl- N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
375





442
639a


embedded image


(S) or (R)-1-Methyl- N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
375





443
700b


embedded image


(R) or (S)-N′-(((R)- 3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- phenyl-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
20% EtOH in MTBE (10 mM NH3—MeOH)
437





444
700a


embedded image


(S) or (R)-N′-(((R)- 3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- phenyl-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
20% EtOH in MTBE (10 mM NH3—MeOH)
437





445
638b


embedded image


(S) or (R)-1- (Difluoromethyl)-N′- ((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane- 1,3′- dicyclopenta[b,e] pyridin]-8′- yl)carbamoyl)-1H- pyrazole-4- sulfonimidamide
CHIRALPAK IG, 5*25 cm, 5 um
5% IPA in MTBE (10 mM NH3—MeOH)
423





446
638a


embedded image


(R) or (S)-1- (Difluoromethyl)-N′- ((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane- 1,3′- dicyclopenta[b,e] pyridin]-8′- yl)carbamoyl)-1H- pyrazole-4- sulfonimidamide
CHIRALPAK IG, 5*25 cm, 5 um
5% IPA in MTBE (10 mM NH3—MeOH)
423





447
637b


embedded image


(S) or (R)-1- (Difluoromethyl)-N′- ((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1H- pyrazole-4- sulfonimidamide
CHIRALPAK IG, 5*25 cm, 5 um
3% IPA in MTBE (10 mM NH3—MeOH)
425





448
637a


embedded image


(R) or (S)-1- (Difluoromethyl)-N′- ((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1H- pyrazole-4- sulfonimidamide
CHIRALPAK IG, 5*25 cm, 5 um
3% IPA in MTBE (10 mM NH3—MeOH)
425





449
645b


embedded image


(S) or (R)-3-Fluoro- 5-(2-hydroxypropan- 2-yl)-N′-((2- isopropyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
455





450
645a


embedded image


(R) or (S)-3-Fluoro- 5-(2-hydroxypropan- 2-yl)-N′-((2- isopropyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
455





451
644b


embedded image


(R) or (S)-1- Isopropyl-N′-((2- isopropyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b] pyridin-4-yl) carbamoyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
20% EtOH in Hex (8 mM NH3•MeOH)
405





452
644a


embedded image


(S) or (R)-1- Isopropyl-N′-((2- isopropyl-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
20% EtOH in Hex (8 mM NH3•MeOH)
405





453
633b


embedded image


(R) or (S)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)benzene- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
50% IPA in Hex (8 mM NH3•MeOH)
415





454
633a


embedded image


(S) or (R)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4-(2- hydroxypropan-2- yl)benzene- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
50% IPA in Hex (8 mM NH3•MeOH)
415





455
625b


embedded image


(R) or (S)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-3-(2- hydroxypropan-2- yl)benzene- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
415





456
625a


embedded image


(S) or (R)-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-3-(2- hydroxypropan-2- yl)benzene- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
415





457
632b


embedded image


(S) or (R)-3-Fluoro- 5-(2-hydroxypropan- 2-yl)-N′-((3-methyl- 2-(trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK ID, 2*25 cm, 5 um
10% IPA in MTBE (0.1% FA)
481





458
632a


embedded image


(R) or (S)-3-Fluoro- 5-(2-hydroxypropan- 2-yl)-N′-((3-methyl- 2-(trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK ID, 2*25 cm, 5 um
10% IPA in MTBE (0.1% FA)
481





459
624b


embedded image


(R) or (S)-4-(2- Hydroxypropan-2- yl)-N′-((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
463





460
624a


embedded image


(S) or (R)-4-(2- Hydroxypropan-2- yl)-N′-((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
20% EtOH in Hex (01.% FA)
463





461
631b


embedded image


(R) or (S)-N′-((3- cyclopropyl-2-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-3- fluoro-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
467





462
631a


embedded image


(S) or (R)-N′-((3- cyclopropyl-2-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-3- fluoro-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
467





463
630b


embedded image


(R) or (S)-N′-((3- cyclopropyl-2-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
450





464
630a


embedded image


(S) or (R)-N′-((3- cyclopropyl-2-ethyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
450





465
623b


embedded image


(S) or (R)-N′-((3- cyclopropyl-2- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
10% EtOH in MTBE (0.1% FA)
435





466
623a


embedded image


(R) or (S)-N′-((3- cyclopropyl-2- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
10% EtOH in MTBE (0.1% FA)
435





467
622b


embedded image


(R) or (S)-4-(2- Hydroxypropan-2- yl)-N′-((3-isopropyl- 2-methyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
50% IPA in MTBE (0.1% FA)
437





468
622a


embedded image


(S) or (R)-4-(2- Hydroxypropan-2- yl)-N′-((3-isopropyl- 2-methyl-6,7- dihydro-5H- cyclopenta[b]pyridin- 4- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
50% IPA in MTBE (0.1% FA)
437





469
621b


embedded image


(R) or (S)-1- (Difluoromethyl)-N′- ((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
20% MeOH (2 mM NH3—MeOH) in CO2
439





470
621a


embedded image


(S) or (R)-1- (Difluoromethyl)-N′- ((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
20% MeOH (2 mM NH3—MeOH) in CO2
439





471
618b


embedded image


(R) or (S)-N′-((3- cyclopropyl-2- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)thiazole-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
436





472
618a


embedded image


(S) or (R)-N′-((3- cyclopropyl-2- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-5- (2-hydroxypropan-2- yl)thiazole-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
436





473
628b


embedded image


(R) or (S)-1- Isopropyl-N′-((3- methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
431





474
628a


embedded image


(S) or (R)-1- Isopropyl-N′-((3- methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
431





475
617b


embedded image


(S) or (R)-1- (Difluoromethyl)-N′- ((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)- 1H-pyrazole-4- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
25% EtOH in Hex (0.1% FA)
439





476
617a


embedded image


(R) or (S)-1- (Difluoromethyl)-N′- ((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)- 1H-pyrazole-4- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
25% EtOH in Hex (0.1% FA)
439





477
610b


embedded image


(S) or (R)-N′-((3- ethyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
15% EtOH in Hex (0.1% FA)
478





478
610a


embedded image


(R) or (S)-N′-((3- ethyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-2- (2-hydroxypropan-2- yl)thiazole-5- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
15% EtOH in Hex (0.1% FA)
478





479
611b


embedded image


(R) or (S)-N′-((3- ethyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-3- fluoro-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IF, 4.6*50 mm, 3 um
20% EtOH in Hex (0.1% FA)
495





480
611a


embedded image


(S) or (R)-N′-((3- ethyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-3- fluoro-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IF, 4.6*50 mm, 3 um
20% EtOH in Hex (0.1% FA)
495





481
698b


embedded image


(R) or (S)-N′-((3- ethyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b] pyridin-4-yl) carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2.0*25 cm, 5 um
20% EtOH in Hex (8 mM NH3•MeOH)
477





482
698a


embedded image


(S) or (R)-N′-((3- ethyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-4- (2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRALPAK IG, 2.0*25 cm, 5 um
20% EtOH in Hex (8 mM NH3•MeOH)
477





483
616b


embedded image


(S) or (R)-4-Fluoro- 5-(2-hydroxypropan- 2-yl)-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
453





484
616a


embedded image


(R) or (S)-4-Fluoro- 5-(2-hydroxypropan- 2-yl)-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
453





485
614b


embedded image


(S) or (R)-4-Fluoro- 5-(2-hydroxypropan- 2-yl)-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane- 1,3′- dicyclopenta[b,e] pyridin]-8′- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
465





486
614a


embedded image


(R) or (S)-4-Fluoro- 5-(2-hydroxypropan- 2-yl)-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane- 1,3′- dicyclopenta[b,e] pyridin]-8′- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
465





487
613b


embedded image


-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- fluoro-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
40% EtOH in Hex (0.1% FA)
467





488
613a


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4- fluoro-5-(2- hydroxypropan-2- yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
40% EtOH in Hex (0.1% FA)
467





489
697b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- ethyl-1H-pyrazole-3- sulfonimidamide
HIRALPAK ID, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
403





490
697a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1- ethyl-1H-pyrazole-3- sulfonimidamide
HIRALPAK ID, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
403





491
607b


embedded image


(R) or (S)-4-(2- Hydroxypropan-2- yl)-N′-((2-(2,2,2- trifluoroethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% IPA in Hex (0.1% FA)
463





492
607a


embedded image


(S) or (R)-4-(2- Hydroxypropan-2- yl)-N′-((2-(2,2,2- trifluoroethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% IPA in Hex (0.1% FA)
463





493
636b


embedded image


(R) or (S)-5- ((Dimethylamino) methyl)-3-fluoro-N′- (((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK IG, 2.0*25 cm, 5 um
15% EtOH in Hex:DCM (3:1, 10 mM NH3—MeOH)
452





494
636a


embedded image


(S) or (R)-5- ((Dimethylamino) methyl)-3-fluoro-N′- (((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl) thiophene-2- sulfonimidamide
CHIRALPAK IG, 2.0*25 cm, 5 um
15% EtOH in Hex:DCM (3:1, 10 mM NH3—MeOH)
452





495
304b


embedded image


(R) or (S)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-6,7- dihydro-5H- pyrazolo[5,1- b][1,3]oxazine-3- sulfonimidamide
CHIRALPAK ID, 2*25 cm, 5 um
10% IPA in MTBE (0.1% FA)
431





496
304a


embedded image


(S) or (R)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-6,7- dihydro-5H- pyrazolo[5,1-b][1,3] oxazine-3- sulfonimidamide
CHIRALPAK ID, 2*25 cm, 5 um
10% IPA in MTBE (0.1% FA)
431





497
306b


embedded image


(R) or (S)-N′-((2- cyclopropyl-3- methyl-6,7- dihydro-5H- cyclopenta[b] pyridin-4-yl) carbamoyl)-6,7- dihydro-5H- pyrazolo[5,1-b][1,3] oxazine-3- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
10% MeOH in MTBE (10 mM NH3—MeOH)
417





498
306a


embedded image


(S) or (R)-N′-((2- cyclopropyl-3- methyl-6,7-dihydro- 5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)- 6,7-dihydro-5H- pyrazolo[5,1-b] [1,3]oxazine-3- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
10% MeOH in MTBE (10 mM NH3—MeOH)
417





499
605e


embedded image


(R, S) or (S, S)-2- (1,2- Dihydroxypropan-2- yl)-N′-((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl) thiazole-5- sulfonimidamide (From Ex. 241)
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
480





500
605e


embedded image


(R, R) or (S, R)-2- (1,2- Dihydroxypropan-2- yl)-N′-((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl) thiazole-5- sulfonimidamide (From Ex. 241)
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
480





501
605g


embedded image


(S, S) or (R, S)-2- (1,2- Dihydroxypropan-2- yl)-N′-((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl) thiazole-5- sulfonimidamide (from Ex. 242)
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
480





502
605h


embedded image


(S, R) or (R, R)-2- (1,2- Dihydroxypropan-2- yl)-N′-((3-methyl-2- (trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl) thiazole-5- sulfonimidamide (from Ex. 242)
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
480
















TABLE 39







Examples in the following table were obtained from chiral HPLC resolutions of


racemic examples described above. The chiral column and eluents are listed in the table. As a


convention, the fastest-eluting diastereomer or isomer is always listed first in the table followed


by the second-fastest-eluting enantiomer of the mixture, and so on. The symbol * at a chiral


center denotes that this chiral center has been resolved and the absolute stereochemistry at that


center has not been determined. Assigned stereochemistry in compound names are tentative.













Final


















Target




LC-MS


Ex. #
Number
Structure
IUPAC Name
Column
Eluents
[M + H]+





503
660d


embedded image


(R, R) or (S, R) or (R, S) or (S, S)-1-isopropyl- N′-((3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-imidazole-4- sulfonimidamide
CHIRALPAK IA, 5*25 cm, 5 um
50% EtOH: CAN (2:1, 2 mM NH3- MeOH) in CO2
403





504
660c


embedded image


(S, R) or (R, S) or (S, S) or (R, R)-1-Isopropyl- N′-((3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-imidazole-4- sulfonimidamide
CHIRALPAK IA, 5*25 cm, 5 um
50% EtOH: CAN (2:1, 2 mM NH3- MeOH) in CO2
403





505
660b


embedded image


(S, S) or (R, S) or (S, R) or (R, R)-1-Isopropyl- N′-((3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-imidazole-4- sulfonimidamide
CHIRALPAK IA, 5*25 cm, 5 um
50% EtOH: CAN (2:1, 2 mM NH3- MeOH) in CO2
403





506
660a


embedded image


(R, S) or (S, S) or (S, R) or (R, R)-1-Isopropyl- N′-((3-metliyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-imidazole-4- sulfonimidamide
CHIRALPAK IA, 5*25 cm, 5 um
50% EtOH: CAN (2:1, 2 mM NH3- MeOH) in CO2
403





507
201f


embedded image


(R, S) and (S, S) or (S, R) and (R, R)-2-(1.2- Dihydroxvpropan- 2-yl)-N′-((3,3- dimethyl- 1,2,3.5.6.7- hexahydrodicyclopenta [b,e]pvridin-8-yl) carbamoyl)thiazole-5- sulfonimidamide (mixture of two isomers)
CHIRAL ART Cellulose- SB, 5*25 cm, 5 um
40% EtOH (2 mM NH3- MeOH) in CO2
466







two diastereomers, most likely








with the same configuration at








sulfur









508
201e


embedded image


(R, R) and (S, R) or (R, S) and (S, S)-2-(1,2- Dihydroxypropan- 2-yl)-N′-((3,3-dimethyl- 1,2,3.5.6.7- hexahydrodicyclopenta [b,e]pyridin-8-yl) carbamoyl)thiazole-5- sulfonimidamide (mixture of two isomers)
CHIRAL ART Cellulose- SB, 5*25 cm, 5 um
40% EtOH (2 mM NH3- MeOH) in CO2
466







two diastereomers, most likely








with the same configuration at








sulfur









509
201d


embedded image


(R, S) or (S, S) or (S, R) or (R, R)- 2-(1.2- Dihydroxypropan- 2-yl)-N′-((3,3- dimethyl-1,2,3,5,6.7- hexahydrodicyclopenta [b,e]pvridin-8- yl)carbamoyl)thiazole-5- sulfonimidamide (From Ex. 507)
CHIRALPAK IF, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
466





510
201c


embedded image


(S, S) or (R, S) or (S, R) or (R. R)-2-(1,2- Dihydroxypropan- 2-yl)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pvridin-8- yl)carbamoyl) thiazole-5- sulfonimidamide (From Ex. 507)
CHIRALPAK IF, 5*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
466





511
201a


embedded image


(R, R) or (S, R) or (R, S) or (S, S)-2-(1,2- Dihydroxypropan- 2-yl)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl) thiazole-5- sulfonimidamide (From Ex. 508)
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
466





512
201b


embedded image


(S, R) or (R, R) or (R, S) or (S, S)-2-(1,2- Dihydroxypropan- 2-yl)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl) thiazole-5- sulfonimidamide (From Ex. 508)
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
466





513
662c


embedded image


(S, S) and (S, R) or (R, S) and (R, R)-N′-((3-Ethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b.e]pvridin-8- yl)carbamoyl)-2-(2- hydroxypropan- 2-yl)thiazole-5- sulfonimidamide (mixture of two isomers)
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
450





514
662d


embedded image


(R, R) or (R, S) or (S, R) or (S, S)-N′-((3-Ethyl- 1,2,3,5,6,7- hexaliydrodicyclopenta [b,e]pyridin-8- yl)caibamoyl)-2-(2- hydroxypropan- 2-yl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
450





515
662d


embedded image


(R, S) or (R, R) or (S, R) or (S, S)-N′-((3-Ethyl- 1,2,3,5,6,7- hexaliydrodicyclopenta [b,e]pyridin-8- yl)caibamoyl)-2-(2- hydroxypropan- 2-yl)thiazole-5- sulfonimidamide
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
450





516
662b


embedded image


(S, R) or (S, S) or (R, S) or (R, R)-N′-((3-Ethyl- 1,2,3,5,6,7- hexaliydrodicyclopenta [b,e]pyridin-8- yl)caibamoyl)-2-(2- hydroxypropan- 2-yl)thiazole-5- sulfonimidamide (from Ex. 513)
CHIRALPAK IG 2.0*25 cm, 5 um
10% EtOH in MTBE (10 mM NH3- MeOH)
450





517
662a


embedded image


(S, S) or (S, R) or (R, S) or (R, R)-N′-((3-Ethyl- 1,2,3,5,6,7- hexaliydrodicyclopenta [b,e]pyridin-8- yl)caibamoyl)-2-(2- hydroxypropan- 2-yl)thiazole-5- sulfonimidamide (from Ex. 513)
CHIRALPAK IG 2.0*25 cm, 5 um
10% EtOH in MTBE (10 mM NH3- MeOH)
450





518
699c


embedded image


(R, S) and (S, S) or (S, R) and (R, R)-5-(1,2- Dihydroxypropan-2-yl)- N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl) carbamoyl)-3- fluorotliophene-2- sulfonimidamide (mixture of two isomers)
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
483





519
699b


embedded image


(S, R) and (R, R) or (R, S) and (S, S)-5-(1,2- Dihydroxypropan-2-yl)- N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl) carbamoyl)-3- fluorotliophene-2- sulfoni midamide (mixture of two isomers)
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
483





520
699a


embedded image


(S, S) and (R, S) or (S, R) and (R, R)-5-(1,2- Dihydroxypropan-2-yl)- N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl) carbamoyl)-3- fluorotliophene-2- sulfonimidamide (From Ex. 518)
CHIRALPAK IG 20*250 mm, 5 um
35% MeOH: ACN (2:8, 0.1% NH3• H2O) in CO2
483





521
640c


embedded image


(R, S) and (S, S) or (S, R) and (R, R)-5-(1,2- Dihydroxypropan-2-yl)- N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl) carbamoyl)-3- fluorotliophene-2- sulfonimidamide (From Ex. 518)
CHIRALPAK IG 20*250 mm, 5 um
35% MeOH: ACN (2:8, 0.1% NH3• H2O) in CO2
483





522
640b


embedded image


(S, R) and (R, R) or (R, S) and (S, S)-5-(1,2- Dihydroxypropan-2-yl)- N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl) carbamoyl)-3- fluorotliophene-2- sulfonimidamide (From Ex. 519)
CHIRALPAK AD 5*25 cm, 5 um
40% MeOH: ACN (2:8, 0.1% NH3• H2O) in CO2
483





523
640a


embedded image


(R, R) and (S, R) or (R, S) and (S, S)-5-(1,2- Dihydroxypropan-2-yl)- N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl) carbamoyl)-3- fluorotliophene-2- sulfonimidamide (From Ex. 519)
CHIRALPAK AD 5*25 cm, 5 um
40% MeOH: ACN (2:8, 0.1% NH3• H2O) in CO2
483





524
656d


embedded image


(R, S) or (R, R) or (S, R) or (S, S)-N′-((2- Cyclopropyl-3,7- dimethyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan- 2-yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





525
656b


embedded image


(S, S) or (S, R) or (R, S) or (R, R)-N′-((2- Cyclopropyl-3,7- dimethyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan- 2-yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





526
656a


embedded image


(R, R) or (R, S) or (S, R) or (S, S)-N′-((2- Cyclopropyl-3,7- dimethyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan- 2-yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





527
656c


embedded image


(S, R) or (S, S) or (R, S) or (R, R)-N′-((2- Cyclopropyl-3,7- dimethyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2- hydroxypropan- 2-yl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





528
668c


embedded image


(R, R) or (R, S) or (S, R) or (S, S)-1- (Difluoromethyl)-N′-((3- ethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG 2.0*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
425





529
668b


embedded image


(R, R) or (R, S) or (S, R) or (S, S)-1- (Difluoromethyl)-N′-((3- ethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG 2.0*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
425





530
668a


embedded image


(S, S) or (S, R) or (R, S) or (R, R)-1- (Difluoromethyl)-N′-((3- ethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG 2.0*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
425





531
668d


embedded image


(S, R) or (S, S) or (R, S) or (R, R)-1- (Difluoromethyl)-N′-((3- ethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG 2.0*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
425





532
671d


embedded image


(R, R) or (R, S) or (S, R) or (S, S)-N′-((3- ethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-3-fluoro-5- (2-hydroxypropan-2-yl) thiophene-2- sulfonimidamide
CHIRALPAK IG 2.0*25 cm, 5 um
30% EtOH in Hex (8 mM) NH3• MeOH)
467





533
671c


embedded image


(R, S) or (R, R) or (S, R) or (S, S)-N′-((3- ethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-3-fluoro-5- (2-hydroxypropan-2-yl) thiophene-2- sulfonimidamide
CHIRALPAK IG 2.0*25 cm, 5 um
30% EtOH in Hex (8 mM) NH3• MeOH)
467





534
671b


embedded image


(S, R) or (S, S) or (R, S) or (R, R)-N′-((3- ethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-3-fluoro-5- (2-hydroxypropan-2-yl) thiophene-2- sulfonimidamide
CHIRALPAK IG 2.0*25 cm, 5 um
30% EtOH in Hex (8 mM) NH3• MeOH)
467





535
671a


embedded image


(S, S) or (S, R) or (R, S) or (R, R)-N′-((3- ethyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-3-fluoro-5- (2-hydroxypropan-2-yl) thiophene-2- sulfonimidamide
CHIRALPAK IG 2.0*25 cm, 5 um
30% EtOH in Hex (8 mM) NH3• MeOH)
467





536
605d


embedded image


(R, S) and (S, S) or (R, R) and (S, R)-2-(l,2- Dihydroxypropan-2-yl)- N′-((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl) thiazole-5- sulfonimidamide (from Ex. 240; mixture of two isomers)
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
480





537
605b


embedded image


(R, R) and (S, R) or (R, S) and (S, S)-2-(l,2- Dihydroxypropan-2-yl)- N′-((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl) thiazole-5- sulfonimidamide (from Ex. 240; mixture of two isomers)
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
480





538
643a


embedded image


(R, R/S) or (S, R/S)-N- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4-(1- hydroxyethyl)-2-(2- hydroxypropan-2-yl) thiazole-5- sulfonimidamide (from Ex. 237; mixture of two isomers)
CHIRALPAK IG 0.46*10 cm, 3 um
30% EtOH in Hex (0.1% FA)
466





539
643b


embedded image


(S, R/S) or (R, R/S)-N- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-4-(1- hydroxyethyl)-2-(2- hydroxypropan-2-yl) thiazole-5- sulfonimidamide (from Ex. 237; mixture of two isomers)
CHIRALPAK IG 0.46*10 cm, 3 um
30% EtOH in Hex (0.1% FA)
466















540
171c


embedded image


(R, R) and (R, S) or (S, R) and (S, S)-1-Isopropyl- N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-pyrazole-4- sulfonimidamide
Column 2: Reg-AD, 30*250 mm, 5 um, 20% IPA in Hex (8 mM NH3•MeOH) to separate two fast- co-eluting isomers from Column 1 Chiralpak IC, 2*25 cm, 5 um, 30% MeOH (0.1% DEA) in CO2
403





541
171b


embedded image


(R, S) and (R, R) or (S, R) and (S, S)-1-Isopropyl- N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-pyrazole-4- sulfonimidamide
Column 2: Reg-AD, 30*250 mm, 5 um, 20% IPA in Hex (8 mM NH3•MeOH) to separate two fast- co-eluting isomers from Column 1 Chiralpak IC, 2*25 cm, 5 um, 30% MeOH (0.1% DEA) in CO2
403





542
171a


embedded image


(S, R) and (S, S) or (R, S) and (R, R)-1-Isopropyl- N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-pyrazole-4- sulfonimidamide
Column 2: CHIRALPAK AD, 5*25 cm, 5 um, 50% EtOH in CO2 to separate two slow-co-eluting isomers from Column 1 Chiralpak IC, 2*25 cm, 5 um, 30% MeOH (0.1% DEA) in CO2
403





543
171d


embedded image


(S, S) and (S, R) or (R, S) and (R, R)-1-Isopropyl- N′-((3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)- 1H-pyrazole-4- sulfonimidamide
Column 2: CHIRALPAK AD, 5*25 cm, 5 um, 50% EtOH in CO2 to separate two slow-co-eluting isomers from Column 1 Chiralpak IC, 2*25 cm, 5 um, 30% MeOH (0.1% DEA) in CO2
403









Example 544
Compound 734



embedded image


N′-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(1,2,3-trihydroxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme VIII)



embedded image


Step 1: N′-(tert-butyldimethylsilyl)-N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridine -8-yl)carbamoyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide (50 mg, 0.12 mmol) in THF (10 mL) in a 25-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 24 mg, 0.61 mmol) at 0° C. The resulting solution was stirred for 10 min at 0° C. To the solution was added 2,2,2-trichloroethyl (3,3-dimethyl-1,2,3,5,6,7-hexa- hydrodicyclopenta[b,e]pyridin-8-yl)carbamate (46 mg, 0.12 mmol) in portions at 0° C. The resulting mixture was stirred for 2 h at 35° C. The reaction was quenched by the addition of 10 mL water/ice at 0° C. and extracted with 3×15 mL of EtOAc. The combined organic layers were washed with brine (3×15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc=3:1). This resulted in 60 mg (77%) of the title compound as an off-white solid. MS-ESI: 636 (M+1).


Step 2: N′-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-(1,2,3-trihydroxypropan-2-yl)thiazole-5-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-2-(5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl)thiazole-5-sulfonimidamide (60 mg, 0.094 mmol) in THF (5 mL) in a 25-mL round-bottom flask was added HCl in 1,4-dioxane(4 M, 1.25 mL) dropwise at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions:)(Bridge Prep OBD C18 Column, 30×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 25% B over 7 min; UV 254/210 nm; Rt: 4.95 min. This resulted in 17.1 mg (38%) of Example 544 as a white solid. MS-ESI: 482 (M+1). 1H NMR (400 MHz, MeOH-d4) δ 8.22 (s, 1H), 3.91-3.83 (m, 4H), 2.98 (t, J=7.6 Hz, 2H), 2.87-2.77 (m, 4H), 2.16-2.09 (m, 2H), 2.00-1.96 (m, 2H), 1.40 (s, 6H).









TABLE 40







Examples in the following table were prepared using similar conditions as described in


Example 9 and Scheme 2 from appropriate starting materials.












Final






Target


Exact Mass


Example #
Number
Structure
IUPAC Name
[M + H]+














545
736


embedded image


N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-2-((R)- 2-hydroxy-1-(2- methoxyethoxy)propan- 2-yl)thiazole-5- sulfonimidamide
524





546
735


embedded image


3-(N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl) sulfamidimidoyl)-N- methylbenzenesulfonamide
478





547
721c


embedded image


4-Ethyl-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)thiophene- 2-sulfonimidamide
405
















TABLE 41







Examples in the following table were prepared using similar conditions as described in


Example 236 and Scheme II from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+













548


embedded image


5-Ethyl-3-fluoro-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiophene-2- sulfonimidamide
423
















TABLE 42







Examples in the following table were prepared using similar conditions as described in


Example 252 and Scheme V from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+













549


embedded image


1-(1,1-Difluoroethyl)-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
425





550


embedded image


4-Chloro-1-ethyl-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
451
















TABLE 43







Examples in the following table were obtained from chiral HPLC resolutions of


racemic examples described above. The chiral column and eluents are listed in the table. As a


convention, the faster-eluting enantiomer is always listed first in the table followed by the


slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral


center has been resolved and the absolute stereochemistry at that center has not been determined.


Assigned stereochemistry in compound names are tentative.














Final








Target




LC-MS


Ex. #
Number
Structure
IUPAC Name
Column
Eluents
[M + H]+
















553
723b


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(R) or (S)-1-(1,1- Difluoroethyl)- N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% IPA in Hex (0.1% FA)
425





554
723a


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(S) or (R)-1-(1,1- Difluoroethyl)-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b, e]pyridin-8- yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% IPA in Hex (0.1% FA)
425





555
721b


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(R) or (S)-4-Ethyl-N′- (((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b, e]pyridin-8- yl)carbamoyl)thiophene- 2-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
405





556
721a


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(S) or (R)-4-Ethyl-N′- (((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b, e]pyridin-8- yl)carbamoylithiophene- 2-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
405





557
720b


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(S) or (R)-5-Ethyl-3- fluoro-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b, e]pyridin-8- yl)carbamoyl)thiophene- 2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
423





558
720a


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(R) or (S)-5-Ethyl-3- fluoro-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b, e]pyridin-8- yl)carbamoyl)thiophene- 2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
30% EtOH in Hex (8 mM NH3•MeOH)
423





559
729b


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(R) or (S)-4-Chloro-1- ethyl-N′-((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
451





560
729a


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(S) or (R)-4-Chloro-1- ethyl-N′-((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H- pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
451









Example 561



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1-(Difluoromethyl)-4-fluoro-N′-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide (Scheme IX)
Examples 562 and 563



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(R)- and (S)-1-(difluoromethyl)-4-fluoro-N′-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide



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Step 1: N-(tert-butyldimethylsilyl)-1-(difluoromethyl)-4-fluoro-N′-((3-methyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethyl silyl)-1-(difluoromethyl)-4-fluoro-1H-pyrazole-3-sulfonimidamide (150 mg, 0.46 mmol) in THF (10 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 54.8 mg, 1.37 mmol) at 0° C. in an ice/water bath. The resulting solution was stirred for 10 min at RT. Then 2,2,2-trichloroethyl (3-methyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (179 mg, 0.46 mmol) was added to the stirred solution. The resulting solution was stirred for 20 h at RT. The reaction was then quenched by the addition of 1.0 mL of MeOH. The resulting mixture was concentrated. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 250 mg (96%) of the title compound as light yellow oil. MS-ESI: 571(M+1).


Step 2: 1-(Difluoromethyl)-4-fluoro-N′-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b] pyridine-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-1-(difluoromethyl)-4-fluoro-N′-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide (250 mg, 0.45 mmol) in THF (5.0 mL) in a 50-mL round-bottom flask was added KF (131 mg, 2.25 mmol) at RT. The resulting solution was stirred for 1 h at RT. The solids were filtered out. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC using the following conditions:)(Bridge Prep C18 OBD Column, 19 ×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 8% B to 28% B over 7 min; UV 210/254 nm; Rt: 5.32 min. This resulted in 155 mg (74%) of Example 561 as an off-white solid. MS-ESI: 457 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.65 (d, J=4.8 Hz, 1H), 8.04 (br s, 2H), 7.86 (t, J=58.4 Hz, 1H), 2.94-2.88 (m, 2H), 2.80-2.74 (m, 2H), 2.20 (s, 3H), 2.07-1.98 (m, 2H).


Step 3: Chiral Resolution
Example 561

(150 mg) was resolved by prep-chiral-HPLC using the following conditions: CHIRALPAK IG, 20*250 mm, 5 um; Mobile Phase A: Hex (0.1% FA), Mobile Phase B: EtOH; Flow rate: 20 mL/min; Gradient: 20% B; 220/254 nm; Rti: 6.505 min (Example 562); Rte: 8.721 min (Example 563); This resulted in 37.0 mg of Example 562 followed by 42.4 mg of Example 563, both as off-white solid.


Example 562
MS-ESI: 457 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.65 (d, J=4.8 Hz, 1H), 8.11 (br s, 2H), 7.86 (t, J=58.4 Hz, 1H), 2.94-2.88 (m, 2H), 2.78-2.67 (m, 2H), 2.20 (s, 3H), 2.09-1.97 (m, 2H).
Example 563

MS-ESI: 457 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 8.65 (d, J=4.4 Hz, 1H), 8.11 (br s, 2H), 7.86 (t, J=58.4 Hz, 1H), 2.94-2.87 (m, 2H), 2.81-2.71 (m, 2H), 2.20 (s, 3H), 2.09-1.96 (m, 2H).









TABLE 49







Examples in the following table were prepared using similar conditions as described in


Example 561 and Scheme IX from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+













564


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(6R)-6-methoxy-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-6,7- dihydro-5H-pymzolo[5,1-b][1,3]oxazine- 3-sulfonimidamide
475





565


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N′-((3-methyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta [b]pyridin-4- yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3- sulfonimidamide
445





566


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4-(2-Hydroxypropan-2-yl)-N′-((2-methyl- 3-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
463





567


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4-(2-Hydroxypropan-2-yl)-N′-((2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
449





568


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1-(Difluoromethyl)-4-fluoro-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
429





569


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1-(Difluoromethyl)-4-fluoro-N′- ((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
441





570


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N′-((2,3-dicyclopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)calbamoyl)-3- fluoro-5-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide
479





571


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N′-((2,3-dicyclopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)calbamoyl)-1- (difluoromethyl)-1H-pymzole-3- sulfonimidamide
437





572


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1-(Difluoromethyl)-N′-((3-ethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)calbamoyl)-4- fluoro-1H-pyrazole-3-sulfonimidamide
471









Example 573



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(R)-1-(fluoromethyl)-N′—(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide (Scheme X)



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Step 1: Tert-butyl((R)-(1-(fluoromethyl)-1H-pyrazol-3-yl)(3-((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)ureido)(oxo-sulfaneylidene)carbamate

To a stirred solution of tert-butyl (S)-(amino(1-(fluoromethyl)-1H-pyrazol-3-yl)(oxo)-λ6-sulfaneylidene) carbamate (10 mg, 0.036 mmol) in THF (1.0 mL) in a 8-mL sealed tube was added K2CO3 (24.8 mg, 0.18 mmol) and 2,2,2-trichloroethyl (R)-(3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b, e]pyridin-8-yl)carbamate (13 mg, 0.036 mmol). The resulting solution was stirred for 2 h at 80° C. The reaction mixture was cooled to RT. The resulting solution was diluted with 20 mL of EtOAc. The solids were filtered out, the filtrate was concentrated under reduced pressure. This resulted in 11 mg (crude) of the title compound as a white solid. MS-ESI: 493 (M+1).


Step 2: (R)-1-(fluoromethyl)-N′-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl) carbamoyl)-1H-pyrazole-3-sulfonimidamide

To a stirred solution of tert-butyl ((R)-(1-(fluoromethyl)-1H-pyrazol-3-yl)(3-((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8-yl)ureido)(oxo)-λ6-sulfaneylidene)carbamate (10 mg) in DCM (10 mL) in a 20-mL sealed tube was added BF3.Et2O (47% wt., 0.050 mL, 0.40 mmol) dropwise at 0° C. The resulting solution was stirred for 90 min at RT. The resulting solution was quenched with 2.0 mL of MeOH. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC using the following conditions:)(Bridge Prep OBD C18 Column, 30*150 mm 5 um; mobile phase, water (10 mM NH4HCO3+0.1% NH3.H2O) and ACN (3% to 30% over 7 min); UV 254/220 nm; Rt: 6.13 min. This resulted in 0.80 mg (5.7% over 2 steps) of Example 573 as a white solid. MS-ESI: 393 (M+1).









TABLE 50







Examples in the following table were prepared using similar conditions as described in


Example 573 and Scheme X from appropriate starting materials. The structures of Examples 575


and 576 were assigned based their proton NMR in comparison with similar literature compounds


(Journal of Organic Chemistry. 2013, 78(11), 5349-5356).













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+













574


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Mixture of (R)-N′-((3,5-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)calbamoyl)-2- (2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide and (R)-N′-((3,6-dimethyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide
478








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575


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(R)-N′-((3,5-dimethyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide
478





576


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(R)-N′-((3,6-dimethyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2-hydroxypropan-2- yl)thiazole-5-sulfonimidamide
478









Example 577



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(R)—N′-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme XI)



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Step 1: Tert-butyl(S)—(N-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoyl)carbamate

To a stirred solution of tert-butyl (S)-(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene) carbamate (90 mg, 0.28 mmol) in THF (10 mL) in a 20-mL sealed tube was added K2CO3 (193 mg, 1.4 mmol) and 2,2,2-trichloroethyl (3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine -4-yl)carbamate (117 mg, 0.28 mmol) at RT. The resulting solution was stirred for 2 h at 80° C. The reaction mixture was cooled to RT. The resulting solution was diluted with 50 mL of EtOAc. The solids were filtered out. The filtrate was concentrated. This resulted in 100 mg (crude) of the title compound as a white solid. MS-ESI: 590 (M+1).


Step 2: (R)-N′-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

A solution of tert-butyl (S)—(N-((3-cyclopropyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidoyl)carbamate (100 mg, 0.17 mmol) in 4 M HC1/dioxane (4 mL) in a 50-mL round-bottom flask was stirred for 30 min at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions:)(Bridge Prep C18 OBD Column, 19×150 mm 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 7% B to 20% B over 10 min; UV 210/254 nm; Rt1: 11.03 min. This resulted in 30 mg (22% over 2 steps) of Example 577 as a white solid. MS-ESI: 490 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.09 (s, 1H), 7.92 (br s, 2H), 6.28 (s, 1H), 2.94-2.87 (m, 2H), 2.84-2.79 (m, 2H), 2.07-1.98 (m, 2H), 1.83-1.78 (m, 1H), 1.50 (s, 6H), 0.93-0.80 (m, 2H), 0.44-0.30 (m, 2H).









TABLE 51







Examples in the following table were prepared using similar conditions as described in


Example 577 and Scheme XI from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+













578


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(R)-N′-((3-cyclopropyl-2-(2,2,2- trifluoroethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-2- (2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide
504





579


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(R)-N′-((2-(1-fluorocyclopropyl)-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-2- (2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide
454









Example 580



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(6R)-N′-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide (Scheme XII)



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Step 1: Tert-butylmethyl((6R)-3-(N′-((5-methyl-6-(trifluoromethyl)-2,3-dihydro-1H-inden-4-yl) carbamoyl)sulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-6-yl)carbamate

To a stirred solution of tert-butyl ((6R)-3-(N′-(tert-butyldimethylsilyl)sulfamidimidoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazin-6-yl)(methyl)carbamate (100 mg, 0.22 mmol) in THF (5.0 mL) in a 50-mL round-bottom flask under nitrogen was added NaH (60% wt. dispersion in mineral oil, 18 mg, 0.44 mmol) at 0° C. in an ice/water bath, followed by 2,2,2-trichloroethyl(5-methyl-6-(trifluoromethyl)-2,3-dihydro -1H-inden-4-yl)carbamate (88 mg, 0.22 mmol) in portions at 0° C. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by adding 5.0 mL of water. The resulting solution was extracted with 3×30 mL of EtOAc, the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 100 mg (crude) of the title compound as a white solid. MS-ESI: 573 (M+1).


Step 2: (6R)—N′-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonimidamide

To a stirred solution of tert-butyl methyl((6R)-3-(N′-((5-methyl-6-(trifluoromethyl)-2,3-dihydro-1H-inden-4-yl)carbamoyl)sulfamidimidoyl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3 ]oxazin-6-yl)carbamate (80 mg, 0.14 mmol) in DCM (3 mL) in a 25-mL round-bottom flask was added BF3.Et2O (47% wt., 0.05 mL, 0.40 mmol) dropwise with stirring at 0° C. in an ice/water bath. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by adding 1.0 mL of water. The resulting solution was extracted with 3×10 mL of EtOAc and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; Mobile Phase A: water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 16% B to 31% B over 7 min; 210/254 nm; Rt1: 6.05 min. This resulted in 50 mg (48%, over two steps) of Example 580 as a white solid. MS-ESI: 474 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.21 (s, 1H), 7.55 (s, 1H), 7.33 (br s, 2H), 4.40-4.19 (m, 3H), 3.99-3.90 (m, 1H), 3.20-3.14 (m, 1H), 2.92 (t, J=7.6 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.34 (s, 3H), 2.23 (s, 3H), 2.13-1.99 (m, 2H).


Example 581



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(R)-N′-((3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme XIII)



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Step 1: Tert-butyl (R)-((3-(3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)ureido) (2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-sulfaneylidene)carbamate

To a stirred solution of tert-butyl (S)-(amino(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene) carbamate (71 mg, 0.22 mmol) in MeCN (10 mL) in a 25-mL round-bottom flask was added DBU (100 mg, 0.66 mmol) and 2,2,2-trichloroethyl (3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl) carbamate (80 mg, 0.22 mmol). The resulting solution was stirred for 6 h at 35° C. in an oil bath. The reaction was then quenched by the addition of 6.0 mL of water. The resulting solution was extracted with 5×20 mL of EtOAc and the organic layers were combined and concentrated. This resulted in 160 mg (crude) of the title compound as a brown solid. MS-ESI: 536 (M+1).


Step 2: (R)—N′-((3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide

To a stirred solution of tert-butyl (R)-((3-(3-cyclopropyl-2-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)ureido)(2-(2-hydroxypropan-2-yl)thiazol-5-yl)(oxo)-λ6-sulfaneylidene)carbamate (120 mg, 0.22 mmol) in dioxane (15 mL) was added conc. HCl (12 M, 0.10 mL, 1.2 mmol) dropwise at RT. The resulting solution was stirred for 2 h at RT. The pH value of the mixture was adjusted to 7 with Sat. NaHCO3 (aq.) then extracted with 5×20 mL of EtOAc and the organic layers were combined, dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions:)(Bridge Prep OBD C18 Column, 30*150 mm*5 um; mobile phase, water (10 mM NH4HCO3+0.1% NH3E2O) and ACN (5% Phase B to 28% over 7 min); UV 210/254 nm; Rt1: 6.05 min. This resulted in 45 mg (46% over two steps) of Example 581 as a white solid. MS-ESI: 436 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.07 (s, 1H), 7.86 (br s, 2H), 6.28 (s, 1H), 2.81-2.64 (m, 4H), 2.46 (s, 3H), 1.97-1.90 (m, 2H), 1.63-1.55 (m, 1H), 1.50 (s, 6H), 0.88-0.77 (m, 2H), 0.32-0.25 (m, 2H).


Example 582



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(R)-4-(1-hydroxyethyl)-N′-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiophene-2-sulfonimidamide (Scheme XIV)



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Step 1: (R)-4-(1-hydroxyethyl)-N′-(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl) carbamoyl)thiophene-2-sulfonimidamide

To a stirred solution of (R)-4-acetyl-N′—(((R)-3-methyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl) carbamoyl)thiophene-2-sulfonimidamide (200 mg, 0.48 mmol) in MeOH (20 mL) in a 50-mL round-bottom flask under nitrogen was added NaBH4 (54 mg, 1.43 mmol) in portions at 0° C. in an ice/water bath. The resulting solution was stirred overnight at RT. The reaction was then quenched by the addition of 10 mL of 1M HCl. The resulting solution was extracted with 2×50 mL of EtOAc and dried over anhydrous sodium sulfate and concentrated. The crude product was purified by Prep-HPLC using the following conditions:)(Bridge Prep C18 OBD Column, 19*150 mm 5 um; mobile phase, water (10 mM NH4HCO3+0.1% NH3E2O) and ACN (5% Phase B to 25% over 7 min); UV 210/254 nm, Rt: 6.63 min. This resulted in 160 mg (80%) of Example 582 as a white solid. MS-ESI: 421 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.71 (br s, 2H), 7.60 (s, 2H), 5.33 (d, J=4.8 Hz, 1H), 4.79-4.68 (m, 1H), 3.05-2.97 (m, 1H), 2.85-2.60 (m, 6H), 2.29-2.21 (m, 1H), 2.01-1.90 (m, 2H), 1.54-1.43 (m, 1H), 1.35 (d, J=6.4 Hz, 3H), 1.20 (d, J=7.2 Hz, 3H).









TABLE 52







Examples in the following table were prepared using similar conditions as described in


Example 582 and Scheme XIV from Example 666.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+













583


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(S)-4-(1-hydroxyethyl)-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiophene-2- sulfonimidamide
421









Example 584



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2-((S)-1,14-dihydroxy-3,6,9,12-tetraoxapentadecan-14-yl)-N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazole-5-sulfonimidamide (Scheme XV)



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Step 1: N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2-((S)-16- hydroxy-1-phenyl-2,5,8,11,14-pentaoxaheptadecan-16-yl)thiazole-5-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-2-((S)-16-hydroxy-1-phenyl-2, 5,8,11,14-pentaoxahepta-decan-16-yl)thiazole-5-sulfonimidamide (100 mg, 0.16 mmol) in THF (5.0 mL) in a 50-mL round-bottom flask under nitrogen was added 2,2,2-trichloroethyl (3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]-pyridin-8-yl)carbamate (60 mg, 0.16 mmol) and NaH (60% wt. dispersion in mineral oil, 13 mg, 0.32 mmol) at 0° C. in an ice/water bath. The resulting solution was stirred for 3 h at RT. The reaction was then quenched by the addition of 5.0 mL of water. The resulting solution was extracted with 3×30 mL of EtOAc and the combined organic layers were dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was eluted from silica gel with DCM/MeOH (10:1). This resulted in 100 mg (85%) of the title compound as a white solid. MS-ESI: 732 (M+1).


Step 2: 2-((S)-1,14-dihydroxy-3,6,9,12-tetraoxapentadecan-14-yl)-N-((3,3-dimethyl-1,2,3,5,6,7 -hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)thiazole-5-sulfonimidamide

To a stirred solution of N-((3,3-dimethyl-1,2,3,5,6,7-hexahydrodicyclopenta[b,e]pyridin-8-yl)carbamoyl)-2- ((S)-16-hydroxy-1-phenyl-2,5,8,11,14-pentaoxaheptadecan-16-yl)thiazole-5-sulfonimidamide (80 mg, 0.11 mmol) in DCM (15 mL) was added BCl3 in DCM (1 M, 0.46 mL, 0.46 mmol) dropwise at 0° C. in an ice/water bath under nitrogen. The resulting mixture was stirred for 5 h at 0° C. The reaction was quenched with water/ice (10 mL) at 0° C. The resulting mixture was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC using the following conditions: XSelect CSH Prep C18 OBD Column, 5 um, 19*150 mm; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 18% B to 28% B over 7 min; UV 210/254 nm; Rt1: 6.20 min. This resulted in 18.7 mg (27%) of Example 584 as a white solid. MS-ESI: 642 (M+1). 1H NMR (300 MHz, MeOH-d4) δ 8.19 (s, 1H), 3.90-3.48 (m, 18H), 3.01-2.91 (m, 2H), 2.89-2.72 (m, 4H), 2.20-2.01 (m, 2H), 2.01-1.80 (m, 2H), 1.57 (s, 3H), 1.28 (s, 6H).


Example 585



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5-(Hydroxymethyl)-1-isopropyl-N′-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide (Scheme XVI)



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Step 1: N-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-N′-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N′-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-1H-pyrazole-3-sulfonimidamide (300 mg, 0.67 mmol) in THF (5.0 mL) under nitrogen was added NaH (60% wt., dispersion in mineral oil, 80.4 mg, 2.01 mmol) in portions at 0° C. The reaction mixture was stirred for 20 min at 0° C. To the above mixture was added 2,2,2-trichloroethyl (3 -methyl-2-(trifluoromethyl) -6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (263 mg, 0.67 mmol) in THF (3.0 mL) dropwise at 0° C. The resulting mixture was stirred for 2 h at RT. The reaction was quenched with water/ice (10 mL) at 0° C. The resulting mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by Prep-TLC with PE/EtOAc (4:1). This resulted in 375 mg (81%) of the title compound as a yellow solid. MS-ESI: 689 (M+1).


Step 2: 5-(Hydroxymethyl)-1-isopropyl-N′-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-5-(((tert-butyldimethylsilyl)oxy)methyl)-1-isopropyl-N′-((3-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1H-pyrazole-3-sulfonimidamide (370 mg, 0.54 mmol) in THF (5.0 mL) was added triethylamine trihydrofluoride (0.33 mL, 2.03 mmol, 4.50 equiv.) in portions at RT. The reaction mixture was stirred for 2 h at RT. The reaction mixture was concentrated under vacuum. The residue was purified by Prep-HPLC using the following conditions)(Bridge Prep OBD C18 Column, 30×150 mm, 5 um; Mobile Phase A: water (10 mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 35% B over 7 min; UV 254/210 nm; Rti: 6.22 min. This resulted in 100 mg (40%) of Example 585 as a white solid. MS-ESI: 461 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 7.41 (br s, 2H), 6.55 (s, 1H), 5.46 (t, J=5.4 Hz, 1H), 4.75-4.61 (m, 1H), 4.55 (d, J=5.6 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.80 (t, J=7.2 Hz, 2H), 2.21 (s, 3H), 2.08-1.94 (m, 2H), 1.39 (t, J=6.6 Hz, 6H).









TABLE 53







Examples in the following table were prepared using similar conditions as described in


Example 544 and Scheme VIII from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+













586


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-4-(hydroxymethyl)-2- (1,2,3-trihydroxypropan-2-yl)thiazole-5- sulfonimidamide
512





587


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4-(Hydroxymethyl)-N′-((2-methyl-3- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)calbamoyl)-2- (1,2,3-trihydroxypropan-2-yl)thiazole-5- sulfonimidamide
526





588


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1-Ethyl-5-(hydroxymethyl)-N′-((3-methyl- 2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)calbamoyl)-1H- pyrazole-3-sulfonimidamide






589


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1-Ethyl-5-(hydroxymethyl)-N′-((1′,5′,6′,7′- tetrahydro-2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
431





590


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1-Ethyl-5-(hydroxymethyl)-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
419





591


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1-ethyl-5-(hydroxymethyl)- 1H-pyrazole-3-sulfonimidamide
433
















TABLE 54







Examples in the following table were prepared using similar conditions as described in


Example 250 and Scheme III from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+













592


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-4- ((dimethylamino)methyl)-2-(2- hydroxypropan-2-yl)thiazole-5- sulfonimidamide
507
















TABLE 55







Examples in the following table were prepared using similar conditions as described in


Example 49 and Scheme 3 from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+













593


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2-(2-Hydroxypropan-2-yl)-N′-((3-oxo- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiazole-5- sulfonimidamide
436
















TABLE 56







Examples in the following table were prepared using similar conditions as described in


Example 236 and Scheme II from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+













594


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N′-((3-ethyl-2-(2,2,2-trifluoroethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-3-fluoro-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
509





595


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5-(Hydroxymethyl)-1-isopropyl-N′- ((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
445





596


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5-(Hydroxymethyl)-1-isopropyl-N-(((R)- 3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
433





597


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1-Ethyl-4-fluoro-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)calbamoyl)-1H- pyrazole-3-sulfonimidamide
435





598


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2-(1,2-Dihydroxypropan-2-yl)-N′-((3,3- dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-4-(hydroxymethyl)thiazole- 5-sulfonimidamide
496





599


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2-((S)-1,2-dihydroxypropan-2-yl)-N′- ((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-4-(hydroxymethyl)thiazole- 5-sulfonimidamide
496





600


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2-((R)-1,2-dihydroxypropan-2-yl)-N′- ((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-4-(hydroxymethyl)thiazole- 5-sulfonimidamide
496





601


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(6R)-6-hydroxy-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-6,7- dihydro-5H-pyrazolo[5,1-b][1,3]oxazine- 3-sulfonimidamide
461





602


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1-Ethyl-4-fuoro-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
407





603


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(6R)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-6-hydroxy-6,7-dihydro-5H- pyrazolo[5,1-b][1,3]oxazine-3- sulfonimidamide
447





604


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2-(1,3-Dihydroxy-2-methylpropan-2-yl)- N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiazole-5-sulfonimidamide
480





605


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-2-(1-hydroxy-2- methylpropan-2-yl)thiazole-5- sulfonimidamide
464





606


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2-(1,2-Dihydroxypropan-2-yl)-N′-((3- methyl-2-(1-methylcyclopropyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiazole-5-sulfonimidamide
466





607


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5-((R)-1,2-dihydroxypropan-2-yl)-3- fluoro-N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2-sulfonimidamide
481





608


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5-((S)-1,2-dihydroxypropan-2-yl)-3- fluoro-N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
481
















TABLE 57







Examples in the following table were prepared using similar conditions as described in


Example 252 and Scheme V from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+





609


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N′-((3-cyclopropyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide
489





610


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N′-((3-((3-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-3-fluoro-5-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
507





611


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N′-((2-(1-fluorocyclopropyl)-3-methyl- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-4-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide
453





612


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3-Fluoro-N′-((2-(1-fluorocyclopropyl)-3- methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-5- (2-hydroxypropan-2-yl)thiophene-2- sulfonimidamide
471





613


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Ethyl 4-(3-(((tert- butyldimethylsilyl)amino)(2-(2- hydroxypropan-2-yl)thiazol-5-yl)(oxo)-l6- sulfaneylidene)ureido)-3-methyl-6,7- dihydro-5H-cyclopenta[b]pyridine-2- carboxylate
582





614


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N′-((2-(difluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-2- (2-hydroxypropan-2-yl)thiazole-5- sulfonimidamide
432





615


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N′-((3-cyclopropyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1-(difluoromethyl)-4- fluoro-1H-pyrazole-3-sulfonimidamide
483





616


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1-Ethyl-4-fluoro-N′-(((S)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
407





617


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1-(Difluoromethyl)-4-fluoro-N′-((3- methyl-2-(2,2,2-trifluoroethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
471





618


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N′-((2,3-dicyclopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1- ethyl-4-fluoro-1H-pyrazole-3- sulfonimidamide
433





619


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1-Ethyl-4-fluoro-N′-((3-methyl-2-(2,2,2- trifluoroethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
449





620


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1-(Difluoromethyl)-4-fluoro-N′-((2- methyl-3-phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
465





621


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1-(Difluoromethyl)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-4-fluoro-1H-pyrazole-3- sulfonimidamide
443
















TABLE 58







Examples in the following table were prepared using similar conditions as described in


Example 9 and Scheme 2 from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+





622


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1-(2-Hydroxyethyl)-N′-((1′,5′,6′,7′- tetrahydro-2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
417





623


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4-((S)-1,2-dihydroxypropan-2-yl)-N′- ((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiophene-2- sulfonimidamide
465





624


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4-((R)-1,2-dihydroxypropan-2-yl)-N′- ((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiophene-2- sulfonimidamide
465





625


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5-((R)-1-(2-(benzyloxy)ethoxy)-2- hydroxypropan-2-yl)-N′-((1,1-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiophene-2- sulfonimidamide
599





626


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1-(2-hydroxyethyl)-5- (hydroxymethyl)-1H-pyrazole-3- sulfonimidamide
449





627


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4-Acetyl-N′-(((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiophene-2- sulfonimidamide
419





628


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1-Ethyl-4-fluoro-N′-((1′,5′,6′,7′- tetrahydro-2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
419





629


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2-Ethyl-N′-(((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiazole-5- sulfonimidamide
406





630


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-6-(2-hydroxypropan-2- yl)pyridine-2-sulfonimidamide
444





631


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3-Ethyl-N′-(((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiophene-2- sulfonimidamide
404





632


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N′-((2,3-dicyclopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1- ethyl-1H-pyrazole-3-sulfonimidamide
415





633


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1-Methyl-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)- 1H-pyrazole-3-sulfonimidamide
403





634


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1-Ethyl-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)- 1H-pyrazole-3-sulfonimidamide
417





635


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N′-((3-hydroxy-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-5-(2-hydroxypropan-2- yl)thiazole-2-sulfonimidamide
438





636


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4-(3-(Amino(2-(2-hydroxypropan-2- yl)thiazol-5-yl)(oxo)-l6- sulfaneylidene)ureido)-3-methyl-6,7- dihydro-5H-cyclopenta[b]pyridine-2- carboxylic acid
440





637


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N′-((2-cyclopropyl-3-methyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1-ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
407





638


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N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1-ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
421





854


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1-Cyclopropyl-4-fluoro-N′-((3- methyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
447





855


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1-Cyclopropyl-4-fluoro-N′-(((R)- 3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
419





856


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N′-((2,3-bis(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
489





857


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1-Cyclopropyl-4-fluoro-N′- ((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
431





858


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1-Cyclopropyl-4-fluoro-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
405





859


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1-cyclopropyl-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
429





860


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1-Cyclopropyl-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
401





861


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1-Cyclopropyl-N′-((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
413





862


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1-Cyclopropyl-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
387
















TABLE 59







Examples in the following table were obtained from chiral HPLC resolutions of racemic


and diastereomeric mixture examples described above. The chiral column and eluents are listed in


the table. As a convention, the faster-eluting enantiomer is always listed first in the table followed


by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral


center has been resolved and the absolute stereochemistry at that center has not been determined.


Assigned stereochemistry in compound names are tentative. Some carbon stereocenters were


assigned arbitrarily for registration purpose, such as the alcohol centers for Examples 661-664.












Ex.




LC-MS


#
Structure
IUPAC Name
Column
Eluents
[M + H]+





639


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(R) or (S)-N′-((3-ethyl-2-(2,2,2- trifluoroethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-3-fluoro- 5-(2-hydroxypropan-2-yl) thiophene-2-sulfonimidamide
CHIRALPAK IA, 4.6 * 50 mm; 3 um
20% EtOH in Hex (0.1% FA)
509





640


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(S) or (R)-N′-((3-ethyl-2-(2,2,2- trifluoroethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-3-fluoro- 5-(2-hydroxypropan-2-yl) thiophene-2-sulfonimidamide
CHIRALPAK IA, 4.6 * 50 mm; 3 um
20% EtOH in Hex (0.1% FA)
509





641


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(R) or (S)-5-(hydroxymethyl)- 1-isopropyl- N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′-yl) carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
445





642


embedded image


(S) or (R)-5-(hydroxymethyl)- 1-isopropyl- N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′-yl) carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
445





643


embedded image


(R) or (S)-5-(hydroxymethyl)- 1-isopropyl- N′-(((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
433





644


embedded image


(S) or (R)-5-(hydroxymethyl)- 1-isopropyl- N′-(((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
433





645


embedded image


(S) or (R)-N′-((3- cyclopropyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-4-(2- hydroxypropan-2-yl) thiophene-2- sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
30% EtOH in Hex (0.2% DEA)
489





646


embedded image


(R) or (S)-N′-((3-((3-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-4-(2- hydroxypropan-2-yl) thiophene- 2-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
30% EtOH in Hex (0.2% DEA)
489





647


embedded image


(R) or (S)-1-(2-hydroxyethyl)- N′-((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane- 1,3′-dicyclopenta[b,e]pyridin]- 8′-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
417





648


embedded image


(S) or (R)-1-(2-hydroxyethyl)- N′-((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane- 1,3′-dicyclopenta[b,e]pyridin]- 8′-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
417





649


embedded image


(R) or (S)-1-ethyl-4-fluoro-N′- ((3-methyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um;
30% EtOH in Hex (0.1% FA)
435





650


embedded image


(S) or (R)-1-ethyl-4-fluoro-N′- ((3-methyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um;
30% EtOH in Hex (0.1% FA)
435





651


embedded image


(R)-4-((S)-1,2- dihydroxypropan- 2-yl)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiophene-2-sulfonimidamide
CHIRALPAK IG, 2 * 25 cm, 5 um
30% EtOH in Hex (8 mM NH3 • MeOH)
465





652


embedded image


(S)-4-((S)-1,2- dihydroxypropan- 2-yl)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiophene-2-sulfonimidamide
CHIRALPAK IG, 2 * 25 cm, 5 um
30% EtOH in Hex (8 mM NH3 • MeOH)
465





653


embedded image


(R)-4-((R)-1,2- dihydroxypropan- 2-yl)-N′- ((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiophene-2-sulfonimidamide
CHIRALPAK IG, 4.6 * 50 mm, 3 um
30% EtOH in Hex (0.1% FA)
465





654


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(S)-4-((R)-1,2- dihydroxypropan- 2-yl)-N′- ((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiophene-2-sulfonimidamide
CHIRALPAK IG, 4.6 * 50 mm, 3 um
30% EtOH in Hex (0.1% FA)
465





655


embedded image


(S) or (R)-(6R)-6-methoxy-N′- ((3-methyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
475





656


embedded image


(R) or (S)-(6R)-6-methoxy-N′- ((3-methyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-6,7-dihydro- 5H-pyrazolo[5,1-b][1,3] oxazine-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
475





657


embedded image


(R) or (S)-N′-((3-((3-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3] oxazine-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
40% EtOH in Hex (0.1% FA)
445





658


embedded image


(S) or (R)-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-6,7-dihydro-5H- pyrazolo[5,1-b][1,3] oxazine-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
40% EtOH in Hex (0.1%
445





659


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(R) or (S)-N′-((3- cyclopropyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-3-fluoro- 5-(2-hydroxypropan-2-yl) thiophene-2-sulfonimidamide
CHIRALPAK IF, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
507





660


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(S) or (R)-N′-((3- cyclopropyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-3-fluoro- 5-(2-hydroxypropan-2-yl) thiophene-2-sulfonimidamide
CHIRALPAK IF, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
507





661


embedded image


(S)-4-((R) or (S)-1- hydroxyethyl)-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiophene-2-sulfonimidamide
CHIRAL ART Cellulose- SB, 2 * 25 cm, 5 um
35% MeOH (8 mM NH3 • MeOH) in CO2
421





662


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(S)-4-((S) or (R)-1- hydroxyethyl)-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl) carbamoyl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2 * 25 cm, 5 um
35% MeOH (8 mM NH3 • MeOH) in CO2
421





663


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(R)-4-((R) or (S)-1- hydroxyethyl)-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiophene-2-sulfonimidamide
Reg-AD, 3 * 25 cm, 5 um
45% MeOH (8 mM NH3 • MeOH) in CO2
421





664


embedded image


(R)-4-((S) or (R)-1- hydroxyethyl)-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiophene-2-sulfonimidamide
Reg-AD, 3 * 25 cm, 5 um
45% MeOH (8 mM NH3 • MeOH) in CO2
421





665


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(R) or (S)-4-acetyl-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
40% MeOH (8 mM NH3 • MeOH) in CO2
419





666


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(S) or (R)-4-acetyl-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin- 8-yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
40% MeOH (8 mM NH3 • MeOH) in CO2
419





667


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(R) or (S)-4-(2-hydroxypropan- 2-yl)-N′-((2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)thiophene-2- sulfonimidamide
Chiralpak IC, 2 * 25 cm, 5 um
15% EtOH in Hex (0.1% FA)
449





668


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(S) or (R)-4-(2-hydroxypropan- 2-yl)-N′-((2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)thiophene-2- sulfonimidamide
Chiralpak IC, 2 * 25 cm, 5 um
15% EtOH in Hex (0.1% FA)
449





669


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(R) or (S)-1-ethyl-4-fluoro-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 2 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
407





670


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(S) or (R)-1-ethyl-4-fluoro-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IG, 2 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
407





671


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(R) or (S)-1-ethyl-4-fluoro- N′-((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
419





672


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(S) or (R)-1-ethyl-4-fluoro- N′-((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane-1,3'- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
419





673


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(S) or (R)-2-ethyl-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiazole-5-sulfonimidamide
CHIRALPAK IE, 3 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
406





674


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(R) or (S)-2-ethyl-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiazole-5-sulfonimidamide
CHIRALPAK IE, 3 * 25 cm, 5 um
50% EtOH in Hex (0.1% FA)
406





675


embedded image


(S)-5-((R)-1,2- dihydroxypropan- 2-yl)-3-fluoro- N′-((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2 * 25 cm, 5 um
30% EtOH in Hex (8 mM NH3 • MeOH)
481





676


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(R)-5-((R)-1,2- dihydroxypropan- 2-yl)-3-fluoro-N′- ((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2 * 25 cm, 5 um
30% EtOH in Hex (8 mM NH3 • MeOH)
481





677


embedded image


(S)-5-((S)-1,2- dihydroxypropan- 2-yl)-3-fluoro-N′- ((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2 * 25 cm, 5 um
30% EtOH in Hex (8 mM NH3 • MeOH)
481





678


embedded image


(R)-5-((S)-1,2- dihydroxypropan- 2-yl)-3-fluoro-N′- ((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2 * 25 cm, 5 um
30% EtOH in Hex (8 mM NH3 • MeOH)
481





679


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(R) or (S)-1-(difluoromethyl)- 4-fluoro-N′-(((R)- 3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IG, 4.6 * 50 mm, 3 um
70% EtOH in Hex (0.1% FA)
429





680


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(S) or (R)-1-(difluoromethyl)- 4-fluoro-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 4.6 * 50 mm, 3 um
70% EtOH in Hex (0.1% FA)
429





681


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(R) or (S)-1-(difluoromethyl)- 4-fluoro- N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
441





682


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(S) or (R)-1-(difluoromethyl)- 4-fluoro- N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
441





683


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(R) or (S)-N′-((2-(1- fluorocyclopropyl)- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-4-(2- hydroxypropan-2-yl)thiophene- 2-sulfonimidamide
CHIRALPAK IG, 4.6 * 50 mm, 3 um
30% EtOH in Hex (0.1% FA)
453





684


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(S) or (R)-N′-((2-(1- fluorocyclopropyl)- 3-methyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-4-(2- hydroxypropan-2-yl)thiophene- 2-sulfonimidamide
CHIRALPAK IG, 4.6 * 50 mm, 3 um
30% EtOH in Hex (0.1% FA)
453





685


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(R) or (S)-3-fluoro-N′-((2-(1- fluorocyclopropyl)-3-methyl- 6,7-dihydro-5H-cyclopenta [b]pyridin-4-yl)carbamoyl)- 5-(2-hydroxypropan-2-yl) thiophene-2-sulfonimidamide
CHIRALPAK IE, 4.6 * 50 mm, 3 um
30% EtOH in Hex (0.1% FA)
471





686


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(S) or (R)-3-fluoro-N′-((2-(1- fluorocyclopropyl)-3-methyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-5-(2- hydroxypropan-2-yl) thiophene-2-sulfonimidamide
CHIRALPAK IE, 4.6 * 50 mm, 3 um
30% EtOH in Hex (0.1% FA)
471





687


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(R) or (S)-1-Ethyl-N′- ((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
50% EtOH in Hex (8 mM NH3 • MeOH)
401





688


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(S) or (R)-1-Ethyl-N′- ((1′,5′,6′,7′-tetrahydro- 2′H-spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
50% EtOH in Hex (8 mM NH3 • MeOH)
401





689


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(R) or (S)-3-Fluoro-5-(2- hydroxypropan-2-yl)-N′- ((2-(2,2,2-trifluoroethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin- 4-yl)carbamoyl)thiophene- 2-sulfonimidamide
Column: CHIRALPAK IC, 2 * 25 cm, 5 um
20% EtOH in Hex (0.1% FA)
481





690


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(S) or (R)-3-Fluoro-5-(2- hydroxypropan-2-yl)-N′- ((2-(2,2,2-trifluoroethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin- 4-yl)carbamoyl)thiophene- 2-sulfonimidamide
CHIRALPAK IC, 2 * 25 cm, 5 um
20% EtOH in Hex (0.1% FA)
481





691


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(R) or (S)-1-Ethyl-N′-((3- methyl-2-(trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK ID, 2.0 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
417





692


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(S) or (R)-1-Ethyl-N′-((3- methyl-2-(trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK ID, 2.0 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
417





693


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(R) or (S)-1-Methyl-N′-((3- methyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
403





694


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(S) or (R)-1-Methyl-N′-((3- methyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
403





695


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(R) or (S)-N′-((2,3- dicyclopropyl-6,7- dihydro-5H-cyclopenta [b]pyridin-4-yl)carbamoyl)- 1-(difluoromethyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK ID, 2.0 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
437





696


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(S) or (R)-N′-((2,3- dicyclopropyl-6,7- dihydro-5H-cyclopenta [b]pyridin-4-yl)carbamoyl)- 1-(difluoromethyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK ID, 2.0 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
437





697


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(R) or (S)-N′-((2,3- dicyclopropyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-3-fluoro-5- (2-hydroxypropan-2-yl) thiophene-2-sulfonimidamide
CHIRALPAK ID, 2.0 * 25 cm, 5 um
50% IPA in Hex (0.1% FA)
479





698


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(S) or (R)-N′-((2,3- dicyclopropyl- 6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-3-fluoro-5-(2- hydroxypropan-2-yl) thiophene-2-sulfonimidamide
CHIRALPAK ID, 2.0 * 25 cm, 5 um
50% IPA in Hex (0.1% FA)
479





699


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(R) or (S)-N′-((2,3- dicyclopropyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1-ethyl-1H- pyrazole-3-sulfonimidamide
CHIRALPAK ID, 2 * 25 cm, 5 um
30% EtOH in Hex:DCM = 3:1 (10 mM NH3—MeOH)
415





700


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(S) or (R)-N′-((2,3- dicyclopropyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1-ethyl-1H- pyrazole-3-sulfonimidamide
CHIRALPAK ID, 2 * 25 cm, 5 um
30% EtOH in Hex:DCM = 3:1 (10 mM NH3—MeOH)
415





701


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(R) or (S)-2-(2- Hydroxypropan- 2-yl)-N′-((2- isopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-3-yl) carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
20% EtOH in Hex (0.1% FA)
424





702


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(S) or (R)-2-(2- Hydroxypropan- 2-yl)-N′-((2- isopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-3-yl) carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
20% EtOH in Hex (0.1% FA)
424





703


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(R/S, S) or (R/S, R)-N′-((3,7- dimethyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide (from Example 273)
Chiralpak IA, 2 * 25 cm, 5 um
10% EtOH in Hex (0.1% FA)
478





704


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(R/S, R) or (R/S, S)-N′-((3,7- dimethyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide (from Example 273)
Chiralpak IA, 2 * 25 cm, 5 um
10% EtOH in Hex (0.1% FA)
478





705


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(S, R) or (S, S)-N′-((3,7- dimethyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide (from Example 704)
CHIRAL ART Cellulose- SB, 2 * 25 cm, 5 um
20% EtOH in Hex (0.1% FA)
478





706


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(R, R) or (R, S)-N′-((3,7- dimethyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-2-(2- hydroxypropan-2-yl)thiazole- 5-sulfonimidamide (from Example 704)
CHIRAL ART Cellulose- SB, 2 * 25 cm, 5 um
20% EtOH in Hex (0.1% FA)
478





707


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(R) or (S)-N′-((2,3- dicyclopropyl-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)- 1-ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
Chiralpak ID, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
433





708


embedded image


(S) or (R)-N′-((2,3- dicyclopropyl-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)- 1-ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
Chiralpak ID, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
433





709


embedded image


(R) or (S)-1-(difluoromethyl)- N′-((3-ethyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-4-fluoro-1H- pyrazole-3-sulfonimidamide
Chiralpak ID, 2 * 25 cm, 5 um
10% EtOH in Hex (0.1% FA)
471





710


embedded image


(S) or (R)-1-(difluoromethyl)- N′-((3-ethyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-4-fluoro-1H- pyrazole-3-sulfonimidamide
Chiralpak ID, 2 * 25 cm, 5 um
10% EtOH in Hex (0.1% FA)
471





711


embedded image


(R) or (S)-1-ethyl-4-fluoro-N′- (((S)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK ID, 2 * 25 cm, 5 um
50% IPA in Hex (0.1% FA)
407





712


embedded image


(S) or (R)-1-ethyl-4-fluoro-N′- (((S)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK ID, 2 * 25 cm, 5 um
50% IPA in Hex (0.1% FA)
407





713


embedded image


(R) or (S)-N′-((2-cyclopropyl- 3-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
40% EtOH in Hex (0.1% FA)
407





714


embedded image


(S) or (R)-N′-((2-cyclopropyl- 3-methyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
40% EtOH in Hex (0.1% FA)
407





715


embedded image


(R) or (S)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
40% EtOH in Hex (0.1% FA)
421





716


embedded image


(S) or (R)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
40% EtOH in Hex (0.1% FA)
421





717


embedded image


(R) or (S)-1-ethyl-4-fluoro-N′- ((3-methyl-2-(2,2,2- trifluoroethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
50% IPA in Hex (0.1% FA)
449





718


embedded image


(S) or (R)-1-ethyl-4-fluoro-N′- ((3-methyl-2-(2,2,2- trifluoroethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IE 2 * 25 cm, 5 um
50% IPA in Hex (0.1% FA)
449





719


embedded image


(S) or (R)-5-(hydroxymethyl)- 1-isopropyl-N′-((3- methyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl) carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IC, 4.6 * 50 mm, 3 um
15% EtOH in Hex (0.1% FA)
461





720


embedded image


(R) or (S)-5-(hydroxymethyl)- 1-isopropyl-N′-((3- methyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 4.6 * 50 mm, 3 um
15% EtOH in Hex (0.1% FA)
461





721


embedded image


(R) or (S)-1-(difluoromethyl)- N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-4- fluoro-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 2 * 25 cm, 5 um
15% EtOH in Hex (0.1% FA)
443





722


embedded image


(S) or (R)-1-(difluoromethyl)- N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-4- fluoro-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 2 * 25 cm, 5 um
15% EtOH in Hex (0.1% FA)
443





723


embedded image


(R) or (S)-1-(difluoromethyl)- 4-fluoro-N′-((3-methyl-2- (2,2,2-trifluoroethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
20% EtOH in Hex (0.1% FA)
471





724


embedded image


(S) or (R)-1-(difluoromethyl)- 4-fluoro-N′-((3-methyl-2- (2,2,2-trifluoroethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
20% EtOH in Hex (0.1% FA)
471





725


embedded image


(S) or (R)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- ethyl-5-(hydroxymethyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK AS, 2 * 25 cm, 5 um
20% EtOH (8 mM NH3 • MeOH) in CO2
433





726


embedded image


(R) or (S)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- ethyl-5-(hydroxymethyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK AS, 2 * 25 cm, 5 um
20% EtOH (8 mM NH3 • MeOH) in CO2
433





727


embedded image


(R) or (S)-1-(difluoromethyl)- 4-fluoro-N′-((2-methyl- 3-phenyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
465





728


embedded image


(S) or (R)-1-(difluoromethyl)- 4-fluoro-N′-((2-methyl-3- phenyl-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2 * 25 cm, 5 um
30% EtOH in Hex (0.1% FA)
465









Compounds 908a, 952a, 983a through 984, and 986 through 1041a in Table 1E can be prepared using one or more methods used to synthesize Examples 1-728.









TABLE 64







Examples in the following table were prepared using similar conditions as described in


Example 585 and Scheme XVI from appropriate starting materials. The carbon stereocenters of


tertiary alcohol at thiazole for Examples 729-732 were assigned arbitrarily for compound


registration purpose.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+





729


embedded image


2-((S)-1,2-dihydroxypropan-2-yl)-N′- (((S)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoylithiazole-5-sulfonimidamide (from chiral Intermediate 117A and Intermediate 262)
452





730


embedded image


2-((S)-1,2-dihydroxypropan-2-yl)-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiazole-5-sulfonimidamide (from chiral Intermediate 117A and Intermediate 161)
452





731


embedded image


2-((R)-1,2-dihydroxypropan-2-yl)-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiazole-5-sulfonimidamide (from chiral Intermediate 117B and Intermediate 161)
452





732


embedded image


2-((R)-1,2-dihydroxypropan-2-yl)-N′- (((S)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)thiazole-5-sulfonimidamide (from chiral Intermediate 117B and Intermediate 262)
452
















TABLE 65







Examples in the following table were prepared using similar conditions as described in


Example 252 and Scheme V from appropriate starting materials.













Exact Mass


Example #
Structure
IUPAC Name
[M + H]+





733


embedded image


1-Ethyl-4-fluoro-N′-((3-(4-fluorophenyl)- 2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
515





734


embedded image


4-Fluoro-1-isopropyl-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
449





735


embedded image


1-(Difluoromethyl)-4-fluoro-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
415





736


embedded image


1-Ethyl-4-fluoro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
393





737


embedded image


N′-((2,3-dicyclopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1- (difluoromethyl)-4-fluoro-1H-pyrazole-3- sulfonimidamide
455





738


embedded image


N′-((3,5-dimethyl-2,6- bis(trifluoromethyl)pyridin-4- yl)carbamoyl)-4-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide
505





739


embedded image


4-Fluoro-1-isopropyl-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide (from chiral Intermediate 161)
421





740


embedded image


1-(Difluoromethyl)-4-fluoro-N′-((3- phenyl-2-(trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl)carbamoyl)- 1H-pyrazole-3-sulfonimidamide
519





741


embedded image


1-Ethyl-4-fluoro-N′-((2-methyl-3-phenyl- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
443





742


embedded image


1-Ethyl-4-fluoro-N′-((3-phenyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
497





743


embedded image


1-Ethyl-N′-((3-ethyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-4-fluoro-1H-pyrazole-3- sulfonimidamide
449





744


embedded image


N′-((3-cyclopropyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1-ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
461





745


embedded image


1-Ethyl-4-fluoro-N′-((3-phenyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
429





746


embedded image


1-Ethyl-4-fluoro-N′-((3-(2-fluorophenyl)- 2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
515





747


embedded image


1-Ethyl-4-fluoro-N′-((3-(3-fluorophenyl)- 2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)cathamoyl)-1H- pyrazole-3-sulfonimidamide
515





748


embedded image


4-Fluoro-N′-(((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b, e]pyridin-8- yl)carbamoyl)-1-phenyl-1H-pyrazole-3- sulfonimidamide
455





749


embedded image


4-Fluoro-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1- phenyl-1H-pyrazole-3-sulfonimidamide
483





750


embedded image


4-Fluoro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1-isopropyl-1H-pyrazole-3- sulfomidamide
407
















TABLE 66







Examples in the following table were prepared using similar conditions as described in Example 9 and Scheme 2


from appropriate starting materials.










Example


Exact Mass


#
Structure
IUPAC Name
[M + H]+





751


embedded image


5-(N′-((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) sulfamidimidoyl)-N,N-dimethyl- thiazole-2-carboxamide
463
















TABLE 67







Examples in the following table were prepared using similar conditions as described in Example


28 and Scheme 2A from appropriate starting materials.










Example


Exact Mass


#
Structure
IUPAC Name
[M + H]+





752


embedded image


2-(1,2-Dihydroxyethyl)-N′- ((3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiazole-5-sulfonimidamide
438





753


embedded image


2-(1,2-Dihydroxyethyl)-N′- ((3,3-dimethyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl) thiazole-5-sulfonimidamide
452
















TABLE 68







Examples in the following table were prepared using similar conditions as described in Example 251 and


Scheme IV from appropriate starting materials.










Example


Exact Mass


#
Structure
IUPAC Name
[M + H]+





754


embedded image


1-Ethyl-4-fluoro-N′-((3-methyl- 2-(trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-1H-pyrazole-5- sulfonimidamide
435
















TABLE 69







Examples in the following table were obtained from chiral HPLC resolutions of racemic and diastereomeric mixture examples described


above. The chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the table


followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that this chiral center has been resolved


and the absolute stereochemistry at that center has not been determined. Assigned stereochemistry in compound names are tentative.

















LC-MS


Ex. #
Structure
IUPAC Name
Column
Eluents
[M + H]+





755


embedded image


(R) or (S)-N′-((3,5-dimethyl- 2,6-bis(trifluoromethyl) pyridin-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiophene- 2- sulfonimidamide
CHIRALPAK IF, 2*25 cm, 5 um
10% EtOH in Hex (0.1% FA)
505





756


embedded image


(S) or (R)-N′-((3,5-dimethyl- 2,6-bis(trifluoromethyl) pyridin-4-yl)carbamoyl)-4-(2- hydroxypropan-2-yl)thiophene- 2- sulfonimidamide
CHIRALPAK IF, 2*25 cm, 5 um
10% EtOH in Hex (0.1% FA)
505





757


embedded image


(R) or (S)-4-fluoro-1-isopropyl- N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
421





758


embedded image


(S) or (R)-4-fluoro-1-isopropyl- N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
421





759


embedded image


(R) or (S)-1-(difluoromethyl)- 4-fluoro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
40% EtOH in Hex (0.1% FA)
415





760


embedded image


(S) or (R)-1-(difluoromethyl)- 4-fluoro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
40% EtOH in Hex (0.1% FA)
415





761


embedded image


(R) or (S)-1-ethyl-4-fluoro-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl) carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 3*25 cm, 5 um
50% EtOH in Hex (8 mM NH3•MeOH)
393





762


embedded image


(S) or (R)-1-ethyl-4-fluoro-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IG, 3*25 cm, 5 um
CHIRALPAK IG, 3*25 cm, 5 um
393





763


embedded image


(R) or (S)-N′-((2,3- dicyclopropyl-6,7- dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1-(difluoromethyl)- 4-fluoro-1H-pyrazole- 3-sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
15% EtOH in Hex (0.1% FA)
455





764


embedded image


(S) or (R)-N′-((2,3- dicyclopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1- (difluoromethyl)-4- fluoro-1H-pyrazole- 3-sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
15% EtOH in Hex (0.1% FA)
455





765


embedded image


(R) or (S)-1-(difluoromethyl)- 4-fluoro-N′-((3-phenyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta [b]pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
10% EtOH in Hex (0.1% FA)
519





766


embedded image


(S) or (R)-1-(difluoromethyl)- 4-fluoro-N′-((3-phenyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
10% EtOH in Hex (0.1% FA)
519





767


embedded image


(R) or (S)-1-ethyl-4-fluoro- N′-((3-phenyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
497





768


embedded image


(S) or (R)-1-ethyl-4-fluoro- N′-((3-phenyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
497





769


embedded image


(R) or (S)-1-ethyl-4-fluoro- N′-((2-methyl-3-phenyl- 6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
443





770


embedded image


(S) or (R)-1-ethyl-4-fluoro- N′-((2-methyl-3-phenyl- 6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
443





771


embedded image


(R) or (S)-1-ethyl-N′-((3- ethyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)- 4-fluoro-1H-pyrazole-3- sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
449





772


embedded image


(S) or (R)-1-ethyl-N′-((3- ethyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)- 4-fluoro-1H-pyrazole-3- sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
449





773


embedded image


(R) or (S)-N′-((3-cyclopropyl- 2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)- 1-ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
461





774


embedded image


(S) or (R)-N′-((3- cyclopropyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1- ethyl-4-fluoro-1H-pyrazole- 3-sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
461





775


embedded image


(R) or (S)-N′-((3-cyclopropyl- 2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1- (difluoromethyl)-4-fluoro- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
10% EtOH in Hex (0.3% FA)
483





776


embedded image


(S) or (R)-N′-((3-cyclopropyl- 2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1- (difluoromethyl)-4-fluoro- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
10% EtOH in Hex (0.3% FA)
483





777


embedded image


(R) or (S)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-4- (hydroxymethyl)-2-(1,2,3- trihydroxypropan-2-yl)- thiazole-5-sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
512





778


embedded image


(S) or (R)-N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl)carbamoyl)- 4-(hydroxymethyl)-2- (1,2,3-trihydroxypropan-2-yl)- thiazole-5-sulfonimidamide
CHIRALPAK IG, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
512





779


embedded image


(R) or (S)-1-ethyl-4-fluoro- N′-((3-(2-fluorophenyl)-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
515





780


embedded image


(S) or (R)-1-ethyl-4-fluoro- N′-((3-(2-fluorophenyl)-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
515





781


embedded image


(R) or (S)-1-ethyl-4-fluoro- N′-((3-(3-fluorophenyl)-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 3*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
515





782


embedded image


(S) or (R)-1-ethyl-4-fluoro- N′-((3-(3-fluorophenyl)-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IC, 3*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
515





783


embedded image


(R) or (S)-4-fluoro-N′-((3- methyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta [b]pyridin-4-yl)carbamoyl)- 1-phenyl-1H-pyrazole- 3-sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
483





784


embedded image


(S) or (R)-4-fluoro-N′-((3- methyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta [b]pyridin-4-yl)carbamoyl)- 1-phenyl-1H-pyrazole-3- sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
483





785


embedded image


(R) or (S)-4-fluoro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl)carbamoyl)-1- isopropyl-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IG, 3*25 cm, 5 um
40% EtOH in Hex (8 mM NH3•MeOH)
407





786


embedded image


(S) or (R)-4-fluoro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl)carbamoyl)- 1-isopropyl-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IG, 3*25 cm, 5 um
40% EtOH in Hex (8 mM NH3•MeOH)
407





787


embedded image


(R) or (S)-1-ethyl-4-fluoro- N′-((3-(4-fluorophenyl)-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
15% EtOH in Hex (0.1% FA)
515





788


embedded image


(S) or (R)-1-ethyl-4-fluoro- N′-((3-(4-fluorophenyl)-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
15% EtOH in Hex (0.1% FA)
515





789


embedded image


(R) or (S)-4-fluoro-1- isopropyl-N′-((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





790


embedded image


(S) or (R)-4-fluoro-1- isopropyl-N′-((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclo-penta [b]pyridin-4-yl)carbamoyl)- 1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





791


embedded image


(R) or (S)-4-fluoro-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1- phenyl-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IE, 4.6*50 mm, 3 um
50% EtOH in Hex (0.1% FA)
455





792


embedded image


(S) or (R)-4-fluoro-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridm-8-yl)carbamoyl)-1- phenyl-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IE, 4.6*50 mm, 3 um
50% EtOH in Hex (0.1% FA)
455





793


embedded image


(R) or (S)-1-ethyl-4- fluoro-N′-((3-phenyl-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)- 1H-pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% EtOH in Hex (0.1% FA)
429





794


embedded image


(S) or (R)-1-ethyl-4-fluoro- N′-((3-phenyl-6,7-dihydro- 5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% EtOH in Hex (0.1% FA)
429









Example 795
Compound 1100



embedded image


N′-((3,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonimidamide (Scheme 2)
Example 796
Compound 1101



embedded image


N′-((3,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonimidamide (Scheme 2)



embedded image


Step 1: Mixture of N-(tert-butyldimethylsilyl)-N′-((3,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonimidamide and N-(tert-butyldimethylsilyl)-N′-((3,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonimidamide

To a stirred solution of N-(tert-butyldimethylsilyl)-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonimidamide (240 mg, 0.78 mmol) in THF (10 mL) under nitrogen was added NaH (60% wt, 62.8 mg, 1.57 mmol) in portions at 0° C., and then to the above solution was added 2,2,2-trichloroethyl (3,5-dimethyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate and 2,2,2-trichloroethyl (3,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (-1:1 mixture, 349 mg, 0.86 mmol) in portions at 0° C. The resulting solution was stirred for 1 h at RT. The reaction was then quenched with 10 mL of water and extracted with 3×10 mL of EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated under vacuum. This resulted in 600 mg (crude mixture) of the title compound as a yellow solid. MS-ESI: 563 (M+1).


Step 2: N′-((3,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonimidamide and N′-((3,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonimidamide

To a stirred solution of the mixture of N-(tert-butyldimethylsilyl)-N′-((3,5-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonimidamide and N-(tert-butyldimethylsilyl)-N-((3,6-dimethyl-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamoyl)-1-ethyl-4-fluoro-1H-pyrazole-3-sulfonimidamide (600 mg, crude from last step) in DCM (10 mL) was added HF-Pyridine (70% wt, 0.1 mL) dropwise at 0° C. The resulting solution was stirred for 10 min at RT. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC using the following conditions: Column: Xselect CSH OBD Column 30*150 mm 5 um; Mobile Phase A: water (10mM NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 25% B over 10 min; 254/210 nm; Rt1: 8.82 min (Example 795), Rt2: 9.26 min (Example 796). This resulted in 19.3 mg (5.5% over two steps) of Example 795 and 19.5 mg (5.5% over two steps) of Example 796 both as a white solid. MS-ESI: both 449 (M+1).


Example 795

(compound 1100): 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.03 (d, J=5.2 Hz, 1H), 7.61 (br s, 2H), 4.15-4.07 (m, 2H), 3.60-3.40 (m, 1H), 3.08-2.90 (m, 1H), 2.89-2.79 (m, 1H), 2.30-2.16 (m, 4H), 1.76-1.52 (m, 1H), 1.40-1.34 (m, 1.5H), 1.09 (d, J=6.9 Hz, 3H).


Example 796

(compound 1101): 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.04 (d, J=4.4 Hz, 1H), 7.53 (br s, 2H), 4.12 (q, J=7.2 Hz, 2H), 3.34-3.05 (m, 1H), 2.95-2.90 (m, 1H), 2.58-2.38 (m, 3H), 2.21 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 1.09 (d, J=6.4 Hz, 3H).









TABLE 70







Examples in the following table were prepared using similar conditions as described in Example 9 and Scheme 2


from appropriate starting materials.











Example
Compound


Exact Mass


#
#
Structure
IUPAC Name
[M + H]+





797
1102


embedded image


4-Fluoro-1-isopropyl- N′-((1′,5′,6′,7′-tetrahydro-2′H-spiro [cyclopropane-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
433





798
1103


embedded image


N′-((2,3-dicyclopropyl-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)-4- fluoro-1-isopropyl-1H- pyrazole-3-sulfonimidamide
447





799
1104


embedded image


N′-((3-cyclopropyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-4-fluoro- 1-isopropyl-1H- pyrazole-3-sulfonimidamide
475





800
1007


embedded image


2-(Difluoromethyl)-N′- ((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)thiazole- 5-sulfonimidamide
456
















TABLE 71







Examples in the following table were prepared using similar conditions as described in Example 252 and Scheme V


from appropriate starting materials.











Example
Compound


Exact Mass


#
#
Structure
IUPAC Name
[M + H]+





801
1006


embedded image


N′-((2,3-dicyclopropyl- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)- carbamoyl)-3-fluoro- 4-(2-hydroxypropan- 2-yl)thiophene-2- sulfonimidamide
479





802
1004


embedded image


1-(1,1-Difluoroethyl)- 4-fluoro-N′-((3-methyl- 2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta [b]pyridin-4-yl) carbamoyl)-1H-pyrazole-3- sulfonimidamide
471





803
1105


embedded image


N′-((3-cyclopropyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta [b]pyridin-4-yl) carbamoyl)-3-fluoro-4-(2- hydroxypropan-2-yl) thiophene-2- sulfonimidamide
507





804
1107


embedded image


3-Fluoro-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl)carbamoyl)- 4-(2-hydroxypropan-2- yl)thiophene-2- sulfonimidamide
439





805
1108


embedded image


3-Fluoro-4-(2-hydroxy- propan-2-yl)-N′-((3- methyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl) carbamoyl)thiophene-2- sulfonimidamide
481





806
1109


embedded image


3-Fluoro-4-(2-hydroxy- propan-2-yl)-N′-(((R)- 3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl)- carbamoyl)thiophene- 2-sulfonimidamide
453





807
1110


embedded image


3-Fluoro-4-(2-hydroxy- propan-2-yl)-N′-((2- methyl-3-phenyl-6,7- dihydro-5H-cyclopenta [b]pyridin-4-yl) carbamoyl)thiophene-2- sulfonimidamide
489





808
1111


embedded image


1-(1,1-Difluoroethyl)-4- fluoro-N′-(((R)-3- methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl) carbamoyl)-1H-pyrazole- 3-sulfonimidamide
443





809
1012


embedded image


1-Ethyl-4-fluoro-N′-((2- methyl-3-(trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin- 4-yl)carbamoyl)-1H- pyrazole-3- sulfonimidamide
435





810
1112


embedded image


1-(1,1-Difluoroethyl)-4- fluoro-N′-((l,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl) carbamoyl)-1H-pyrazole- 3-sulfonimidamide
429





811
1114


embedded image


1-Cyclopropyl-4-fluoro- N′-((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta [b]pyridin-4-yl) carbamoyl)-1H-pyrazole-3- sulfonimidamide
446
















TABLE 72







Examples in the following table were prepared using similar conditions as described in Example 68 and Scheme 6


from appropriate starting materials.











Example
Compound


Exact Mass


#
#
Structure
IUPAC Name
[M + H]+





812
1113


embedded image


N′-((3-(3,4- difluorophenyl)-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)- 1-ethyl-4-fluoro- 1H-pyrazole-3- sulfonimidamide
533
















TABLE 73







Examples in the following table were obtained from chiral HPLC resolutions of racemic and diastereomeric mixture examples


described above. The chiral column and eluents are listed in the table. As a convention, the faster-eluting enantiomer is always


listed first in the table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center denotes that


this chiral center has been resolved and the absolute stereochemistry at that center has not been determined. Assigned


stereochemistry in compound names are tentative.














Com-







Ex.
pound




LC-MS


#
#
Structure
IUPAC Name
Column
Eluents
[M + H]+





813
1102a


embedded image


(R) or (S)-4-Fluoro-1-isopropyl-N′- ((1′,5′,6′,7′-tetrahydro-2′H-spiro [cyclopropane-1,3′-dicyclopenta[b,e] pyridin]-8′-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
50% EtOH in Hex (0.1% FA)
433





814
1102b


embedded image


(S) or (R)-4-Fluoro-1-isopropyl-N′- ((1′,5′,6′,7′-tetrahydro-2′H-spiro [cyclopropane-1,3′-dicyclopenta[b,e] pyridin]-8′-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
50% EtOH in Hex (0.1% FA)
433





815
1103a


embedded image


(R) or (S)-N′-((2,3-dicyclopropyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-4-fluoro-1-isopropyl- 1H-pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
447





816
1103b


embedded image


(S) or (R)-N′-((2,3-dicyclopropyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-4-fluoro-1-isopropyl- 1H-pyrazole-3-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
447





817
1100a


embedded image


(R, R) or (R, S)-N′-((3,5-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





818
1100b


embedded image


(R, S) or (R, R)-N′-((3,5-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





819
1100c


embedded image


(S, R) or (S, S)-N′-((3,5-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





820
1100d


embedded image


(S, S) or (S, R)-N′-((3,5-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





821
1101a


embedded image


(R, R/S)-N′-((3,6-dimethyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-1-ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
1st peak and 2nd peak, Chiralpak ID, 2*25 cm, um
20% EtOH in Hex (0.1% FA)
449





822
1101b


embedded image


(S, R) or (S, S)-N′-((3,6-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
3rd peak, Chiralpak ID, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449





823
1101c


embedded image


(S, S) or (S, R)-N′-((3,6-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
4th peak, Chiralpak ID, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449















824
1101d


embedded image


(R, R) or (R, S)-N′-((3,6-dimethyl- 2-(trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide (Separated from Example 821)
CHIRAL ART Amylose-C NEO, 3*25 cm, 5 um 30% EtOH:Hex = 1:1 (2 mM NH3•MeOH) in CO2
449





825
1101e


embedded image


(R, S) or (R, R)-N′-((3,6-dimethyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide (Separated from Example 821)
CHIRAL ART Amylose-C NEO, 3*25 cm, 5 um 30% EtOH:Hex = 1:1 (2 mM NH3•MeOH) in CO2
449
















826
1104a


embedded image


(R) or (S)-N′-((3-cyclopropyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-4-fluoro-1- isopropyl-1H-pyrazole-3- sulfonimidamide
CHIRALPAK ID, 4.6*50 mm, 3 um
30% EtOH in Hex (0.1% FA)
475





827
1104b


embedded image


(S) or (R)-N′-((3-cyclopropyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-4-fluoro-1- isopropyl-1H-pyrazole-3- sulfonimidamide
CHIRALPAK ID, 4.6*50 mm, 3 um
30% EtOH in Hex (0.1% FA)
475





828
1007b


embedded image


(S) or (R)-2-(Difluoromethyl)- N′-((3-methyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IA, 3*25 cm, 5 um
15% EtOH in Hex (0.1% FA)
456





829
1007a


embedded image


(R) or (S)-2-(Difluoromethyl)- N′-((3-methyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b] pyridin-4-yl)carbamoyl)thiazole-5- sulfonimidamide
CHIRALPAK IA, 3*25 cm, 5 um
15% EtOH in Hex (0.1% FA)
456





830
1106a


embedded image


(R) or (S)-N′-((2,3-dicyclopropyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-3-fluoro-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
CHIRALPAK ID, 2.0*25 cm, 5 um
40% IPA in Hex (0.1% FA)
479





831
1106b


embedded image


(S) or (R)-N′-((2,3-dicyclopropyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-3-fluoro-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
CHIRALPAK ID, 2.0*25 cm, 5 um
40% IPA in Hex (0.1% FA)
479





832
1004a


embedded image


(R) or (S)-1-(1,1-Difluoroethyl)-4- fluoro-N′-((3-methyl-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
20% IPA in Hex (0.1% FA)
471





833
1004b


embedded image


(S) or (R)-1-(1,1-Difluoroethyl)-4- fluoro-N′-((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
20% IPA in Hex (0.1% FA)
471





834
1105a


embedded image


(R) or (S)-N′-((3-cyclopropyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-3-fluoro-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
CHIRALPAK ID 4.6*50 mm, 3 um
50% IPA in Hex (0.1% FA)
507





835
1105b


embedded image


(S) or (R)-N′-((3-cyclopropyl-2- (trifluoromethyl)-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)-3-fluoro-4-(2- hydroxypropan-2-yl)thiophene-2- sulfonimidamide
CHIRALPAK ID 4.6*50 mm, 3 um
50% IPA in Hex (0.1% FA)
507





836
1113a


embedded image


(S) or (R)-N′-((3-(3,4- difluorophenyl)-2- (trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1-ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IG 2*25 cm, 5 um
20% IPA in Hex (0.1% FA)
533





837
1113b


embedded image


(R) or (S)-N′-((3-(3,4- difluorophenyl)-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1-ethyl-4-fluoro-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IG 2*25 cm, 5 um
20% IPA in Hex (0.1% FA)
533





838
1107a


embedded image


(R) or (S)-3-fluoro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)thiophene-2-sulfonimidamide
CHIRALPAK IG 2*25 cm, 5 um
30% EtOH in Hex (0.3% FA)
439





839
1107b


embedded image


(S) or (R)-3-fluoro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-4-(2-hydroxypropan- 2-yl)thiophene-2-sulfonimidamide
CHIRALPAK IG 2*25 cm, 5 um
30% EtOH in Hex (0.3% FA)
439





840
1108a


embedded image


(R) or (S)-3-fluoro-4-(2- hydroxypropan-2-yl)-N′-((3- methyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRALPAK IG 2*25 cm, 5 um
15% EtOH in Hex (0.1% FA)
481





841
1108b


embedded image


(S) or (R)-3-fluoro-4-(2- hydroxypropan-2-yl)-N′-((3- methyl-2-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)thiophene-2- sulfonimidamide
CHIRALPAK IG 2*25 cm, 5 um
15% EtOH in Hex (0.1% FA)
481





842
1109a


embedded image


(R) or (S)-3-fluoro-4-(2- hydroxypropan-2-yl)-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl)carbamoyl) thiophene-2-sulfonimidamide
CHIRALPAK IG 2*25 cm, 5 um
30% EtOH in Hex (0.3% FA)
453





843
1109b


embedded image


(S) or (R)-3-fluoro-4-(2- hydroxypropan-2-yl)-N′- (((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8-yl)-carbamoyl) thiophene-2-sulfonimidamide
CHIRALPAK IG 2*25 cm, 5 um
30% EtOH in Hex (0.3% FA)
453





844
1110a


embedded image


(S) or (R)-3-fluoro-4-(2- hydroxypropan-2-yl)-N′-((2- methyl-3-phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
15% EtOH in Hex (0.3% FA)
489





845
1110b


embedded image


(R) or (S)-3-fluoro-4-(2- hydroxypropan-2-yl)-N′-((2- methyl-3-phenyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl) carbamoyl)thiophene-2- sulfonimidamide
CHIRAL ART Cellulose- SB, 2*25 cm, 5 um
15% EtOH in Hex (0.3% FA)
489





846
1115a


embedded image


(R) or (S)-1-(1,1-difluoroethyl)-4- fluoro-N′-((l,2,3,5,6,7-hexa- hydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IG 2*25 cm, 5 um
40% EtOH in Hex (0.1% FA)
429





847
1115b


embedded image


(S) or (R)-1-(1,1-difluoroethyl)-4- fluoro-N′-((1,2,3,5,6,7-hexa- hydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
CHIRALPAK IG 2*25 cm, 5 um
40% EtOH in Hex (0.1% FA)
429





848
1116a


embedded image


(R) or (S)-1-ethyl-4-fluoro-N′-((2- methyl-3-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IE 2*25 cm, 5 um
50% EtOH in Hex:DCM = 3:1 (10 mM NH3•MeOH)
435





849
1116b


embedded image


(S) or (R)-1-ethyl-4-fluoro-N′-((2- methyl-3-(trifluoromethyl)-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IE 2*25 cm, 5 um
50% EtOH in Hex:DCM = 3:1 (10 mM NH3•MeOH)
435





850
1117a


embedded image


(R) or (S)-1-(1,1-difluoroethyl)-4- fluoro-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% IPA in Hex (0.1% FA)
443





851
1117b


embedded image


(S) or (R)-1-(1,1-difluoroethyl)- 4-fluoro-N′-(((R)-3-methyl- 1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
50% IPA in Hex (0.1% FA)
443
















TABLE 73A







Examples in the following table were obtained from chiral HPLC resolutions of


racemic and diastereomeric mixture examples described above. The chiral column and eluents


are listed in the table. As a convention, the faster-eluting enantiomer is always listed first in the


table followed by the slower-eluting enantiomer of the pair. The symbol * at a chiral center


denotes that this chiral center has been resolved and the absolute stereochemistry at that center


has not been determined. Assigned stereochemistry in compound names are tentative.

















LC-MS


Ex. #
Structure
IUPAC Name
Column
Eluents
[M + H]+





863


embedded image


(R) or (S)-1-cyclopropyl-4-fluoro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
20% EtOH in Hex:DCM = 3:1 (10 mM NH3•MeOH)
405





864


embedded image


(S) or (R)-1-cyclopropyl-4-fluoro- N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
Chiralpak IC, 2*25 cm, 5 um
20% EtOH in Hex:DCM = 3:1 (10 mM NH3•MeOH)
405





865


embedded image


(R) or (S)-1-cyclopropyl-4-fluoro- N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropan-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
20% EtOH in Hex:DCM = 3:1 (10 mM NH3•MeOH)
431





866


embedded image


(S) or (R)-1-cyclopropyl-4-fluoro- N′-((1′,5′,6′,7′-tetrahydro-2′H- spiro[cyclopropan-1,3′- dicyclopenta[b,e]pyridin]-8′- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
Chiralpak ID, 2*25 cm, 5 um
20% EtOH in Hex:DCM = 3:1 (10 mM NH3•MeOH)
431





867


embedded image


(R) or (S)-1-cyclopropyl-4-fluoro- N′-(((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin- 8-yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK ID, 2*25 cm, 5 um
20% EtOH in Hex:DCM = 3:1 (10 mM NH3•MeOH)
419





868


embedded image


(S) or (R)-1-cyclopropyl-4-fluoro- N′-(((R)-3-methyl-1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-1H- pyrazole-3-sulfonimidamide
CHIRALPAK ID, 2*25 cm, 5 um
20% EtOH in Hex:DCM = 3:1 (10 mM NH3•MeOH)
419





869


embedded image


(R) or (S)-1-cyclopropyl-4-fluoro- N′-((3-methyl-2-(trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
447





870


embedded image


(S) or (R)-1-cyclopropyl-4-fluoro- N′-((3-methyl-2-(trifluoromethyl)- 6,7-dihydro-5H-cyclopenta[b]pyridin- 4-yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
447





871


embedded image


(R) or (S)-N′-((2,3- bis(trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
CHIRALPAK, IE, 2*25 cm, 5 um
30% EtOH in Hex (0.1% FA)
489





872


embedded image


(S) or (R)-N′-((2,3- bis(trifluoromethyl)-6,7-dihydro- 5H-cyclopenta[b]pyridin-4-yl) carbamoyl)-1-ethyl-4-fluoro- 1H-pyrazole-3-sulfonimidamide
CHIRALPAK IE, 2*25 cm, 5 um
30% EtOH in Hex (0.1%)
489
















TABLE 74







Examples in the following table were prepared using similar conditions as described in


Example 252 and Scheme V from appropriate starting materials.











Example
Compound


Exact Mass


#
#
Structure
IUPAC Name
[M + H]+





852
1118


embedded image


N′-((3-methyl-2- (trifluoromethyl)-6,7- dihydro-5H-cyclopenta [b]pyridin-4-yl) carbamoyl)-2- (trifluoromethyl) thiazole-5- sulfonimidamide
474





853
1119


embedded image


4-Fluoro-1-((R)-2- hydroxypropyl)-N′- ((1′,5′,6′,7′- tetrahydro-2′H- spiro[cyclopropane-1,3′- dicyclopenta[b,e]pyridin]- 8′-yl)carbamoyl)-1H- pyrazole-3- sulfonimidamide
449










The following protocol is suitable for testing the activity of the compounds disclosed herein.


Procedure 1: IL-1β Production in PMA-Differentiated THP-1 Cells Stimulated with Gramicidin.


THP-1 cells were purchased from the American Type Culture Collection and sub-cultured according to instructions from the supplier. Cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml)), and maintained in log phase prior to experimental setup. Prior to the experiment, compounds were dissolved in dimethyl sulfoxide (DMSO) to generate a 30 mM stock. The compound stock was first pre-diluted in DMSO to 3, 0.34, 0.042 and 0.0083 mM intermediate concentrations and subsequently spotted using Echo550 liquid handler into an empty 384-well assay plate to achieve desired final concentration (e.g. 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017 μM). DMSO was backfilled in the plate to achieve a final DMSO assay concentration of 0.37%. The plate was then sealed and stored at room temperature until required.


THP-1 cells were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16-18 hours. On the day of the experiment the media was removed and adherent cells were detached with trypsin for 5 minutes. Cells were then harvested, washed with complete RPMI 1640, spun down, and resuspended in RPMI 1640 (containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml). The cells were plated in the 384-well assay plate containing the spotted compounds at a density of 50,000 cells/well (final assay volume 50 μl). Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5 μM) (Enzo) for 2 hours. Plates were then centrifuged at 340 g for 5 min. Cell free supernatant (40 μL) was collected using a 96—CHannel PlateMaster (Gilson) and the production of IL-1β was evaluated by HTRF (cisbio). The plates were incubated for 18 h at 4° C. and read using the preset HTRF program (donor emission at 620 nm, acceptor emission at 668 nm) of the SpectraMax i3x spectrophotometer (Molecular Devices, software SoftMax 6). A vehicle only control and a dose titration of CRID3 (100-0.0017 μM) were run concurrently with each experiment. Data was normalized to vehicle-treated samples (equivalent to 0% inhibition) and CRID3 at 100 μM (equivalent to 100% inhibition). Compounds exhibited a concentration-dependent inhibition of IL-1β production in PMA-differentiated THP-1 cells.


Procedure 2: IL-1β Production in PMA-Differentiated THP-1 Cells Stimulated with Gramicidin.


THP-1 cells were purchased from the American Type Culture Collection and sub-cultured according to instructions from the supplier. Prior to experiments, cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml)), and maintained in log phase prior to experimental setup. Prior to the experiment THP-1 were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16-18 hours. Compounds were dissolved in dimethyl sulfoxide (DMSO) to generate a 30mM stock. On the day of the experiment the media was removed and adherent cells were detached with trypsin for 5 minutes. Cells were then harvested, washed with complete RPMI 1640, spun down, resuspended in RPMI 1640 (containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml). The cells were plated in a 384-well plate at a density of 50,000 cells/well (final assay volume 50 μM). Compounds were first dissolved in assay medium to obtain a 5× top concentration of 500 μM. 10 step dilutions (1:3) were then undertaken in assay medium containing 1.67% DMSO. 5× compound solutions were added to the culture medium to achieve desired final concentration (e.g. 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017 μM). Final DMSO concentration was at 0.37%. Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5 μM) (Enzo) for 2 hours. Plates were then centrifuged at 340 g for 5 min. Cell free supernatant (40 μL) was collected using a 96—CHannel PlateMaster (Gilson) and the production of IL-1β was evaluated by HTRF (cisbio). A vehicle only control and a dose titration of CRID3 (100-0.0017 μM) were run concurrently with each experiment. Data was normalized to vehicle-treated samples (equivalent to 0% inhibition) and CRID3 at 100 μM (equivalent to 100% inhibition). Compounds exhibited a concentration-dependent inhibition of IL-1β production in PMA-differentiated THP-1 cells.


Tables B1, B2, B3, and B4 show the biological activity of compounds in hTHP-1 assay containing 2% fetal bovine serum. Table B5 and B6 shows the biological activity of compounds in hTHP-1 assay containing 10% fetal bovine serum. Key: <0.008 μM=“++++++”; ≥0.008 and <0.04 μM=“+++++”; >0.04 and <0.2 μM=“++++”; ≥0.2 and <1 μM=“+++”; ≥1 and <5 μM=“++”; ≥5 and <30 μM=“+”. ND=not determined.









TABLE B1







Average IC50 of compounds in hTHP-1 assay









Example #
Compound Number
hTHP-1 IC50












1
165 
++


2
165a
+++


3
165b
+


4
163 
+++


5
128 
+++


6
110 
+


7
164 
++


8
167 
++


9
159 
++


10
135 
++


11
119 
++


12
122 
+++


13
125 
++


14
126 
++++


15
101 
++++


16
114 
++++


17
117 
+


18
116 
+


19
130 
+


20
170 
++


21
171 
++


22
172 
+++


23
173 
+++


24
174 
+++


25
175 
+++


26
176 
+


27
177 
+


28
118 
++


29
150 
++


30
121 
+++


31
178 
+


32
179 
++


33


34
107 
+++


35
155 
++++


36
166 
+


37
149 
+++


38
105 
++++


39
141 
++++


40
103 
++++


41
127 
++++


42
102 
++++


43
131 
+++


44
123 
++


45
180 
++


46
113 
>30


47
181 
+++


48
182 
>14


49
183 
+


50
154 
+++


51
120 
+++


52
162 
++++


53
104 
+++


54
168 
+++


55
158 
++


56
157 
+


57
156 
>30


58
160 
+


59
129 
+++


60
161 
++


61
153 
++++


62
152 
+++


63
151 
+++


64
147 
+


65
146 
+


66
133 
>14


67
112 
>30


68
115 
++


69
106 
++++


70
148 
++++


71
132 
>27


72
140 
++++


73
139 
+++


74
134 
++


75
145 
+


76
144 
>30


77
143 
>30


78
142 
>30


79
138 
+


80
137 
>30


81
136 
++++


82
124 
+++


83
128a
+++


84
128b
+


85
150a
+


86
150b
+++


87
163a
++++


88
163b
+


91
167a
+


92
167b
+++


93
164b
+


94
164a
++


95
161a
+


96
161b
++


97
159a
++


98
159b
+


99
158a
++


100
158b
>30


101
157a
>30


102
157b
+


103
160a
++


104
160b
+


105
 162ab
++


106
 162aa
+


107
 162bb
++++


108
 162ba
+++


109
156a
>30


110
156b
++


111
155a
++++


112
155b
++


113
149a
+++


114
149b
>30


115
106a
++++


116
106b
++


117
148a
+++


118
148b
++


119
147a
>30


120
147b
++


121
107a
+++


122
107b
+


123
145a
+++


124
145b
++


125
105a
++++


126
105b
++


127
153a
+


128
153b
++++


129
133a
>30


130
133b
>30


131
137a
>10


132
137b
>30


133
136a
++


134
136b
++++


135
140a
++++


136
140b
+


137
 140aa
++++


138
 140ab
++


139
 140ba
+


140
 140bb
>30


141
 129aa
++++


142
 129ab
>30


143
 129ba
++


144
 129bb
+


145
127a
++


146
127b
++++


147
130a
>30


148
130b
++


149
126a
++++


150
126b
+


151
168a
+


152
168b
+++


153
141b
++++


154
141a
++


155
 141aa
+++++


156
 141ab
+++


157
 141ba
++


158
 141bb
+


159
104a
+++


160
104b
+


161
 168aa
+


162
 168ab
>30


163
 168ba
+++


164
 168bb
++


165
122a
++++


166
122b
+


167
 103aa
++


168
 103ab
+


169
 103ba
+++++


170
 103bb
+++


171
102a
++


172
102b
+++++


173
101a
++


174
101b
+++++


175
125a
>30


176
125b
++


177
132a
+


178
132b
>30


179
131b
+


180
131a
+++


181
 131aab
+++


182
131c
+


183
131d
+


184
131e
+


185
131f
++


186
131g
+++


187
121a
++++


188
121b
+


189
169a
+


190
169b
++++


191
119a
++


192
119b
>30


193
118a
+++


194
118b
>24


195
 134aa
>30


196
 134ab
>30


197
 134ba
++


198
 134bb
+


199
117a
>30


200
117b
+


201
172a
+


202
172b
+++


203
173a
+++


204
173b
>20


205
183a
++


206
183b
>30


207
183c
+


208
183d
>30


209
116a
>30


210
116b
+


211
114a
++++


212
114b
++


213
124a
+


214
124b
+++


215
154a
++


216
154b
>28


217
120a
>30


218
120b
>30


219
142a
>30


220
142b
>30


221
143a
>30


222
143b
>30


223
184a
++++


224
184b
+


225
184c
+


226
184d
++


227
174a
+


228
174b
++++


229
175a
+


230
175b
+++


231
180a
+++


232
180b
>30


33
111 
>30



185b
>30



185a
+



185 
>30



201a
++++




















TABLE B2







Example #
Compound #
hTHP-1 IC50 (uM)









233
652
++



234
652b
>30



235
652a
+++



236
695
+



237
643
+



238
201
+++



239
640
+++



240
605
+++



241
605f
+++



242
605a
+++



243
691
++



244
688
++



245
676
++



246
669
+



247
612
++



248
627
+++



249
607
++



250
665
>30



251
693
++



252
645
++++



253
672
+



254
702
++



255
692
++



256
656
++



257
681
++++



258
668
+



259
658
+



260
667
+++



261
703
+



262
664
++



263
632
+++



264
624
++++



265
631
++++



266
630
+++



267
623
+++



268
621
++



269
629
++



270
610
+



271
611
+++



272
609
++



273
608
++



274
616
++++



275
604
+++



276
603
++++



277
304
++



278
306
+



279
677
++



280
661
++



281
647
++



282
619
+



283
618
++



284
626
++++



285
696
+



286
682
++



287
653
ND



288
641
+



289
694
++



290
687
+



291
660
+



292
140c
+++



293
635
+



294
689
++



295
642
++++



296
686
+++



297
680
++



298
674
++



299
684
+++



300
683
++



301
679
+



302
673
+



303
704
++



304
664
+



305
663
++



306
651
+



307
659
++



308
662
+



309
649
+



310
650
+++



311
648
++



312
615
++



313
620
+



314
185
>30



315
690
++



316
675
++



317
678
++



318
671
++



319
657
+



320
670
+++



321
655
+



322
654
+++



323
634
++++



324
639
++



325
646a
++



326
638
+



327
637
+



328
633
>30



329
625
+



330
622
+



331
628
+++



332
617
+



333
614
+++



334
613
+++



335
602
++



336
636c
+++



337
601
+



338
685
++



339
685b
++



340
685a
>30



341
694b
++



342
694a
>30



343
687b
+



344
687a
>30



345
689b
+



346
689a
>30



347
642b
++++



348
642a
+



349
686b
+



350
686a
+++



351
170b
+



352
170a
+++



353
680b
++



354
680a
+



355
682b
++



356
682a
>30



357
653b
>30



358
653a
+



359
674b
++



360
674a
>30



361
684b
+



362
684a
++++



363
683b
+



364
683a
+++



365
673b
>30



366
673a
++



367
705b
++



368
705a
+



369
664b
++



370
664a
>30



371
663b
++



372
663a
>30



373
651b
++



374
651a
+



375
659b
+++



376
659a
+



377
649b
>30



378
649a
+



379
650b
+



380
650a
++++



381
648b
>30



382
648a
+++



383
615b
++



384
615a
>30



385
620b
++



386
620a
>30



387
185a
+



388
185b
>30



389
115b
++



390
115a
+



391
701b
>30



392
701a
+



393
692b
++



394
692a
+



395
695b
+



396
695a
>30



397
691b
++



398
691a
+



399
688b
+



400
688a
+++



401
690b
++



402
690a
>30



403
661b
+



404
661a
+++



405
647b
>30



406
647a
++



407
676b
++



408
676a
>30



409
181b
++++



410
181a
++



411
675b
+



412
675a
++



413
681b
+++



414
681a
++



415
669b
+



416
669a
>30



417
176b
++



418
176a
>30



419
182b
+



420
182a
>30



421
678b
>30



422
678a
++



423
658b
++



424
658a
>30



425
667b
+++



426
667a
+



427
657b
+



428
657a
>30



429
670b
++++



430
670a
+



431
612b
++



432
612a
>30



433
626b
++++



434
626a
+



435
665b
++



436
665a
>30



437
654b
+++



438
654a
++



439
634b
++++



440
634a
+



441
639b
+++



442
639a
>30



443
700b
+++



444
700a
>30



445
638b
>30



446
638a
++



447
637b
>30



448
637b
++



449
645b
+



450
645a
++++



451
644b
++



452
644a
>30



453
633b
+



454
633a
>30



455
625b
++



456
625a
>30



457
632b
+



458
632a
++++



459
624b
++++



460
624a
++



461
631b
++++



462
631a
+



463
630b
+++



464
630a
+



465
623b
+



466
623a
++++



467
622b
+



468
622a
+



469
621b
++



470
621a
+



471
618b
+++



472
618a
>30



473
628b
+++



474
628a
>30



475
617b
>30



476
617a
+



477
610b
+



478
610a
++



479
611b
+++



480
611a
+



481
698b
+++



482
698a
++



483
616b
+



484
616a
++++



485
614b
++



486
614a
++++



487
613b
++



488
613a
++++



489
697b
++++



490
697a
+



491
607b
++



492
607a
>30



493
636b
++++



494
636a
+



495
304b
++



496
304a
>30



497
306b
+



498
306a
+



499
605e
+



500
605c
+++



501
605g
+



502
605h
+++



503
660d
+



504
660c
>30



505
660b
>30



506
660a
>30



507
201f
+



508
201e
++++



509
201d
+



510
201c
+



511
201a
+++++



512
201b
++++



513
662c
ND



514
662e
++



515
662d
+



516
662b
>30



517
662a
>30



518
699c
+



519
699b
+++++



520
699a
>30



521
640c
++



522
640b
++++



523
640a
+++++



524
656d
++



525
656b
+



526
656a
+++



527
656c
+



528
668c
+



529
668b
+



530
668a
>30



531
668d
>30



532
671d
+++



533
671c
++



534
671b
+



535
671a
>30



536
605d
>30



537
605b
+++



538
643a
+



539
643b
+



540
171c
++



541
171b
+



542
171a
>30



543
171d
>30



544
734
+++



545
736
++



546
735
++



547
721c
++++



548
720c
+++



549
723c
+++



550
729
+++



553
723b
++++



554
723a
+



555
721b
++++



556
721a
+



557
720b
+



558
720a
+++



559
729b
++++



560
729a
+




601a
+++




601b
+




602a
>30.0000




602b
++




604a
+




604b
+++




608a
+++




608b
+




608c
+++




608d
++




706
>30.0000




707
>30.0000




708
>30.0000




709
>30.0000




710
>30.0000




711
>30.0000




712
>30.0000




713
++




716a
++++




716b
+++




717
+++




718a
++++




719
+++




722
++




724
+++




725a
++




726
++




726a
>30.0000




726b
+++




727
+++




727a
++




727b
++++




728
++




728a
+




728b
+++




730
+




730a
+




730b
++




731
++




731a
+




731b
+++




733
++




737
+++




738
>30.0000




















TABLE B3







Example #
IC50 (μM)









561
+++



562
+++



563
+



564
++



565
+



566
+++



567
+



568
++++



569
+++



570
+++



571
++



572
++



573
++



574
++



575
++



576
+++



577
++



578
++



579
++



580
++



581
>30



582
++++



583
++



584
>30



585
++



586
+++



587
+



588
++



589
++



590
++



591
++



592
>30



593
>30



594
++



595
++



596
++



597
++++



598
+++



599
++



600
+++



601
+



602
+++++



603
++



604
++++



605
+++



606
>30



607
+++



608
++++



609
+++



610
+++



611
++



612
++



613
>30



614
>30



615
+++



616
+++



617
+



618
++++



619
++



620
+++



621
++++



622
++



623
+++



624
+++



625
++



626
+++



627
+++



628
++++



629
+++



630
+



631
++



632
++



633
+



634
++



635
>30



636
>30



637
+++



638
+++++



639
+++



640
+



641
++



642
>30



643
++



644
>30



645
+



646
++++



647
+++



648
+



649
++++



650
++



651
++++



652
+



653
++++



654
+



655
>30



656
++



657
++



658
>30



659
+++



660
+



661
++



662
+



663
++++



664
++++



665
+++



666
+



667
++



668
>30



669
+++++



670
++



671
+++++



672
++



673
+



674
+++



675
+



676
+++



677
+



678
+++++



679
++++



680
+



681
++++



682
++



683
++



684
>30



685
+++



686
>30



687
+++



688
+



689
++



690
>30



691
+++



692
+



693
++



694
>30



695
++



696
+



697
++++



698
++



699
+++



700
+



701
+



702
>30



703
++



704
+++



705
+



706
+++



707
+++++



708
+



709
++



710
+



711
++++



712
+



713
++++



714
++



715
++++++



716
++



717
++



718
>30



719
++



720
~30



721
++++



722
++



723
++



724
>30



725
>30



726
+++



727
++++



728
++



Compound 984a
+



Compound 984b
++++



Compound 983
++++



Compound 985a
++



Compound 985b
+++




















TABLE B4







Example #
hTHP-1 IC50









729
++



730
+++



731
++++



732
++



733
++++



734
+++



735
+++



736
+++



737
+++



738
++



739
+++++



740
++++



741
++++



742
+++++



743
++



744
++++



745
++



746
+++++



747
+++++



748
+++



749
++



750
+++



751
++



752
++



753
+++



754
++



755
+++



756
+



757
+++++



758
++



759
+++



760
>30



761
++++



762
+



763
+++



764
+



765
+++++



766
++



767
+++++



768
+++



769
+



770
++++



771
+++



772
+



773
++++



774
+



775
++++



776
+



777
+++



778
++



779
+++++



780
+++



781
+++++



782
+++



783
++



784
+



785
++++



786
+



787
+++++



788
++



789
++++



790
+



791
+++



792
>30



793
+++



794
+





















TABLE B5








hTHP-1 IC50
hTHP-1 IC50



Example #
in 2% FBS
in 10% FBS









795
++
++



796
+++++
+++



797
+++++
+++++



798
++++
++++



799
+++
ND



800
ND
+



801
ND
++++



802
ND
+++



803
ND
++++



804
ND
++++



805
ND
++++



806
ND
+++++



807
ND
++++



808
ND
+++++



809
ND
++++



810
ND
ND



811
ND
++++



812
ND
++++



813
+++++
+++++



814
++
++



815
++++
+++++



816
+
++



817
+
++



818
+++
++++



819
+
+



820
>30 μM
>30 μM



821
++++
ND



822
++
++



823
+
+



824
ND
+++



825
ND
+++++



826
ND
++++



827
ND
++



828
ND
+



829
ND
++



830
ND
++++



831
ND
++



832
ND
++++



833
ND
++



834
ND
++++



835
ND
+++



836
ND
+++



837
ND
+++++



838
ND
++++



839
ND
++



840
ND
++++



841
ND
++



842
ND
+++++



843
ND
+++



844
ND
+++



845
ND
++++++



846
ND
+++



847
ND
+



848
ND
+++++



849
ND
++



850
ND
+++++



851
ND
+++



852
ND
+



853
ND
+++++




















TABLE B6








hTHP-1



Example #
IC50 in 10% FBS









854
++++



855
+++++



856
++++



857
++++



858
++++



861
++++



863
++++



864
+++



865
++++



866
++++



867
++++++



868
+++



869
+++++



870
++










Study Example 1

The CARD8 gene is located within the inflammatory bowel disease (IBD) 6 linkage region on chromosome 19. CARD8 interacts with NLRP3, and Apoptosis-associated Speck-like protein to form a caspase-1 activating complex termed the NLRP3 inflammasome. The NLRP3 inflammasome mediates the production and secretion of interleukin-1β, by processing pro-IL-1β into mature secreted IL-1β. In addition to its role in the inflammasome, CARD8 is also a potent inhibitor of nuclear factor NF-κB. NF-κB activation is essential for the production of pro-IL-1ϑ. Since over-production of IL-1β and dyregulation of NF-KB are hallmarks of Crohn's disease, CARD8 is herein considered to be a risk gene for inflammatory bowel disease. A significant association of CARD8 with Crohn's disease was detected in two British studies with a risk effect for the minor allele of the non-synonymous single-nucleotide polymorphism (SNP) of a C allele at rs2043211. This SNP introduces a premature stop codon, resulting in the expression of a severely truncated protein. This variant CARD8 protein is unable to suppress NF-κB activity, leading to constitutive production of pro-IL-1β, which is a substrate for the NLRP3 inflammasome. It is believed that a gain-of-function mutation in an NLRP3 gene (e.g., any of the gain-of-function mutations described herein, e.g., any of the gain-of-function mutations in an NLRP3 gene described herein) combined with a loss-of-function mutation in a CARD8 gene (e.g., a C allele at r52043211) results in the development of diseases related to increased NLRP3 inflammasome expression and/or activity. Patients having, e.g., a gain-of-function mutation in an NLRP3 gene and/or a loss-of-function mutation in a CARD8 gene are predicted to show improved therapeutic response to treatment with an NLRP3 antagonist.


A study is designed to determine: whether NLRP3 antagonists inhibit inflammasome function and inflammatory activity in cells and biopsy specimens from patients with Crohn's disease or ulcerative colitis; and whether the specific genetic variants identify patients with Crohn's disease or ulcerative colitis who are most likely to respond to treatment with an NLRP3 antagonist.


The secondary objectives of this study are to: determine if an NLRP3 antagonist reduces inflammasome activity in Crohn's disease and ulcerative biopsy samples (comparing Crohn's disease and ulcerative colitis results with control patient results); determine if an NLRP3 antagonist reduced inflammatory cytokine RNA and protein expression in Crohn's disease and ulcerative colitis samples; determine if baseline (no ex vivo treatment) RNA levels of NLRP3, ASC, and IL-113 are greater in biopsy samples from patients with anti-TNFα agent resistance status; and stratify the results according to presence of specific genetic mutations in genes encoding ATG16L1, NLRP3, and CARD8 (e.g., any of the mutations in the ATG16L1 gene, NLRP3 gene, and CARD8 gene described herein).


Methods



  • Evaluation of baseline expression of NLRP3 RNA and quantify inhibition of inflammasome activity by an NLRP3 antagonist in biopsies of disease tissue from patients with Crohn's disease and ulcerative colitis.

  • Determine if NLRP3 antagonist treatment reduces the inflammatory response in biopsies of disease from patients with Crohn's disease based on decreased expression of inflammatory gene RNA measured with Nanostring.

  • Sequence patient DNA to detect specific genetic mutations in the ATG16L1 gene, NLRP3 gene, and CARD8 gene (e.g., any of the exemplary mutations in these genes described herein) and then stratify the results of functional assays according to the presence of these genetic mutations.
    • Experimental Design


      Human subjects and tissue:
    • Endoscopic or surgical biopsies from areas of disease in patients with Crohn's disease and ulcerative colitis who are either anti-TNFα treatment naive or resistant to anti-TNFα treatment; additionally biopsies from control patients (surveillance colonoscopy or inflammation-free areas from patients with colorectal cancer) are studied.


      Ex vivo Treatment Model:



Organ or LPMC culture as determined appropriate


Endpoints to be measured:

    • Before ex vivo treatment—NLRP3 RNA level
    • After ex vivo treatment—inflammasome activity (either processed IL-10, processed caspase-1, or secreted IL-1(3); RNA for inflammatory cytokines (Nanostring); viable T cell number and/or T cell apoptosis.


Data Analysis Plan:





    • Determine if NLRP3 antagonist treatment decreases processed IL-1β, processed caspase-1 or secreted IL-113, and inflammatory cytokine RNA levels.

    • Stratify response data according to treatment status at biopsy and the presence of genetic mutations in the NLRP3 gene, CARD8 gene, and ATG16L1 gene (e.g., any of the exemplary genetic mutations of these genes described herein).





Study Example 2
Treatment of Anti-TNFα Resistant Patients with NLRP3 Antagonists

PLoS One 2009 Nov. 24;4(11):e7984, describes that mucosal biopsies were obtained at endoscopy in actively inflamed mucosa from patients with Ulcerative Colitis, refractory to corticosteroids and/or immunosuppression, before and 4-6 weeks after their first infliximab (an anti-TNFα agent) infusion and in normal mucosa from control patients. The patients in this study were classified for response to infliximab based on endoscopic and histologic findings at 4-6 weeks after first infliximab treatment as responder or non-responder. Transcriptomic RNA expression levels of these biopsies were accessed by the inventors of the invention disclosed herein from GSE 16879, the publically available Gene Expression Omnibus (https:www.ncbi.nlm.nih.gov/geo/geo2r/?acc=GSE16879). Expression levels of RNA encoding NLRP3 and IL-1β were determined using GEO2R (a tool available on the same website), based on probe sets 207075_at and 205067_at, respectively. It was surprisingly found that in Crohn's disease patients that are non-responsive to the infliximab (an anti-TNFα agent) have higher expression of NLRP3 and IL-1β RNA than responsive patients (FIGS. 1 and 2). Similar surprising results of higher expression of NLRP3 and IL-1β RNA in UC patients that are non-responsive to infliximab (an anti-TNFα agent) compared to infliximab (an anti-TNFα agent) responsive patients (FIGS. 3 and 4) were found.


Said higher levels of NLRP3 and IL-1β RNA expression levels in anti-TNFα agent non-responders, is hypothesised herein to lead to NLRP3 activation which in turns leads of release of IL-1β that induces IL-23 production, leading to said resistance to anti-TNFα agents. Therefore, treatment of Crohn's and UC anti-TNFα non-responders with an NLRP3 antagonist would prevent this cascade, and thus prevent development of non-responsiveness to anti-TNFα agents. Indeed, resistance to anti-TNFα agents is common in other inflammatory or autoimmune diseases. Therefore, use of an NLRP3 antagonist for the treatment of inflammatory or autoimmune diseases will block the mechanism leading to non-responsiveness to anti-TNFα□agents. Consequently, use of NLRP3 antagonists will increase the sensitivity of patients with inflammatory or autoimmune diseases to anti-TNFα agents, resulting in a reduced dose of anti-TNFα agents for the treatment of these diseases. Therefore, a combination of an NLRP3 antagonist and an anti-TNFα agent can be used in the treatment of diseases wherein TNFα is overexpressed, such as inflammatory or autoimmune diseases, to avoid such non-responsive development of patients to anti-TNFα agents. Preferably, this combination threatment can be used in the treatment of IBD, for example Crohn's disease and UC.


Further, use of NLRP3 antagonists offers an alternative to anti-TNFα agents for the treatment of diseases wherein TNFα is overexpressed. Therefore, NLRP3 antagonists offers an alternative to anti-TNFα agents inflammatory or autoimmune diseases, such as IBD (e.g. Crohn's disease and UC).


Systemtic anti-TNFα agents are also known to increase the risk of infection. Gut restricted NLRP3 antagonists, however, offers a gut targeted treatment (i.e. non-systemic treatment), preventing such infections. Therefore, treatment of TNFα gut diseases, such as IBD (i.e. Crohn's disease and UC), with gut restricted NLRP3 antagonists has the additional advantage of reducing the risk of infection compared to anti-TNFα agents.


Proposed Experiment:


Determine the expression of NLRP3 and caspase-1 in LPMCs and epithelial cells in patients with non-active disease, in patients with active disease, in patients with active disease resistant to corticosteroids, patients with active disease resistant to TNF-blocking agents. The expression of NLRP3 and caspase-1 in LPMCs and epithelial cells will be analyzed by RNAScope technology. The expression of active NLRP3 signature genes will be analyzed by Nanostring technology. A pilot analysis to determine feasibility will be performed with 5 samples from control, 5 samples from active CD lesions, and 5 samples from active UC lesions.


Study Example 3

It is presented that NLRP3 antagonists reverse resistance to anti-TNF induced T cell depletion/apoptosis in biopsy samples from IBD patients whose disease is clinically considered resistant or unresponsive to anti-TNF therapy.


A study is designed to determine: whether NLRP3 antagonists inhibit inflammasome function and inflammatory activity in cells and biopsy specimens from patients with Crohn's disease or ulcerative colitis; and whether an NLRP3 antagonist will synergize with anti-TNFα therapy in patients with Crohn's disease or ulcerative colitis.


The secondary objectives of this study are to: determine if an NLRP3 antagonist reduces inflammasome activity in Crohn's disease and ulcerative biopsy samples (comparing Crohn's disease and ulcerative colitis results with control patient results); determine if an NLRP3 antagonist reduced inflammatory cytokine RNA and protein expression in Crohn's disease and ulcerative colitis samples; determine if an NLRP3 antagonist in the absence of co-treatment with anti-TNFα antibody induces T cell depletion in Crohn's disease and ulcerative colitis biopsy samples; and determine if baseline (no ex vivo treatment) RNA levels of NLRP3, ASC, and IL-1β are greater in biopsy samples from patients with anti-TNFα agent resistance status.


Methods



  • Evaluation of baseline expression of NLRP3 RNA and quantify inhibition of inflammasome activity by an NLRP3 antagonist in biopsies of disease tissue from patients with Crohn's disease and ulcerative colitis.

  • Determine if there is synergy between an NLRP3 antagonist and anti-TNF antibody with respect to effects on T cell depletion/apoptosis in biopsies of disease from patients with Crohn's disease and ulcerative colitis.

  • Determine if NLRP3 antagonist treatment reduces the inflammatory response in biopsies of disease from patients with Crohn's disease based on decreased expression of inflammatory gene RNA measured with Nanostring.



Experimental Design

Human subjects and tissue:

    • Endoscopic or surgical biopsies from areas of disease in patients with Crohn's disease and ulcerative colitis who are either anti-TNFα treatment naive or resistant to anti-TNFα treatment; additionally biopsies from control patients (surveillance colonoscopy or inflammation-free areas from patients with colorectal cancer) are studied.


Ex Vivo Treatment Model:

Organ or LPMC culture as determined appropriate


Ex Vivo Treatments:

NLRP3 antagonist (2 concentrations), negative control (vehicle), positive control (caspase-1 inhibitor) each in the presence or absence of anti-TNF antibody at a concentration appropriate to distinguish differences in the T cell apoptotic between biopsies from anti-TNF resistant and anti-TNF-sensitive Crohn's disease patients. Each treatment condition is evaluated in a minimum in duplicate samples.


Endpoints to be measured:


Before ex vivo treatment—NLRP3 RNA level

    • After ex vivo treatment- inflammasome activity (either processed IL-113, processed caspase-1, or secreted IL-1β); RNA for inflammatory cytokines (Nanostring); viable T cell number and/or T cell apoptosis.
    • Data Analysis Plan:
    • Determine if NLRP3 antagonist co-treatment increases T cell apoptosis/deletion in response to anti-TNF.
    • Determine if the level of NLRP3 RNA expression is greater in TNF-resistant Crohn's disease and ulcerative colitis samples compared to anti-TNF treatment-naïve samples.
    • Determine if NLRP3 antagonist treatment decreases processed IL-1β, processed caspase-1 or secreted IL-10, and inflammatory cytokine RNA levels.


Biological Assay—Nigericin-Stimulated IL-1β Secretion Assay in THP-1 Cells

Monocytic THP-1 cells (ATCC: TIB-202) were maintained according to providers' instructions in RPMI media (RPMI/Hepes+10% fetal bovine serum+Sodium Pyruvate+0.05 mM Beta-mercaptoethanol (1000× stock)+Pen-Strep). Cells were differentiated in bulk with 0.5 μM phorbol 12-myristate 13-acetate (PMA; Sigma #P8139) for 3 hours, media was exchanged, and cells were plated at 50,000 cells per well in a 384-well flat-bottom cell culture plates (Greiner, #781986), and allowed to differentiate overnight. Compound in a 1:3.16 serial dilution series in DMSO was added 1:100 to the cells and incubated for 1 hour. The NLRP3 inflammasome was activated with the addition of 15 μM (final concentration) Nigericin (Enzo Life Sciences, #BML-CA421-0005), and cells were incubated for 3 hours. 10 μL supernatant was removed, and IL-1β levels were monitored using an HTRF assay (CisBio, #621L1PEC) according to manufacturers' instructions. Viability and pyroptosis was monitored with the addition of PrestoBlue cell viability reagent (Life Technologies, #A13261) directly to the cell culture plate.


A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.

Claims
  • 1. A compound of Formula AA
  • 2. The compound of claim 1, wherein A is a 5-membered heteroaryl.
  • 3. The compound of claim 1, wherein A is a 6- to 10-membered heteroaryl.
  • 4. The compound of claim 1, wherein A is a C6-C10 aryl.
  • 5. The compound of any one of claims 1-2, wherein A is a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR1.
  • 6. The compound of any one of claims 1-2, wherein A is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety.
  • 7. The compound of any one of claims 1-2, and 6, wherein A is thiophenyl.
  • 8. The compound of any one of claims 1-2, wherein A is thiazolyl.
  • 9. The compound of any one of claims 1-2, wherein A is pyrazolyl.
  • 10. The compound of any one of claims 1 and 4, wherein A is phenyl.
  • 11. The compound of any one of claims 1-10, wherein m=1 and n=0.
  • 12. The compound of any one of claims 1-2, 8, and 11, wherein the optionally substituted ring A is
  • 13. The compound of any one of claims 1-2, 8, and 11, wherein the optionally substituted ring A is
  • 14. The compound of any one of claims 1-2, 8, and 11, wherein the optionally substituted ring A is
  • 15. The compound of any one of claims 1-2, 8, and 11, wherein the optionally substituted ring A is
  • 16. The compound of any one of claims 1-2, 9, and 11, wherein the optionally substituted ring A is
  • 17. The compound of any one of claims 1-2, and 11, wherein the optionally substituted ring A is
  • 18. The compound of any one of claims 1-2, and 11, wherein the optionally substituted ring A is
  • 19. The compound of any one of claims 1, 4, and 11, wherein the optionally substituted ring A is
  • 20. The compound of any one of claims 1-10, wherein m=1 and n=1.
  • 21. The compound of any one of claims 1-2, 8, and 20, wherein the optionally substituted ring A is
  • 22. The compound of any one of claims 1-2, 9, and 20, wherein the optionally substituted ring A is
  • 23. The compound of any one of claims 1-2, 9, and 20, wherein the optionally substituted ring A is
  • 24. The compound of any one of claims 1-2, 9, and 20, wherein the optionally substituted ring A is
  • 25. The compound of any one of claims 1-2, 8, and 20, wherein the optionally substituted ring A is
  • 26. The compound of any one of claims 1, 2, 7, and 20, wherein the optionally substituted ring A is
  • 27. The compound of any one of claims 1, 2, 7, and 20, wherein the optionally substituted ring A is
  • 28. The compound of any one of claims 1, 4, 10, and 20, wherein the optionally substituted ring A is
  • 29. The compound of any one of claims 1-28, wherein R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.
  • 30. The compound of any one of claims 1-29, wherein R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, halo, or NR8R9.
  • 31. The compound of any one of claims 1-29, wherein R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3 -dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.
  • 32. The compound of any one of claims 1-28, wherein R1 is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.
  • 33. The compound of any one of claims 1-28 and 32, wherein R1is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl.
  • 34. The compound of any one of claims 1-28 and 32, wherein R1 is fluoro.
  • 35. The compound of any one of claims 1-34, wherein R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.
  • 36. The compound of any one of claims 1-34, wherein R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.
  • 37. The compound of any one of claims 1-34, wherein R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3 -dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.
  • 38. The compound of any one of claims 1-34, wherein R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.
  • 39. The compound of any one of claims 1-10, 20, 22-25, and 27, wherein R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring (e.g., C5 or C6 carbocyclic ring) or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g., methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g., isopropoxyl), OC3-C10 cycloalkyl, NR8R9, ═NR10 CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g., amino, methylamino, or dimethylamino), NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 40. The compound of any one of claims 1-10, 20, 22-23, 25, and 27, wherein R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C5-C6 carbocyclic ring optionally independently substituted with one or more sub stituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino; or R1 and R2 are on adjacent atoms, and taken together, independently form:
  • 41. The compound of any one of claims 1-10, 20, 22-23, 25, and 27, wherein R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic C4-C12 carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.
  • 42. The compound of any one of claims 1-10, 20, 22-23, 25, and 27, wherein R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.
  • 43. The compound of any one of claims 1-2 and 8, wherein A is thiazolyl (e.g., 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); and R2, when present, is C1-C6 alkyl optionally substituted with hydroxy (e.g., methyl, hydroxymethyl, or hydroxyethyl).
  • 44. The compound of any one of claims 1-2 and 9, wherein A is pyrazolyl (e.g., 3-pyrazolyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted with 1-3 halo (e.g., fluoro).
  • 45. The compound of claim 1, wherein A is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted with NR8R9 (e.g., dimethylamino); and R2, when present, is halo (e.g., fluoro).
  • 46. The compound of any one of claims 1-2 and 7, wherein A is thiophenyl (e.g., 2-thiophenyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., isopropyl, 2-hydroxy-2-propyl, or 1-propanoyl).
  • 47. The compound of any one of claims 1-2, wherein the optionally substituted ring A is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from 0 and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2),and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 48. The compound of any one of claims 1-2, 9, and 47, wherein the optionally substituted ring A is a pyrazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2),and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 49. The compound of any one of claims 1-2 and 47, wherein the optionally substituted ring A is an imidazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 50. The compound of any one of claims 1-2 and 7, wherein the optionally substituted ring A is a thiophenyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 51. The compound of any one of claims 1-2 and 9, wherein the optionally substituted ring A is
  • 52. The compound of any one of claims 1-2 and 9, wherein the optionally substituted ring A is
  • 53. The compound of any one of claims 1-52, wherein B is pyridyl, or an N-oxide thereof.
  • 54. The compound of any one of claims 1-53, wherein the B is 3-pyridyl.
  • 55. The compound of any one of claims 1-54, wherein o=2 and p=1.
  • 56. The compound of any one of claims 1-55, wherein the substituted ring B is
  • 57. The compound of claim 1-56, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 58. The compound of any one of claims 1-57, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.
  • 59. The compound of any one of claims 1-58, wherein each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 60. The compound of any one of claims 1-59, wherein each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 61. The compound of any one of claims 1-60, wherein each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 62. The compound of any one of claims 1-61, wherein each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 63. The compound of any one of claims 1-53, wherein the substituted ring B is 4-pyridyl.
  • 64. The compound of any one of claims 1-53 and 63, wherein o=2 and p=0.
  • 65. The compound of any one of claims 1-53 and 63-64, wherein the substituted ring B is
  • 66. The compound of any one of claims 1-53 and 63-65, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 67. The compound of any one of claims 1-53 and 63-66, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.
  • 68. The compound of any one of claims 1-53 and 63-67, wherein each R6 is isopropyl.
  • 69. The compound of any one of claims 1-53 and 63, wherein o=2 and p=2.
  • 70. The compound of any one of claims 1-53, 63, and 69, wherein the substituted ring B is
  • 71. The compound of any one of claims 1-53, 63, and 69-70, wherein each R6is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 72. The compound of any one of claims 1-53, 63, and 69-71, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 73. The compound of any one of claims 1-53, 63, and 69-72, wherein each R6is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 74. The compound of any one of claims 1-53, 63, and 69-73, wherein each R7is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 75. The compound of any one of claims 1-53, 63, and 69-74, wherein each R7is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 76. The compound of any one of claims 1-53, 63, and 69-75, wherein each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 77. The compound of any one of claims 1-53, 63, and 69-76, wherein one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, and S, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 78. The compound of any one of claims 1-53, 63, and 69-76, wherein one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 79. The compound of any one of claims 77-78, wherein the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted with one or more oxo, CH3, or hydroxy.
  • 80. The compound of claim 79, wherein the C5 carbocyclic ring is substituted with one CH3.
  • 81. The compound of claim 79, wherein the C5 carbocyclic ring is geminally substituted with two CH3.
  • 82. The compound of any one of claims 77-78, wherein the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.
  • 83. The compound of any one of claims 1 and 43-52, wherein the substituted ring B is
  • 84. The compound of any one of claims 1 and 43-52, wherein the substituted ring B is
  • 85. The compound of any one of claims 1 and 43-52, wherein the substituted ring B is
  • 86. The compound of any one of claims 1 and 43-52, wherein the substituted ring B is
  • 87. The compound of any one of claims 1 and 43-52, wherein the substituted ring B is
  • 88. A compound of Formula AA
  • 89. The compound of claim 88, wherein the compound of Formula AA is a compound of Formula AA-1
  • 90. The compound of any one of claims 88-89, wherein A′ is a 6- to 10-membered heteroaryl.
  • 91. The compound of any one of claims 88-89, wherein A′ is a C6-C10 aryl.
  • 92. The compound of any one of claims 88-89, wherein A′ is a 5-membered heteroaryl comprising 2 or more heteroatoms and/or heteroatomic groups.
  • 93. The compound of any one of claims 88-89, wherein A′ is a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR1.
  • 94. The compound of any one of claims 88-89, wherein A′ is a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety.
  • 95. The compound of any one of claims 88-89 and 94, wherein A′ is thiophenyl.
  • 96. The compound of any one of claims 88-89 and 92, wherein A′ is thiazolyl.
  • 97. The compound of any one of claims 88-89 and 92, wherein A′ is pyrazolyl.
  • 98. The compound of any one of claims 88-89 and 91, wherein A′ is phenyl.
  • 99. The compound of any one of claims 88-98, wherein m=1 and n=0.
  • 100. The compound of any one of claims 88-89, 92, 96, and 99, wherein the optionally substituted ring A′ is
  • 101. The compound of any one of claims 88-89, 92, 96, and 99, wherein the optionally substituted ring A′ is
  • 102. The compound of any one of claims 88-89, 92, 96, and 99, wherein the optionally substituted ring A′ is
  • 103. The compound of any one of claims 88-89, 92, 96, and 99, wherein the optionally substituted ring A′ is
  • 104. The compound of any one of claims 88-89, 92, 97, and 99, wherein the optionally substituted ring A′ is
  • 105. The compound of any one of claims 88-89, 91, 98, and 99, wherein the optionally substituted ring A′ is
  • 106. The compound of any one of claims 88-98, wherein m=1 and n=1.
  • 107. The compound of any one of claims 88-89, 92, 96, and 106, wherein the optionally substituted ring A′ is
  • 108. The compound of any one of claims 88-89, 92, 97, and 106, wherein the optionally substituted ring A is
  • 109. The compound of any one of claims 88-89, 92, 97, and 106, wherein the optionally substituted ring A is
  • 110. The compound of any one of claims 88-89, 92, 96, and 106, wherein the optionally substituted ring A′ is
  • 111. The compound of any one of claims 88-89, 91, 98, and 106, wherein the optionally substituted ring A′ is
  • 112. The compound of any one of claims 88-111, wherein R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.
  • 113. The compound of any one of claims 88-112, wherein R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.
  • 114. The compound of any one of claims 88-112, wherein R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.
  • 115. The compound of any one of claims 88-114, wherein R1, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.
  • 116. The compound of any one of claims 88-115, wherein R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl.
  • 117. The compound of any one of claims 88-115, wherein R1 is fluoro.
  • 118. The compound of any one of claims 88-98 and 106-117, wherein R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.
  • 119. The compound of any one of claims 88-98 and 106-118, wherein R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.
  • 120. The compound of any one of claims 88-98 and 106-118, wherein R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.
  • 121. The compound of any one of claims 88-98 and 106-120, wherein R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.
  • 122. The compound of any one of claims 88-98, 106, 108, and 110, wherein R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring (e.g., C5 or C6 carbocyclic ring) or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl (e.g., methyl), C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy (e.g., isopropoxyl), OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9 (e.g., amino, methylamino, or dimethylamino), ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 123. The compound of any one of claims 88-98, 106, 108, and 110, wherein R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C5-C6 carbocyclic ring optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino; or R1 and R2 are on adjacent atoms, and taken together, independently form:
  • 124. The compound of any one of claims 88-98, 106, 108, and 110, wherein R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic C4-C12 carbocyclic ring, wherein the carbocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.
  • 125. The compound of any one of claims 88-98, 106, 108, and 110, wherein R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic or heterocyclic ring is optionally substituted with one or more substituents each independently selected from hydroxy, halo, oxo, methyl, isopropoxyl, azetidinyl, oxetanyl, wherein the methyl, isopropoxyl, azetidinyl, and oxetanyl are optionally substituted with one or more substituents each independently selected from hydroxy, fluoro, amino, methylamino, and dimethylamino.
  • 126. The compound of any one of claims 88-89, 92, and 96, wherein A′ is thiazolyl (e.g., 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1; R1 is C1-C6 alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); and R2, when present, is C1-C6 alkyl optionally substituted with hydroxy (e.g., methyl, hydroxymethyl, or hydroxyethyl).
  • 127. The compound of any one of claims 88-89, 92, and 97, wherein A′ is pyrazolyl (e.g., 3-pyrazolyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted with 1-3 halo (e.g., fluoro).
  • 128. The compound of any one of claims 88-89, 91, and 98, wherein A′ is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted with NR8R9 (e.g., dimethylamino); and R2, when present, is halo (e.g., fluoro).
  • 129. The compound of any one of claims 88-89 and 94-95, wherein A′ is thiophenyl; m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., isopropyl, 2-hydroxy-2-propyl, or 1-propanoyl).
  • 130. The compound of any one of claims 88-89, wherein the optionally substituted ring A′ is selected from the group consisting of a 5-membered heteroaryl comprising 2 or more heteroatoms, a 5-membered heteroaryl comprising 1 heteroatom or heteroatomic group selected from N, NH, and NR1, and a 5-membered heteroaryl comprising 1 heteroatom selected from O and S, wherein the heteroatom is not bonded to the position of the heteroaryl that is bonded to the S(O)(NHR3)═N moiety; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 131. The compound of any one of claims 88-89, 92, 97, and 130, wherein the optionally substituted ring A′ is a pyrazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 132. The compound of any one of claims 88-89, 92, and 130, wherein the optionally substituted ring A′ is an imidazolyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein a) when each of the adjacent atoms is a carbon atom, then the heterocyclic ring includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2; and b) when one or both of the adjacent atoms is/are a nitrogen atom(s), then the heterocyclic ring includes from 0-2 heteroatoms and/heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 (in addition to the aforementioned nitrogen atom(s) attached to R1 and/or R2), and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 133. The compound of any one of claims 88-89 and 94-95, wherein the optionally substituted ring A′ is a thiophenyl; m is 1; n is 1; R1 and R2 are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 134. The compound of any one of claims 88-89, 92, and 97, wherein the optionally substituted ring A is
  • 135. The compound of any one of claims 88-89, 92, and 97, wherein the optionally substituted ring A is
  • 136. The compound of any one of claims 88-135, wherein B is pyridyl, or an N-oxide thereof.
  • 137. The compound of any one of claims 88-136, wherein B is 3-pyridyl, or an N-oxide thereof.
  • 138. The compound of any one of claims 88-137, wherein o=2 and p=1.
  • 139. The compound of any one of claims 88-138, wherein the substituted ring B is
  • 140. The compound of any one of claims 88-139, wherein each R6″ is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 141. The compound of any one of claims 88-140, wherein each R6″ is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.
  • 142. The compound of any one of claims 88-141, wherein each R6″ is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 143. The compound of any one of claims 88-142, wherein each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 144. The compound of any one of claims 88-143, wherein each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 145. The compound of any one of claims 88-144, wherein each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 146. The compound of any one of claims 88-136, wherein B is 4-pyridyl, or an N-oxide thereof.
  • 147. The compound of any one of claims 88-136 and 146, wherein o=2 and p=0.
  • 148. The compound of any one of claims 88-136 and 146-147, wherein the substituted ring B is
  • 149. The compound of any one of claims 88-136 and 146-148, wherein each R6″ is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 150. The compound of any one of claims 88-136 and 146-149, wherein each R6″ is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.
  • 151. The compound of any one of claims 88-136 and 146-150, wherein each R6″ is isopropyl.
  • 152. The compound of any one of claims 88-136 and 146, wherein o=2 and p=2.
  • 153. The compound of any one of claims 88-136, 146, and 152, wherein the substituted ring B is
  • 154. The compound of any one of claims 88-136, 146, and 152-153, wherein each R6″ is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 155. The compound of any one of claims 88-136, 146, and 152-154, wherein each R6″ is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 156. The compound of any one of claims 88-136, 146, and 152-155, wherein each R6″ is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 157. The compound of any one of claims 88-136, 146, and 152-156, wherein each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 158. The compound of any one of claims 88-136, 146, and 152-157, wherein each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 159. The compound of any one of claims 88-136, 146, and 152-158, wherein each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 160. The compound of any one of claims 88-89, 139-142, and 153-159, wherein one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 161. The compound of any one of claims 88-89, 139-142, and 153-159, wherein one pair of R6″ and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 162. The compound of any one of claims 160-161, wherein the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted with one or more oxo, CH3, or hydroxy.
  • 163. The compound of claim 162, wherein the C5 carbocyclic ring is substituted with one CH3.
  • 164. The compound of claim 162, wherein the C5 carbocyclic ring is geminally substituted with two CH3.
  • 165. The compound of any one of claims 160-161, wherein the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.
  • 166. The compound of any one of claims 88-89 and 96, wherein the optionally substituted ring A′ is thiazolyl (e.g., 2-thiazolyl or 5-thiazolyl); m is 1; n is 0 or 1 (e.g., n is 1); R1 is C1-C6 alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); and R2, when present, is C1-C6 alkyl optionally substituted with hydroxyl (e.g., methyl, hydroxymethyl, or hydroxyethyl).
  • 167. The compound of any one of claims 88-89 and 97, wherein the optionally substituted ring A′ is pyrazolyl (e.g., 3-pyrazolyl); m is 1; n is 0; and R1 is C1-C6 alkyl optionally substituted with 1-3 halo (e.g., fluoro (e.g., R1 is C1-C6 alkyl substituted with 2-3 fluoro)).
  • 168. The compound of any one of claims 88-89 and 98, wherein the optionally substituted ring A′ is phenyl; m is 1; n is 0 or 1; and R1 is C1-C6 alkyl optionally substituted with NR8R9 (e.g., dimethylamino); and R2, when present, is halo (e.g., fluoro (e.g., R1 is C1-C6 alkyl substituted with 2-3 fluoro)).
  • 169. The compound of any one of claims 88-89, 126-135 and, 166-168, wherein the substituted ring B is
  • 170. The compound of any one of claims 88-89, 126-135 and, 166-168, wherein the substituted ring B is
  • 171. The compound of any one of claims 88-89, 126-135 and, 166-168, wherein the substituted ring B is
  • 172. The compound of any one of claims 88-89, 126-135 and, 166-168, wherein the substituted ring B is
  • 173. The compound of claim 88, wherein the compound of Formula AA is a compound of Formula AA-2
  • 174. The compound of any one of claims 88 and 173 wherein A″ is thiophenyl.
  • 175. The compound of any one of claims 88 and 173-174, wherein m′=1 and n′=0.
  • 176. The compound of any one of claims 88 and 173-175, wherein the optionally substituted ring A″ is
  • 177. The compound of any one of claims 88 and 173-175, wherein the optionally substituted ring A″ is
  • 178. The compound of any one of claims 88 and 173-177, wherein R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12;S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.
  • 179. The compound of any one of claims 88 and 173-178, wherein R1, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.
  • 180. The compound of any one of claims 88 and 173-178, wherein R1, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.
  • 181. The compound of any one of claims 88 and 173-180, wherein R1, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.
  • 182. The compound of any one of claims 88 and 173-181, wherein R1, when present, is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl.
  • 183. The compound of any one of claims 88 and 173-181, wherein R1 is fluoro.
  • 184. The compound of any one of claims 88, 173, 174, and 178-183, wherein R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.
  • 185. The compound of any one of claims 88, 173, 174, and 178-184, wherein R2, when present, is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.
  • 186. The compound of any one of claims 88, 173, 174, and 178-184, wherein R2, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3; and S(O2)NR11R12.
  • 187. The compound of any one of claims 88, 173, 174, and 178-186, wherein R2, when present, is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.
  • 188. The compound of any one of claims 88 and 173-187, wherein B is pyridyl, or an N-oxide thereof.
  • 189. The compound of any one of claims 88 and 173-188, wherein B is 3-pyridyl, or an N-oxide thereof.
  • 190. The compound of any one of claims 88 and 173-189, wherein o=2 and p=1.
  • 191. The compound of any one of claims 88 and 173-190, wherein the substituted ring B is
  • 192. The compound of any one of claims 88 and 173-191, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 193. The compound of any one of claims 88 and 173-192, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.
  • 194. The compound of any one of claims 88 and 173-193, wherein each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 195. The compound of any one of claims 88, 173-189, and 192-194, wherein each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 196. The compound of any one of claims 88, 173-189, and 192-195, wherein each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 197. The compound of any one of claims 88, 173-189, and 192-196, wherein each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 198. The compound of any one of claims 88 and 173-188, wherein B is 4-pyridyl, or an N-oxide thereof.
  • 199. The compound of claims 88, 173-188, and 198, wherein o=2 and p=0.
  • 200. The compound of any one of claims 88, 173-188, and 198-199, wherein the substituted ring B is
  • 201. The compound of any one of claims 88, 173-188, and 198-200, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 202. The compound of any one of claims 88, 173-188, and 198-201, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.
  • 203. The compound of any one of claims 88, 173-188, and 198-202, wherein each R6 is isopropyl.
  • 204. The compound of claims 88, 173-188, and 198, wherein o=2 and p=2.
  • 205. The compound of claims 88, 173-188, 198, and 204, wherein the substituted ring B is
  • 206. The compound of claims 88, 173-188, 198, and 204-205, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 207. The compound of claims 88, 173-188, 198, and 204-206, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 208. The compound of any one of claims 88, 173-188, 198, and 204-207, wherein each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 209. The compound of any one of claims 88, 173-188, 198, and 204-208, wherein each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 210. The compound of any one of claims 88, 173-188, 198, and 204-209, wherein each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 211. The compound of claims 88, 173-188, 198, and 204-210 wherein each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 212. The compound of any one of claims 88, 173-188, 198, and 204-210, wherein one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 213. The compound of any one of claims 88, 173-188, 198, and 204-210, wherein one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 214. The compound of any one of claims 212-213, wherein the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted with one or more oxo, CH3, or hydroxy.
  • 215. The compound of claim 214, wherein the C5 carbocyclic ring is substituted with one CH3.
  • 216. The compound of claim 214, wherein the C5 carbocyclic ring is geminally substituted with two CH3.
  • 217. The compound of any one of claims 212-213, wherein the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.
  • 218. The compound of claim 173, wherein A″ is thiophenyl (e.g., 2-thiophenyl); m′ is 1; n′ is 0; and R1 is C1-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., isopropyl, 2-hydroxy-2-propyl, or 1-propanoyl).
  • 219. The compound of any one of claims 173 and 218, wherein A″ is 2-thiophenyl.
  • 220. The compound of any one of claims 173 and 218, wherein the substituted ring B is
  • 221. The compound of any one of claims 173 and 218, wherein the substituted ring B is
  • 222. The compound of any one of claims 173 and 218, wherein the substituted ring B is
  • 223. The compound of any one of claims 173 and 218, wherein the substituted ring B is
  • 224. The compound of claim 88, wherein the compound of Formula AA is a compound of Formula AA-3
  • 225. The compound of any one of claims 88 and 224, wherein A″ is thiophenyl.
  • 226. The compound of any one of claims 88 and 224-225, wherein m″=1 and n″=1.
  • 227. The compound of any one of claims 88 and 224-226, wherein the optionally substituted ring A″ is
  • 228. The compound of any one of claims 88 and 224-226, wherein the optionally substituted ring A″ is
  • 229. The compound of any one of claims 88 and 224-226, the optionally substituted ring A″ is
  • 230. The compound of any one of claims 88 and 224-229, wherein when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted with one or more hydroxy, C2-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; Cl; Br; I; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12;S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.
  • 231. The compound of any one of claims 88 and 224-230, wherein R1′, when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted with one or more hydroxyl, or NR8R9.
  • 232. The compound of any one of claims 88 and 224-230, wherein R1′, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; isopropyl; ethyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.
  • 233. The compound of any one of claims 88 and 224-232, wherein is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl.
  • 234. The compound of any one of claims 88 and 224-233, wherein R2′, when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted with one or more hydroxy, C2-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; Cl; Br; I; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.
  • 235. The compound of any one of claims 88 and 224-234, wherein R2′, when present, is independently selected from the group consisting of C2-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.
  • 236. The compound of any one of claims 88 and 224-234, wherein R2′, when present, is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; isopropyl; ethyl; 2-hydroxy-2-propyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3-dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; 1-(dimethylamino)ethyl; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.
  • 237. The compound of any one of claims 88 and 224-236, wherein R2′ is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl.
  • 238. The compound of any one of claims 88, 224-226, and 228-229, wherein one pair of R1′ and R2′ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2,wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 239. The compound of any one of claims 88 and 224-238, wherein B is pyridyl, or an N-oxide thereof.
  • 240. The compound of any one of claims 88 and 224-239, wherein B is 3-pyridyl, or an N-oxide thereof.
  • 241. The compound of any one of claims 88 and 224-240, wherein o=2 and p=1.
  • 242. The compound of any one of claims 88 and 224-241, wherein the substituted ring B is
  • 243. The compound of claims 88 and 224-242, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 244. The compound of any one of claims 88 and 224-243, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.
  • 245. The compound of any one of claims 88 and 224-244, wherein each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 246. The compound of any one of claims 88 and 224-245, wherein each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 247. The compound of any one of claims 88 and 224-246, wherein each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 248. The compound of any one of claims 88 and 224-247, wherein each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 249. The compound of any one of claims 88 and 224-239 , wherein B is 4-pyridyl, or an N-oxide thereof.
  • 250. The compound of any one of claims 88, 224-239, and 249, wherein o=2 and p=0.
  • 251. The compound of any one of claims 88, 224-239, and 249-250, wherein the substituted ring B is
  • 252. The compound of any one of claims 88, 224-239, and 249-251, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 253. The compound of any one of claims 88, 224-239, and 249-252, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl and C3-C7 cycloalkyl.
  • 254. The compound of any one of claims 88, 224-239, and 249-253, wherein each R6 is isopropyl.
  • 255. The compound of any one of claims 88, 224-239, and 249-254, wherein o=2 and p=2.
  • 256. The compound of any one of claims 88, 224-239, and 249-255, wherein the substituted ring B is
  • 257. The compound of any one of claims 88, 224-239, and 249-256, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 258. The compound of any one of claims 88, 224-239, and 249-257, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 259. The compound of any one of claims 88, 224-239, and 249-258, wherein each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 260. The compound of any one of claims 88, 224-239, and 249-259, wherein each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 261. The compound of any one of claims 88, 224-239, and 249-260, wherein each R7, when present, is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 262. The compound of any one of claims 88, 224-239, and 249-261, wherein each R7, when present, is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 263. The compound of any one of claims 88, 224-239, and 249-262, wherein one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10 COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 264. The compound of any one of claims 88, 224-239, and 249-262, wherein one pair of R6 and R7 on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 265. The compound of any one of claims 263-264, wherein the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted with one or more oxo, CH3, or hydroxy.
  • 266. The compound of claim 265, wherein the C5 carbocyclic ring is substituted with one CH3.
  • 267. The compound of claim 265, wherein the C5 carbocyclic ring is geminally substituted with two CH3.
  • 268. The compound of any one of claims 263-264, wherein the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.
  • 269. The compound of any one of claims 88 and 224, wherein A″ is thiophenyl (e.g., 2-thiophenyl); m″ is 1; n″ is 1; R1′ is C2-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., 2-hydroxy-2-propyl); and R2′ is C2-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., 2-hydroxy-2-propyl).
  • 270. The compound of any one of claims 88, 224, and 269, wherein the substituted ring B is
  • 271. The compound of any one of claims 88, 224, and 269, wherein the substituted ring B is
  • 272. The compound of any one of claims 88, 224, and 269, wherein the substituted ring B is
  • 273. The compound of any one of claims 88, 224, and 269, wherein the substituted ring B is
  • 274. The compound of claim 88, wherein the compound of Formula AA is a compound of Formula AA-4
  • 275. The compound of any one of claims 88 and 274, wherein A″ is thiophenyl.
  • 276. The compound of any one of claims 88 and 274-275, wherein the optionally substituted ring A″ is
  • 277. The compound of any one of claims 88 and 274-275, wherein the optionally substituted ring A″ is
  • 278. The compound of any one of claims 88 and 274-275, the optionally substituted ring A″
  • 279. The compound of any one of claims 88 and 274-278, wherein R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.
  • 280. The compound of any one of claims 88 and 274-279, wherein R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.
  • 281. The compound of any one of claims 88 and 274-279, wherein R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3 -dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.
  • 282. The compound of any one of claims 88 and 274-281, wherein R1 is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; 1,2-dihydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.
  • 283. The compound of any one of claims 88 and 274-282, wherein R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl.
  • 284. The compound of any one of claims 88 and 274-282, wherein R1 is fluoro.
  • 285. The compound of any one of claims 88 and 274-284, wherein R2″ is fluoro.
  • 286. The compound of any one of claims 88 and 274-284, wherein R2″ is methyl.
  • 287. The compound of any one of claims 88, 274-275, and 277-278, wherein one pair of R1 and R2″ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4-C12 carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring that includes from 1-3 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2 and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, OC3-C10 cycloalkyl, NR8R9, ═NR10, CN, COOC1-C6 alkyl, OS(O2)C6-C10 aryl, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR8R9, wherein the C1-C6 alkyl, C1-C6 alkoxy, S(O2)C6-C10 aryl, C6-C10 aryl, 5- to 10-membered heteroaryl, C3-C10 cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, C1-C6 alkoxy, oxo, NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 288. The compound of any one of claims 88 and 274-287, wherein o=2 and p=1.
  • 289. The compound of any one of claims 88 and 274-288, wherein the substituted ring B is
  • 290. The compound of any one of claims 88 and 274-289, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 291. The compound of any one of claims 88 and 274-290, wherein each R6 is independently selected from the group consisting of: C1-C6 alkyl, halo, C3-C7 cycloalkyl, and C6-C10 aryl.
  • 292. The compound of any one of claims 88 and 274-291, wherein each R6 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 293. The compound of any one of claims 88 and 274-292, wherein each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, NR10 COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 294. The compound of any one of claims 88 and 274-293, wherein each R7 is independently selected from the group consisting of: C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 295. The compound of any one of claims 88 and 274-294, wherein each R7 is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl.
  • 296. The compound of any one of claims 88 and 274-278, wherein the optionally substituted ring A″ is thiophenyl (e.g., 2-thiophenyl); R1 is C1-C6 alkyl optionally substituted with hydroxyl or oxo (e.g., methyl or 2-hydroxy-2-propyl); and R2″ is methyl.
  • 297. The compound of any one of claims 88, 274-278, and 296, wherein the substituted ring B′ is
  • 298. The compound of any one of claims 1-297, wherein R3 is hydrogen.
  • 299. The compound of any one of claims 1-297, wherein R3 is CHO.
  • 300. The compound of claim 88, wherein the compound of Formula AA is a compound of Formula AA-5
  • 301. The compound of any one of claims 88 and 300, wherein
  • 302. The compound of any one of claims 88 and 300, wherein
  • 303. The compound of any one of claims 88 and 300-302, wherein R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxy, C1-C6 alkyl optionally substituted with one or more halo, oxo, C1-C6 alkoxy, or NR8R9; C3-C7 cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkoxy, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; 3- to 7-membered heterocycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C1-C6 alkyl, or NR8R9 wherein the C1-C6 alkoxy or C1-C6 alkyl is further optionally substituted with one to three hydroxy, halo, NR8R9, or oxo; C1-C6 haloalkyl; C1-C6 alkoxy; C1-C6 haloalkoxy; halo; CN; CO—C1-C6 alkyl; CO—C6-C10 aryl; CO(5- to 10-membered heteroaryl); CO2C1-C6 alkyl; CO2C3-C8 cycloalkyl; OCOC1-C6 alkyl; OCOC6-C10 aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C6-C10 aryl; 5- to 10-membered heteroaryl; NH2; NHC1-C6 alkyl; N(C1-C6 alkyl)2; CONR8R9; SF5; S(O2)NR11R12; S(O)C1-C6 alkyl; and S(O2)C1-C6 alkyl.
  • 304. The compound of any one of claims 88 and 300-302, wherein R1 is independently selected from the group consisting of C1-C6 alkyl optionally substituted with one or more hydroxyl, halo, or NR8R9.
  • 305. The compound of any one of claims 88 and 300-302, wherein R1 is selected from the group consisting of 1-hydroxy-2-methylpropan-2-yl; 1,2-dihydroxy-2-propyl; methyl; ethyl; difluoromethyl; isopropyl; 2-hydroxy-2-propyl; hydroxymethyl; 1-hydroxyethyl; 2-hydroxyethyl; 1-hydroxy-2-propyl; 1-hydroxy-1-cyclopropyl; 1-hydroxy-1-cyclobutyl; 1-hydroxy-1-cyclopentyl; 1-hydroxy-1-cyclohexyl; morpholinyl; 1,3 -dioxolan-2-yl; COCH3; COCH2CH3; 2-methoxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; 1-(dimethylamino)ethyl; fluoro; chloro; phenyl; pyridyl; pyrazolyl; S(O2)CH3, and S(O2)NR11R12.
  • 306. The compound of any one of claims 88 and 300-305, wherein R1 is selected from the group consisting of methyl; ethyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; 1,2-dihydroxy-2-propyl; (dimethylamino)methyl; (methylamino)methyl; and fluoro.
  • 307. The compound of any one of claims 88 and 300-305, wherein R1 is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl;.
  • 308. The compound of any one of claims 88 and 300-305, wherein R1 is fluoro.
  • 309. The compound of any one of claims 88 and 300-308, wherein R2″ is F.
  • 310. The compound of any one of claims 88 and 300-308, wherein R2″ is methyl.
  • 311. The compound of any one of claims 88 and 300-310, wherein o=2 and p=0.
  • 312. The compound of any one of claims 88 and 300-311, wherein the substituted ring B is
  • 313. The compound of any one of claims 88 and 300-312, wherein each R6′ is independently selected from the group consisting of: unbranched C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the unbranched C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 314. The compound of any one of claims 88 and 300-313, wherein each R6′ is independently selected from the group consisting of: unbranched C1-C6 alkyl and C3-C7 cycloalkyl.
  • 315. The compound of any one of claims 88 and 300-310, wherein o=2 and p=2.
  • 316. The compound of any one of claims 88, 300-310, and 315, wherein the substituted ring B is
  • 317. The compound of any one of claims 88, 300-310, and 315-316, wherein each R6′ is independently selected from the group consisting of: unbranched C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the unbranched C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 318. The compound of any one of claims 88, 300-310, and 315-317, wherein each R6′ is independently selected from the group consisting of: unbranched C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 319. The compound of any one of claims 88, 300-310, and 315-317, wherein each R6′ is independently selected from the group consisting of: methyl, cyclopropyl, fluoro, and phenyl.
  • 320. The compound of any one of claims 88, 300-310, and 315-319, wherein each R7′, when present, is independently selected from the group consisting of: unbranched C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, halo, CN, C6-C10 aryl, 5- to 10-membered heteroaryl, CO—C1-C6 alkyl; CONR8R9, and 4- to 6-membered heterocycloalkyl, wherein the unbranched C1-C6 alkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C1-C6 alkoxy, NR8R9, ═NR10, COOC1-C6 alkyl, CONR8R9, 4- to 6-membered heterocycloalkyl, C6-C10 aryl, 5- to 10-membered heteroaryl, OCOC1-C6 alkyl, OCOC6-C10 aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC1-C6 alkyl, NHCOC6-C10 aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC2-C6 alkynyl.
  • 321. The compound of any one of claims 88, 300-310, and 315-320, wherein each R7′, when present, is independently selected from the group consisting of: unbranched C1-C6 alkyl, C3-C7 cycloalkyl, halo, and C6-C10 aryl.
  • 322. The compound of any one of claims 88, 300-310, and 315-321, wherein each R7′, when present, is independently selected from the group consisting of: methyl, cyclopropyl, fluoro, and phenyl.
  • 323. The compound of any one of claims 88, 300-310, and 315-322, wherein one pair of R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring or at least one 5- to 8-membered heterocyclic ring containing 1 or 2 heteroatoms and/or heteroatomic groups independently selected from O, NH, NR13, S, S(O), and S(O)2, wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 324. The compound of any one of claims 88, 300-310, and 315-322, wherein one pair of R6′ and R7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C4-C8 carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR8R9, CH2NR8R9, ═NR10, COOC1-C6 alkyl, C6-C10 aryl, and CONR8R9.
  • 325. The compound of any one of claims 323-324, wherein the C4-C8 carbocyclic ring is a C5 carbocyclic ring optionally substituted with one or more oxo, CH3, or hydroxy.
  • 326. The compound of claim 325, wherein the C5 carbocyclic ring is substituted with one CH3.
  • 327. The compound of claim 325, wherein the C5 carbocyclic ring is geminally substituted with two CH3.
  • 328. The compound of any one of claims 323-324, wherein the C4-C8 carbocyclic ring is a C7 carbocyclic ring, wherein the C7 carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.
  • 329. The compound of claim 300, wherein the substituted ring B″ is
  • 330. The compound of claim 300, wherein the substituted ring B″ is
  • 331. A compound selected from the group consisting of the compounds below:
  • 332. A compound selected from the group consisting of the compounds in Table 1C and pharmaceutically acceptable salts thereof.
  • 333. A compound selected from the group consisting of the compounds in Table 1D and pharmaceutically acceptable salts thereof.
  • 334. A compound selected from the group consisting of the compounds in Table 1E or Table 1F (e.g., Table 1E; e.g., Table 1F) and pharmaceutically acceptable salts thereof
  • 335. The compound of any one of claims 1-330, wherein the sulfur in the moiety S(═O)(NHR3)═N— has (S) stereochemistry.
  • 336. The compound of any one of claims 1-330, wherein the sulfur in the moiety S(═O)(NHR3)═N— has (R) stereochemistry.
  • 337. A pharmaceutical composition comprising a compound or salt as claimed in any one of claims 1-336 and one or more pharmaceutically acceptable excipients.
  • 338. A method for modulating NLRP3 activity, the method comprising contacting NLRP3 with an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 339. The method of claim 338, wherein the modulating comprises antagonizing NLRP3.
  • 340. The method of any one of claims 338-339, which is carried out in vitro.
  • 341. The method of claim 338-340, wherein the method comprises contacting a sample comprising one or more cells comprising NLRP3 with the compound.
  • 342. The method of any one of claims 338-339 and 341, which is carried out in vivo.
  • 343. The method of claim 342, wherein the method comprises administering the compound to a subject having a disease in which NLRP3 signaling contributes to the pathology and/or symptoms and/or progression of the disease.
  • 344. The method of claim 343, wherein the subject is a human.
  • 345. A method of treating a disease, disorder or condition that is a metabolic disorder, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 346. The method of claim 345, wherein the metabolic disorder is Type 2 diabetes, atherosclerosis, obesity or gout.
  • 347. A method of treating a disease, disorder or condition that is a disease of the central nervous system, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 348. The method of claim 347, wherein the disease of the central nervous system is Alzheimer's disease, multiple sclerosis, Amyotrophic Lateral Sclerosis or Parkinson's disease.
  • 349. A method of treating a disease, disorder or condition that is lung disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 350. The method of claim 349, wherein the lung disease is asthma, COPD or pulmonary idiopathic fibrosis.
  • 351. A method of treating a disease, disorder or condition that is liver disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 352. The method of claim 351, wherein the liver disease is NASH syndrome, viral hepatitis or cirrhosis.
  • 353. A method of treating a disease, disorder or condition that is pancreatic disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 354. The method of claim 353, wherein the pancreatic disease is acute pancreatitis or chronic pancreatitis.
  • 355. A method of treating a disease, disorder or condition that is kidney disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 356. The method of claim 355, wherein the kidney disease is acute kidney injury or chronic kidney injury.
  • 357. A method of treating a disease, disorder or condition that is intestinal disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 358. The method of claim 357, wherein the intestinal disease is Crohn's disease or Ulcerative Colitis.
  • 359. A method of treating a disease, disorder or condition that is skin disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 360. The method of claim 359, wherein the skin disease is psoriasis.
  • 361. A method of treating a disease, disorder or condition that is musculoskeletal disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 362. The method of claim 361, wherein the musculoskeletal disease is scleroderma.
  • 363. A method of treating a disease, disorder or condition that is a vessel disorder, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 364. The method of claim 363, wherein the vessel disorder is giant cell arteritis.
  • 365. A method of treating a disease, disorder or condition that is a disorder of the bones, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 366. The method of claim 365, wherein the disorder of the bones is osteoarthritis, osteoporosis or osteopetrosis disorders.
  • 367. A method of treating a disease, disorder or condition that is eye disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 368. The method of claim 367, wherein the eye disease is glaucoma or macular degeneration.
  • 369. A method of treating a disease, disorder or condition that is a disease caused by viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 370. The method of claim 369, wherein the diseases caused by viral infection is HIV or AIDS.
  • 371. A method of treating a disease, disorder or condition that is an autoimmune disease, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 372. The method of claim 371, wherein the autoimmune disease is Rheumatoid Arthritis, Systemic Lupus Erythematosus, Autoimmune Thyroiditis, Addison's disease, pernicious anemia, cancer and aging.
  • 373. A method of treating a disease, disorder or condition that is cancer or aging, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 374. A method of treating a disease, disorder or condition that is a cancer selected from: myelodysplastic syndromes (MDS); non-small cell lung cancer, such as non-small cell lung cancer in patients carrying mutation or overexpression of NLRP3; acute lymphoblastic leukemia (ALL), such as ALL in patients resistant to glucocorticoids treatment; Langerhan's cell histiocytosis (LCH); multiple myeloma; promyelocytic leukemia; acute myeloid leukemia (AML); chronic myeloid leukemia (CIVIL); gastric cancer; and lung cancer metastasis, comprising administering to a subject in need of such treatment an effective amount of a compound as claimed in any one of claims 1-336 or a pharmaceutical composition as claimed in claim 337.
  • 375. The method of claim 374, wherein the cancer is MDS.
  • 376. The method of claim 374, wherein the cancer is non-small lung cancer.
  • 377. The method of claim 374, wherein the cancer is acute lymphoblastic leukemia.
  • 378. The method of claim 374, wherein the cancer is LCH.
  • 379. The method of claim 374, wherein the cancer is multiple myeloma.
  • 380. The method of claim 374, wherein the cancer is promyelocytic leukemia.
  • 381. The method of claim 374, wherein the cancer is acute myeloid leukemia (AML).
  • 382. The method of claim 374, wherein the cancer is chronic myeloid leukemia (CML).
  • 383. The method of claim 374, wherein the cancer is gastric cancer.
  • 384. The method of claim 374, wherein the cancer is lung cancer metastasis.
  • 385. The method of any one of claims 338-384, further comprising administering a therapeutically effective amount of an anti-TNFα agent to the subject.
  • 386. The method of claim 385, wherein the NLRP3 antagonist is administered to the subject prior to administration of the anti-TNFα agent to the subject.
  • 387. The method of claim 385, wherein the anti-TNFα agent is administered to the subject prior to the administration of the NLRP3 antagonist to the subject.
  • 388. The method of claim 385, wherein the NLRP3 antagonist and the anti-TNFα agent are administered to the subject at substantially the same time.
  • 389. The method of claim 385, wherein the NLRP3 antagonist and the anti-TNFα agent are formulated together in a single dosage form.
  • 390. The compound of claim 1, wherein m=0, 1, or 2;n=0, 1, or 2;o=1 or 2;p=0, 1, 2, or 3; wherein the sum of o and p is from 1 to 4;whereinA is a pyrazolyl,B is a pyridinyl.
  • 391. The compound of claim 390, wherein A is pyrazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 or 2 R2.
  • 392. The compound of claim 390, wherein A is pyrazolyl optionally substituted with 1 R1 and optionally substituted with 1 or 2 R2.
  • 393. The compound of claim 390, wherein A is pyrazolyl optionally substituted with 1 or 2 R1 and optionally substituted with 1 R2.
  • 394. The compound of any one of claims 390 to 393, wherein B is a pyridin-4-yl.
  • 395. The compound of any one of claims 390 to 394, wherein B is
  • 396. The compoudn of any one of claims 390 to 395, wherein B is
PCT Information
Filing Document Filing Date Country Kind
PCT/US2019/060770 11/11/2019 WO
Provisional Applications (13)
Number Date Country
62760209 Nov 2018 US
62760244 Nov 2018 US
62760248 Nov 2018 US
62768811 Nov 2018 US
62769151 Nov 2018 US
62769165 Nov 2018 US
62795919 Jan 2019 US
62796356 Jan 2019 US
62796361 Jan 2019 US
62836575 Apr 2019 US
62836577 Apr 2019 US
62836585 Apr 2019 US
62895595 Sep 2019 US