COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY

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

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, C_1-10indicates 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 NH₂group.

The term “oxo” refers to O. By way of example, substitution of a CH₂a 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

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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-C₁₀aryl;

B is a 6-membered heteroaromatic ring containing 1-3 N atoms, or an N-oxide thereof; wherein at least one R⁶is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA;

R¹and R²are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NR⁸R⁹, C(O)R¹³, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, R¹⁵, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆alkyl sub stituent and each C₁-C₆alkoxy sub stituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃alkylene)C₆-C₁₀aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, and 5- to 10-membered heteroaryl are each optionally substituted with one or more substituents independently selected from halo, C₁-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form at least one monocyclic or bicyclic C₄-C₁₂carbocyclic 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, NR¹³S, S(O), and S(O)₂(in addition to the aforementioned nitrogen atom(s) attached to R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, hydroxy, oxo, CN, NO₂, COC₁—C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)2, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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;

or at least one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOH, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R¹⁰is C₁-C₆alkyl;

each of R⁸and R⁹at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³and CONR¹¹R¹²; wherein the C₁-C₆alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆alkoxy, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²;

or R⁸and R⁹taken 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-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆alkyl), and hydroxy;

R¹³is C₁-C₆alkyl, C₁-C₆haloalkyl, or —(Z¹—Z²)_a1—Z³;

each of R¹¹and R¹²at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, and —(Z¹—Z²)_a1—Z³;

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

each Z¹is independently C₁-C₆alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z²is independently a bond, NH, N(C₁-C₆alkyl), —O—, —S—, or 5-10 membered heteroarylene;

Z³is independently C₆-C₁₀aryl, C₂-C₆alkyenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, 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-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, oxo, N(C₁-C₆alkyl)2, NH₂, NH(C₁-C₆alkyl), and hydroxy;

R³is selected from hydrogen, cyano, hydroxy, CO₂C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkyl, and

embedded image

wherein the C₁-C₂alkylene group is optionally substituted with oxo;

R¹⁴is hydrogen, C₁-C₆alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶;

R¹⁵is —(Z⁴—Z⁵)_a2—Z⁶;

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

each Z⁴is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃alkyl)-;

provided that the Z⁴group directly attached to R¹or R²is —O— or —S—;

each Z⁵is independently C₁-C₆alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶is OH, OC₁-C₆alkyl, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂, NHC(O)(C₁-C₆alkyl), NHC(O)(C₁-C₆alkoxy), or an optionally substituted group selected from the group consisting of:

C₆-C₁₀aryl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, 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-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆alkyl), 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-C₁₀aryl;

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

wherein at least one R⁶is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA;

wherein the C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, R¹⁵, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy sub stituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃alkylene)C₆-C₁₀aryl, halo, NR⁸R⁹, or oxo;

R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁—C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents, independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R^9,═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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;

R¹⁰is C₁-C₆alkyl; each of R⁸and R⁹at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, C₂-C₆alkenyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³and CONR¹¹R¹²; wherein the C₁-C₆alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆alkoxy, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl, 3- to 7-membered heterocycloalkyl, or NR¹¹R¹²;

R¹³is C₁-C₆alkyl, C₁-C₆haloalkyl, or —(Z¹—Z²)_a1—Z³;

each of R¹¹and R¹²at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, and —(Z¹—Z²)_a1—Z³;

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

each Z¹is independently C₁-C₆alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z²is independently a bond, NH, N(C₁-C₆alkyl), —O—, —S—, or 5-10 membered heteroarylene;

R³is selected from hydrogen, cyano, hydroxy, CO₂C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkyl, and

embedded image

wherein the C₁-C₂alkylene group is optionally substituted with oxo;

R¹⁵is —(Z⁴—Z⁵)_a2—Z⁶;

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

each Z⁴is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃alkyl)-; provided that the Z⁴group directly attached to R¹or R²is —O— or —S—;

each Z⁵is independently C₁-C₆alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶is OH, OC₁-C₆alkyl, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂, NHC(O)(C₁-C₆alkyl), NHC(O)(C₁-C₆alkoxy), or an optionally substituted group selected from the group consisting of:

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

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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-C₁₀aryl;
B is a 6-membered heteroaromatic ring containing 1-3 N atoms, or an N-oxide thereof;
wherein
at least one R⁶is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA;
R¹and R²are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl,
wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;
- wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;
R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁—C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁—C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,
wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;
R¹⁰is C₁-C₆alkyl;
each of R⁸and R⁹at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³and CONR¹¹R¹²; wherein the C₁-C₆alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆alkoxy, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl or 3- to 7-membered heterocycloalkyl; or R⁸and R⁹taken 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;
R¹³is C₁-C₆alkyl, C₁-C₆haloalkyl, C₆-C₁₀aryl, or 5- to 10-membered heteroaryl; each of R¹¹and R¹²at each occurrence is independently selected from hydrogen and C₁-C₆alkyl; and
R³is selected from hydrogen, cyano, hydroxy, CO₂C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkyl, and

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wherein the C₁-C₂alkylene group is optionally substituted with oxo; R¹⁴is hydrogen, C₁-C₆alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, 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-C₁₀aryl,

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 R⁶is 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 R^6′ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-5;

at least one R^6″ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-1;

wherein the C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, R¹⁵, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃alkylene)C₆-C₁₀aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, and 5- to 10-membered heteroaryl, are each optionally substituted with one or more substituents independently selected from halo, C₁-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic ring or one monocyclic or bicyclic 5- to-12-membered heterocyclic ring wherein:

wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R^1′ and R^2′ are each independently selected from C₂-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, Cl, Br, I, CN, NO₂, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NR⁸R⁹, C(O)R¹³, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C₂-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, R¹⁵, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R^1′ or R^2′ C₃-C₇cycloalkyl or of the R^1′ or R^2′ 3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃alkylene)C₆-C₁₀aryl, halo, NR⁸R⁹, or oxo;

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, and 5- to 10-membered heteroaryl are optionally substituted with one or more substituents independently selected from halo, C₁-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R^1′ and R^2′ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹,

wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R^2″ is F or CH₃; or

when the compound of Formula AA is a compound of Formula AA-4, one pair of R¹and R^2″ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, hydroxy, oxo, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein the 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, and 5- to 10-membered heteroaryl, are optionally substituted with one or more substituents independently selected from halo, C₁-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOH, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R^6′ and R^7′ are each independently selected from unbranched C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, hydroxy, oxo, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R^6′ and R^7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkoxy that R^6′ or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6′ or R^7′ 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;

or one pair of R^6′ and on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOH, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R^6″ is selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, hydroxy, oxo, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R^6″ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6″ 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;

or one pair of R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOH, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R¹⁰is C₁-C₆alkyl;

R¹³is C₁-C₆alkyl, C₁-C₆haloalkyl, or —(Z¹—Z²)_a1—Z³; each of R¹¹and R²at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, and —(Z¹—Z²)_a1—Z³;

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

each Z¹is independently C₁-C₆alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z²is independently a bond, NH, N(C₁-C₆alkyl), —O—, —S—, or 5-10 membered heteroarylene;

Z³is independently C₆-C₁₀aryl, C₂-C₆alkyenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, 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-C₆alkyl, C₁-C₆haloalkyl, C alkoxy, oxo, N(C₁-C₆alkyl)₂, NH₂, NH(C₁-C₆alkyl), and hydroxy;

R³is selected from hydrogen, cyano, hydroxy, CO₂C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkyl, and

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wherein the C₁-C₂alkylene group is optionally substituted with oxo;

R¹⁵is —(Z⁴—Z⁵)_a2—Z⁶;

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

each Z⁴is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃alkyl)-;

provided that the Z⁴group directly attached to R¹or R²is —O— or —S—;

each Z⁵is independently C₁-C₆alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶is OH, OC₁-C₆alkyl, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂, NHC(O)(C₁-C₆alkyl), NHC(O)(C₁-C₆alkoxy), or an optionally substituted group selected from the group consisting of:

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-C₁₀aryl,

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 R⁶is 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 R^6′ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-5;

at least one R^6″ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-1;

wherein the C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, R¹⁵, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- to 7-membered heterocycloalkyl is further optionally independently substituted with one to three hydroxy, —O(C₀-C₃alkylene)C₆-C₁₀aryl, halo, NR⁸R⁹, or oxo;

wherein the C₂-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, R¹⁵, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOG-C₁₀aryl, OCO(5- to 10-membered heteroaryl), and OCO(3- to 7-membered heterocycloalkyl);

wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R^2″ is F or CH₃; or

R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

R^6′ and R^7′ are each independently selected from unbranched C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R^6′ and R^7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkoxy that R^6′ or R^7′ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6′ or R^7′ 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;

or one pair of R^6′ and R^7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOH, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R^6″ is selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R^6″ is optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and

R¹⁰is C₁-C₆alkyl;

R¹³is C₁-C₆alkyl, C₁-C₆haloalkyl, or —(Z¹—Z²)_a1—Z³; each of R¹¹and R¹²at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, and —(Z¹—Z²)_a1—Z³;

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

each Z¹is independently C₁-C₆alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy;

each Z²is independently a bond, NH, N(C₁-C₆alkyl), —O—, —S—, or 5-10 membered heteroarylene;

R³is selected from hydrogen, cyano, hydroxy, CO₂C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkyl, and

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wherein the C₁-C₂alkylene group is optionally substituted with oxo;

R¹⁵is —(Z⁴—Z⁵)_a2—Z⁶;

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

each Z⁴is independently selected from —O—, —S—, —NH—, and —N(C₁-C₃alkyl)-;

provided that the Z⁴group directly attached to R¹or R²is —O— or —S—;

each Z⁵is independently C₁-C₆alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxy; and

Z⁶is OH, OC₁-C₆alkyl, NH₂, NH(C₁-C₆alkyl), N(C₁-C₆alkyl)₂, NHC(O)(C₁-C₆alkyl), NHC(O)(C₁-C₆alkoxy), or an optionally substituted group selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

In another aspect, described 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-C₁₀aryl,
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 R⁶is 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 R^6′is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-5;
at least one R^6″ is ortho to the bond connecting the B ring to the NHC(O) group of Formula AA-1;
R¹and R²are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10- membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;

wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;
R^1′ and R^2′ are each independently selected from C₂-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, Cl, Br, I, CN, NO₂, COC₁-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10- membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH-(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl,
wherein the C₂-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl; wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R^1′ or R^2′ C₃-C₇cycloalkyl or of the R^1′ or R^2′ 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R^1′ and R^2′ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;
R^2″ is F or CH₃;
or, when the compound of Formula AA is a compound of Formula AA-4, one pair of R¹and R^2″ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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)₂and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;
R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,
wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;
R^6′ and R^7′ are each independently selected from unbranched C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,
wherein R^6′ and R^7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkoxy that R^6′ or R^7′ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6′ or R^7′ 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R^6′ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;
R^6″ is selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R^6″ is optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R^6″ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6″ 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;

R¹⁰is C₁-C₆alkyl;
each of R⁸and R⁹at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, C₁-C₆haloalkyl, (C═NR13)NR¹¹R¹², S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³and CONR¹¹R¹²; wherein the C₁-C₆alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆alkoxy, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl or 3- to 7-membered heterocycloalkyl; or R⁸and R⁹taken 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;
R¹³is C₁-C₆alkyl, C₁-C₆haloalkyl, C₆-C₁₀aryl, or 5- to 10-membered heteroaryl;
each of R¹¹and R¹²at each occurrence is independently selected from hydrogen and C₁-C₆alkyl; and
R³is selected from hydrogen, cyano, hydroxy, CO₂C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆alkyl, and

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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-C₁₀aryl

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-C₁₀aryl.

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 R¹or R²at 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 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is naphthyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is furanyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 R².

In some embodiments, A is furanyl optionally substituted with 1 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is thiophenyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is oxazolyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is thiazolyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is oxazolyl optionally substituted with 2 R¹or optionally substituted with 2 R².

In some embodiments, A is thiazolyl optionally substituted with 2 R¹or optionally substituted with 2 R².

In some embodiments, A is pyrazolyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is pyrazolyl optionally substituted with 1 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is pyrazolyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 R².

In some embodiments, A is pyridyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is indazolyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is imidazolyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is pyrrolyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is oxazolyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is furanyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is isoxazolyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is isothiazolyl optionally substituted with 1 or 2 R¹and 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 R¹and optionally substituted with 1 R².

In some embodiments, A is pyridinyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is pyridimidinyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is pyrazinyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is pyridazinyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is triazinyl optionally substituted with 1 or 2 R¹and optionally substituted with 1 or 2 R².

In some embodiments, A is phenyl substituted with 1 R¹and optionally substituted with 1 R².

In some embodiments, A is naphthyl substituted with 1 R¹and optionally substituted with 1 R².

In some embodiments, A is furanyl substituted with 1 R¹and optionally substituted with 1 R².

In some embodiments, A is thiophenyl substituted with 1 R¹and optionally substituted with 1 R².

In some embodiments, A is oxazolyl substituted with 1 R¹and optionally substituted with 1 R².

In some embodiments, A is thiazolyl substituted with 1 R¹and optionally substituted with 1 R².

In some embodiments, A is pyrazolyl substituted with 1 R¹and optionally substituted with 1 R².

In some embodiments, A is pyridyl substituted with 1 R¹and optionally substituted with 1 R².

In some embodiments, A is indazolyl optionally substituted with 1 R¹and optionally substituted with 1 R².

In some embodiments, A is phenyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is furanyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is thiophenyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is oxazolyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is thiazolyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is pyrazolyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is pyridyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is imidazolyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is pyrrolyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is oxazolyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is furanyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is isoxazolyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is isothiazolyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is triazolyl (e.g., 1,2,3-triazolyl or 1,2,4-triazolyl) substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is pyridimidinyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is pyrazinyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is pyridazinyl substituted with 1 R¹and substituted with 1 R².

In some embodiments, A is triazinyl substituted with 1 R¹and 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 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 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 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 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 R¹and R²are each independently selected from C₃alkyl, C₅-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, F, I, CN, NO₂, COC₂-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₂-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH-(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;
wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄or C₆-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA, when ring A is pyridyl, then R¹and R²are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₂-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH-(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;
- wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, 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-C₁₀aryl.

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-C₁₀aryl.

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 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 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 R¹and R²are each independently selected from C₃alkyl, C₅-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, F, I, CN, NO₂, COC₂-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₂-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH-(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁—C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;
- wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C4 or C₆-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-1, when ring A is pyridyl, then R¹and R²are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₂-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH-(C═NR¹³) NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;
- wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, 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 thiophen-2-yl.

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

In some embodiments, A″ is furan-2-yl substituted with 2 R^1′.

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

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

In some embodiments, A″ is thiophen-2-yl substituted with 2 R^1′.

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

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

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 thiophen-2-yl.

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

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 R^2″

The Groups R¹and R²

In some embodiments, R′, when present, is independently selected from the group consisting of C₁-C₆alkyl optionally substituted with one or more hydroxy, C₁-C₆alkyl optionally substituted with one or more halo, oxo, C₁-C₆alkoxy, or NR⁸R⁹; C₃-C₇cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆alkoxy, C₁-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl 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-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; C₁-C₆haloalkyl; C₁-C₆alkoxy; C₁-C₆haloalkoxy; halo; CN; CO—C₁-C₆alkyl; CO—C₆-C₁₀aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆alkyl; CO₂C₃-C₈cycloalkyl; OCOC₁-C₆alkyl; OCOC₆-C₁₀aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆alkyl; N(C₁-C₆alkyl)₂; CONR⁸R⁹; SF₅; S(O₂)NR¹¹R¹²; S(O)C₁-C₆alkyl; and S(O₂)C₁-C₆alkyl.

In some embodiments, R¹, when present, is independently selected from the group consisting of C₁-C₆alkyl 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, R¹is 2-hydroxy-2-propyl. For example, R¹is 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, R¹is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R¹is 2-hydroxy-2-propyl; or R¹is 1,2-dihydroxy-2-propyl).

In some embodiments, R², when present, is independently selected from the group consisting of C₁-C₆alkyl optionally substituted with one or more hydroxy, C₁-C₆alkyl optionally substituted with one or more halo, oxo, C₁-C₆alkoxy, or NR⁸R⁹; C₃-C₇cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆alkoxy, C₁-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl 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-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; C₁-C₆haloalkyl; C₁-C₆alkoxy; C₁-C₆haloalkoxy; halo; CN; CO—C₁-C₆alkyl; CO—C₆-C₁₀aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆alkyl; CO₂C₃-C₈cycloalkyl; OCOC₁-C₆alkyl; OCOC₆-C₁₀aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆alkyl; N(C₁-C₆alkyl)₂; CONR⁸R⁹; SF₅; S(O₂)NR¹¹R¹²; S(O)C₁-C₆alkyl; and S(O₂)C₁-C₆alkyl.

In some embodiments, R², when present, is independently selected from the group consisting of C₁-C₆alkyl 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 R¹when present is independently a C₁-C₆alkyl substituted with one or more hydroxy.

In certain of these embodiments, one or more R¹is 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 R¹when present is independently a C₁-C₆alkyl 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 R¹is 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 R¹when present is independently a C₁-C₆alkyl 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 R¹is 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 R¹is 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 R¹is independently selected from:

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In certain embodiments (e.g., a2>1), one or more R¹is

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In some embodiments, one or more R¹is independently C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹and further optionally substituted with one or more halo.

In certain of these embodiments, one or more R¹is 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 R¹is dimethylaminomethyl or methylaminomethyl).

In some embodiments, one or more R¹is C₁-C₆alkyl that is optionally substituted with one or more halo. In certain of these embodiments, one or more R¹is C₂-C₆alkyl that is optionally substituted with one or more halo. As non-limiting examples, R¹is ethyl or difluoromethyl.

In some embodiments, one or more R¹when present is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo and further optionally substituted with one or more C₁-C₆alkyl. For example, R¹is 5-methyl-oxazolidin-2-one-5-yl.

In certain of any of the foregoing embodiments of R¹, one or more R²is independently selected from C₁-C₆alkyl, C₁-C₆alkyl optionally substituted with one or more hydroxy, C₁-C₆alkyl optionally substituted with one or more C₁-C₆alkoxy, and halo.

In some embodiments, R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic ring (e.g., C₅or C₆carbocyclic 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 R¹and/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-C₆alkyl (e.g., methyl), C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy (e.g., isopropoxyl), OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹(e.g., amino, methylamino, or dimethylamino), ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₅-C₆carbocyclic 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

R¹and R²are 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, R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic C₄-C₁₂carbocyclic 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, R¹and R²are 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 R¹and/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, R¹and R²are different.

In some embodiments, R¹and R²are the same.

In some embodiments, R¹is para or meta to R².

In some embodiments, R¹is para or ortho to R².

In some embodiments, R¹is ortho or meta to R².

In some embodiments, R¹is para to R².

In some embodiments, R¹is meta to R².

In some embodiments, R¹is ortho to R².

The Groups R¹and R²when Formula AA is Formula AA-1

In some embodiments, R¹, when present, is independently selected from the group consisting of C₁-C₆alkyl optionally substituted with one or more hydroxy, C₁-C₆alkyl optionally substituted with one or more halo, oxo, C₁-C₆alkoxy, or NR⁸R⁹; C₃-C₇cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆alkoxy, C₁-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl 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-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; C₁-C₆haloalkyl; C₁-C₆alkoxy; C₁-C₆haloalkoxy; halo; CN; CO—C₁-C₆alkyl; CO—C₆-C₁₀aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆alkyl; CO₂C₃-C₈cycloalkyl; OCOC₁-C₆alkyl; OCOC₆-C₁₀aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆alkyl; N(C₁-C₆alkyl)₂; CONR⁸R⁹; SF₅; S(O₂)NR¹¹R¹²; S(O)C₁-C₆alkyl; and S(O₂)C₁-C₆alkyl.

In some embodiments, R¹, when present, is independently selected from the group consisting of C₁-C₆alkyl 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; 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 independently selected from the group consisting of C₁-C₆alkyl 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; 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 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 R¹when present is independently a C₁-C₆alkyl substituted with one or more hydroxy.

In some embodiments, one or more R¹when present is independently a C₁-C₆alkyl 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 R¹is 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 R¹when present is independently a C₁-C₆alkyl 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), one or more R¹is 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 R¹is independently selected from:

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In certain embodiments (e.g., a2 >1), one or more R¹is

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In some embodiments, one or more R¹is independently C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹and further optionally substituted with one or more halo.

In some embodiments, one or more R¹when 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, R¹is 5-methyl-oxazolidin-2-one-5-yl.

In some embodiments of the compound of Formula AA-1, R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl (e.g., methyl), C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy (e.g., isopropoxyl), OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹(e.g., amino, methylamino, or dimethylamino), ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-1, R¹and R²are 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

R¹and R²are on adjacent atoms, and taken together, independently form

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In some embodiments of the compound of Formula AA-1, R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form at least one bicyclic spirocyclic C₄-C₁₂carbocyclic 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, R¹and R²are 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 R¹and/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 R¹and R²when Formula AA is Formula AA-2

In some embodiments, R¹, when present, is independently selected from the group consisting of C₁-C₆alkyl 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; 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, when present, is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R¹is 2-hydroxy-2-propyl; or R¹is 1,2-dihydroxy-2-propyl).

In some embodiments, R², when present, is independently selected from the group consisting of C₁-C₆alkyl 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 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 R¹when present is independently a C₁-C₆alkyl substituted with one or more hydroxy.

In some embodiments, one or more R¹when present is independently a C₁-C₆alkyl 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 R¹is 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 R¹when present is independently a C₁-C₆alkyl 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), one or more R¹is 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 R¹is independently selected from:

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In certain embodiments (e.g., a2 >1), one or more R¹is

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In some embodiments, one or more R¹is independently C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹and further optionally substituted with one or more halo.

In some embodiments, one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, NR¹⁰CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

The Groups R^1′

and R^2′ when Formula AA is Formula AA-3

In some embodiments, R^1′, when present, is independently selected from the group consisting of C₂-C₆alkyl optionally substituted with one or more hydroxy, C₂-C₆alkyl optionally substituted with one or more halo, oxo, C₁-C₆alkoxy, or NR⁸R⁹; C₃-C₇cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆alkoxy, C₁-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl 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-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; C₁-C₆haloalkyl; C₁-C₆alkoxy; C₁-C₆haloalkoxy; Cl; Br; I; CN; CO—C₁-C₆alkyl; CO—C₆-C₁₀aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆alkyl; CO₂C₃-C₈cycloalkyl; OCOC₁-C₆alkyl; OCOC₆-C₁₀aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆alkyl; N(C₁-C₆alkyl)₂; CONR⁸R⁹; SF₅; S(O₂)NR¹¹R¹²; S(O)C₁-C₆alkyl; and S(O₂)C₁-C₆alkyl.

In some embodiments, R^1′, when present, is independently selected from the group consisting of C₂-C₆alkyl optionally substituted with one or more hydroxyl, or NR⁸R⁹.

In some embodiments, R^1′, 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, R^1′ is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl. For example, R^1′ is 2-hydroxy-2-propyl. As another example, R^1′ is 1,2-dihydroxy-2-propyl.

In some embodiments, R^1′, 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, R^1′ is 2-hydroxy-2-propyl.

In some embodiments, R²′, when present, is independently selected from the group consisting of C₂-C₆alkyl optionally substituted with one or more hydroxy, C₂-C₆alkyl optionally substituted with one or more halo, oxo, C₁-C₆alkoxy, or NR⁸R⁹; C₃-C₇cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆alkoxy, C₁-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl 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-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; C₁-C₆haloalkyl; C₁-C₆alkoxy; C₁-C₆haloalkoxy; Cl; Br; I; CN; CO—C₁-C₆alkyl; CO—C₆-C₁₀aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆alkyl; CO₂C₃-C₈cycloalkyl; OCOC₁-C₆alkyl; OCOC₆-C₁₀aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆alkyl; N(C₁-C₆alkyl)₂; CONR⁸R⁹; SF₅; S(O₂)NR¹¹R¹²; S(O)C₁-C₆alkyl; and S(O₂)C₁-C₆alkyl.

In some embodiments, R^2′, when present, is independently selected from the group consisting of C₂-C₆alkyl optionally substituted with one or more hydroxyl, halo, or NR⁸R⁹.

In some embodiments, R^2′, 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, R^2′ is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R^2′ is 2-hydroxy-2-propyl; or R^2′ is 1,2-dihydroxy-2-propyl).

In some embodiments, R^2′, 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, R^2′ is 2-hydroxy-2-propyl.

In some embodiments, one or more R^1′ when present is independently a C₂-C₆alkyl substituted with one or more hydroxy.

In certain of these embodiments, one or more R^1′ 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 R^1′ when present is independently a C₂-C₆alkyl 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 R^1′ 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 R^1′ when present is independently a C₂-C₆alkyl 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 R^1′ 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 R^1′ 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 R^1′ 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 R^1′ is independently C₂-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹and further optionally substituted with one or more halo.

In certain of these embodiments, one or more R^1′ 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 R^1′ is C₂-C₆alkyl that is optionally substituted with one or more halo. In certain of these embodiments, one or more R^1′ is C₂-C₆alkyl that is optionally substituted with one or more halo. As non-limiting examples, R^1′ is ethyl or difluoroethyl.

In some embodiments, one or more R^1′ when present is 3- to 7-membered heterocycloalkyl optionally substituted with one or more oxo and further optionally substituted with one or more C₁-C₆alkyl. For example, R^1′ is 5-methyl-oxazolidin-2-one-5-yl.

In certain of any of the foregoing embodiments of R^1′, one or more R^2′ is independently selected from C₂-C₆alkyl, C₂-C₆alkyl optionally substituted with one or more hydroxy, C₂-C₆alkyl optionally substituted with one or more C₁-C₆alkoxy, Br, Cl, and I.

In some embodiments, one pair of R^1′ and R^2′ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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)₂and wherein the carbocyclic ring or heterocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, halo, oxo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, R^1′ and R^2′ are the same.

In some embodiments, R^1′ and R^2′ are different.

In some embodiments, R^1′ is meta to R^2′.

In some embodiments, R^1′ is ortho to R^2′.

R¹and R^2″ when Formula AA is Formula AA-4

In some embodiments, R¹is independently selected from the group consisting of C₁-C₆alkyl optionally substituted with one or more hydroxy, C₁-C₆alkyl optionally substituted with one or more halo, oxo, C₁-C₆alkoxy, or NR⁸R⁹; C₃-C₇cycloalkyl optionally substituted with one or more hydroxy, halo, oxo, C₁-C₆alkoxy, C₁-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl 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-C₆alkyl, or NR⁸R⁹wherein the C₁-C₆alkoxy or C₁-C₆alkyl is further optionally substituted with one to three hydroxy, halo, NR⁸R⁹, or oxo; C₁-C₆haloalkyl; C₁-C₆alkoxy; C₁-C₆haloalkoxy; halo; CN; CO—C₁-C₆alkyl; CO—C₆-C₁₀aryl; CO(5- to 10-membered heteroaryl); CO₂C₁-C₆alkyl; CO₂C₃-C₈cycloalkyl; OCOC₁-C₆alkyl; OCOC₆-C₁₀aryl; OCO(5- to 10-membered heteroaryl); OCO(3- to 7-membered heterocycloalkyl); C₆-C₁₀aryl; 5- to 10-membered heteroaryl; NH₂; NHC₁-C₆alkyl; N(C₁-C₆alkyl)₂; CONR⁸R⁹; SF₅; S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl; and S(O₂)C₁-C₆alkyl.

In some embodiments, R¹is independently selected from the group consisting of C₁-C₆alkyl optionally substituted with one or more hydroxyl, halo, or NR⁸R⁹.

In some embodiments, R¹is 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, R¹is 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, R¹is 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, R¹is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R¹is 2-hydroxy-2-propyl; or R¹is 1,2-dihydroxy-2-propyl).

In some embodiments, R¹is 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, R¹is 2-hydroxy-2-propyl. n some embodiments of the compound of Formula AA-4, R¹is fluoro.

In some embodiments, R^2″ is fluoro.

In some embodiments, R^2″ is methyl.

In some embodiments, one or more R¹when present is independently a C₁-C₆alkyl substituted with one or more hydroxy.

In some embodiments, one or more R¹when present is independently a C₁-C₆alkyl 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 R¹is 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 R¹when present is independently a C₁-C₆alkyl 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), one or more R¹is 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 R¹is independently selected from:

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In certain embodiments (e.g., a2>1), one or more R¹is

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In some embodiments, one or more R¹is independently C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹and further optionally substituted with one or more halo.

In some embodiments, one or more R¹when 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, R¹is 5-methyl-oxazolidin-2-one-5-yl.

In some embodiments, one pair of R¹and R^2″ on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, R¹and R^2″ are the same.

In some embodiments, R¹and R^2″ are different.

In some embodiments, R¹is meta to R^2″.

In some embodiments, R¹is ortho to R^2″.

R¹and R^2″ when Formula AA is Formula AA-5

In some embodiments, R¹is independently selected from the group consisting of C₁-C₆alkyl optionally substituted with one or more hydroxyl, halo, or NR⁸R⁹.

In some embodiments, R¹is 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, R¹is 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl (e.g., R¹is 2-hydroxy-2-propyl; or R¹is 1,2-dihydroxy-2-propyl).

In some embodiments, R¹is selected from the group consisting of methyl; difluoromethyl; 2-hydroxy-2-propyl; hydroxymethyl; (dimethylamino)methyl; and fluoro. For example, R¹is 2-hydroxy-2-propyl. For example, R¹is fluoro.

In some embodiments, one or more R¹when present is independently a C₁-C₆alkyl substituted with one or more hydroxy.

In some embodiments, one or more R¹when present is independently a C₁-C₆alkyl 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 R¹is 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 R¹when present is independently a C₁-C₆alkyl 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), one or more R¹is 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 R¹is independently selected from:

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In certain embodiments (e.g., a2>1), one or more R¹is

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In some embodiments, one or more R¹is independently C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹and further optionally substituted with one or more halo.

In certain of any of the foregoing embodiments of one or more R²is independently selected from C₁-C₆alkyl, C₁-C₆alkyl optionally substituted with one or more hydroxy, C₁-C₆alkyl optionally substituted with one or more C₁-C₆alkoxy, and halo.

In some embodiments, R^2″ 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

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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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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 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

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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 i

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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 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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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 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, the substituted ring Bis

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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

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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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In some embodiments, the substituted ring Bis

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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 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, 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 Bis

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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

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In some embodiments, the substituted ring B is

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In some embodiments, the substituted ring B

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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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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

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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 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, R^6′, R^6″, R⁷, and R^7′

The Groups R⁶and R⁷

In some embodiments, R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

In some embodiments, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments, R⁶and R⁷are each independently selected from a C₂-C₆alkyl, C₂-C₆haloalkyl, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl; or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, R⁶and R⁷are each independently selected from a C₂-C₆alkyl, C₂-C₆haloalkyl, C₂-C₆alkoxy, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl.

In some embodiments, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl, halo, C₃-C₇cycloalkyl, and C₆-C₁₀aryl.

In some embodiments, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl and C₃-C₇cycloalkyl.

In some embodiments, each R⁶is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl. For example, each R⁶is isopropyl.

In some embodiments, each R⁷, when present, is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR²⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments, each R⁷, when present, is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl.

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 R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In certain embodiments (when one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹),the C₄-C₈carbocyclic ring is a C₅carbocyclic ring optionally substituted with one or more oxo, CH₃, or hydroxy. For example, the C₅carbocyclic ring is substituted with one CH₃. For example, the C₅carbocyclic ring is geminally substituted with two CH₃.

In certain embodiments (when one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹), the C₄-C₈carbocyclic ring is a C₇carbocyclic ring, wherein the C₇carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.

In some embodiments, each of R⁶and R⁷is independently selected from the group consisting of: C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl; or

one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

The Groups R^6″ and R⁷when Formula AA is Formula AA-1

wherein R^6″ is optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R^6″ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6″ 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;

In some embodiments of the compound of Formula AA-1, each R^6″ is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments of the compound of Formula AA-1, each R^6″ is independently selected from the group consisting of: C₁-C₆alkyl, halo, C₃-C₇cycloalkyl, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula AA-1, each R^6″ is independently selected from the group consisting of: C₁-C₆alkyl and C₃-C₇cycloalkyl.

In some embodiments of the compound of Formula AA-1, each R^6″ is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl. For example, each R^6″ 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-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments of the compound of Formula AA-1, R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

In some embodiments of the compound of Formula AA-1, each R⁷, when present, is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl.

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 R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-1, one pair of R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In certain embodiments of the compound of Formula AA-1 (when one pair of R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹), the C₄-C₈carbocyclic ring is a C₈carbocyclic ring optionally substituted with one or more oxo, CH₃, or hydroxy. For example, the C₈carbocyclic ring is substituted with one CH₃. For example, the C₈carbocyclic ring is geminally substituted with two CH₃.

In certain embodiments of the compound of Formula AA-1 (when one pair of R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹), the C₄-C₈carbocyclic ring is a C₇carbocyclic ring, wherein the C₇carbocyclic 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, R^6″ is selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R^6″ is optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R^6″ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6″ 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;

In some embodiments of the compound of Formula AA-1, R^6″ is selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₂-C₆alkoxy, C₁-C₆haloalkoxy, I, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R^6″ is optionally substituted with one or more substituents independently selected from hydroxy, Cl, Br, I, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R^6″ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6″ 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
R⁷is selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₂-C₆alkoxy, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-1, R^6″ is selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₁-C₆haloalkoxy, I, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R^6″ is optionally substituted with one or more substituents independently selected from hydroxy, Cl, Br, I, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R^6″ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6″ 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
R⁷is selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, OOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, each of R^6″ and R⁷is independently selected from the group consisting of: C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl; or

one pair of R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

The Groups R⁶and R⁷when Formula AA is Formula AA-2

In some embodiments of the compound of Formula AA-2, R⁶and R⁷are each independently selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₂-C₆alkoxy, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-2, R⁶and R⁷are each independently selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-2, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments of the compound of Formula AA-2, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl, halo, C₃-C₇cycloalkyl, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula AA-2, each R⁷is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula AA-2, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl and C₃-C₇cycloalkyl.

In some embodiments of the compound of Formula AA-2, each R⁶is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl. For example, each R⁶is isopropyl.

In some embodiments of the compound of Formula AA-2, each R⁷, when present, is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments of the compound of Formula AA-2, each R⁷is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula AA-2, each R⁷is 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 R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-2, one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In certain embodiments of the compound of Formula AA-2 (when one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.), the C₄-C₈carbocyclic ring is a C₅carbocyclic ring optionally substituted with one or more oxo, CH₃, or hydroxy. For example, the C₅carbocyclic ring is substituted with one CH₃. For example, the C₅carbocyclic ring is geminally substituted with two CH₃.

In certain embodiments of the compound of Formula AA-2 (when one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹), the C₇carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.

In some embodiments, each of R⁶and R⁷is independently selected from the group consisting of: C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl; or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

The Groups R⁶and R⁷when Formula AA is Formula AA-3

In some embodiments of the compound of Formula AA-3, R⁶and R⁷are each independently selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₂-C₆alkoxy, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-3, R⁶and R⁷are each independently selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-3, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments of the compound of Formula AA-3, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl, halo, C₃-C₇cycloalkyl, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula AA-3, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl and C₃-C₇cycloalkyl.

In some embodiments of the compound of Formula AA-3, each R⁶is independently selected from the group consisting of: methyl, isopropyl, cyclopropyl, fluoro, and phenyl. For example, each R⁶is isopropyl.

In some embodiments of the compound of Formula AA-3, each R⁷, when present, is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments of the compound of Formula AA-3, each R⁷, when present, is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl.

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 R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-3, one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In certain embodiments of the compound of Formula AA-3 (when one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹), the C₄-C₈carbocyclic ring is a C₅carbocyclic ring optionally substituted with one or more oxo, CH₃, or hydroxy. For example, the C₅carbocyclic ring is substituted with one CH₃. For example, the C₅carbocyclic ring is geminally substituted with two CH₃.

In certain embodiments of the compound of Formula AA-3 (when one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹)the C₄-C₈carbocyclic ring is a C₇carbocyclic ring, wherein the C₇carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.

In some embodiments, each of R⁶and R⁷is independently selected from the group consisting of: C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl; or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

The Groups R⁶and R⁷when Formula AA is Formula AA-4

In some embodiments of the compound of Formula AA-4, R⁶and IC are each independently selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₂-C₆alkoxy, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-4, R⁶and R⁷are each independently selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;

or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-4, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments of the compound of Formula AA-4, each R⁶is independently selected from the group consisting of: C₁-C₆alkyl, halo, C₃-C₇cycloalkyl, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula AA-4, each R⁶is 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-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments of the compound of Formula AA-4, each R⁷, when present, is independently selected from the group consisting of: C₁-C₆alkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl.

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 R⁶and R⁷is independently selected from the group consisting of: C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl; or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

The Groups R^6′ and R^7′ when Formula AA is Formula AA-5

In some embodiments of the compound of Formula AA-5, R^6′ and R^7′ are each independently selected from unbranched C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R^6′ and R^7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkoxy that R^6′ or R^7′ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6′ or R^7′ 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;

or one pair of R^6′ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOH, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-5, R^6′ and R^7′ are each independently selected from unbranched C₂-C₆alkyl, C₂-C₆haloalkyl, C₂-C₆alkoxy, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

wherein R^6′ and R^7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkoxy that R^6′ or R^7′ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6′ or R^7′ 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R^6′ and R^7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-5, R^6′ and R^7′ are each independently selected from unbranched C₂-C₆alkyl, C₂-C₆haloalkyl, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R^6′ and R^7′ are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkoxy that R^6′ or R^7′ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6′ or R^7′ 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R^6′ and R^7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-5, each R^6′ is independently selected from the group consisting of: unbranched C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the unbranched C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments of the compound of Formula AA-5, each R^6′ is independently selected from the group consisting of: unbranched C₁-C₆alkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula AA-5, each R^6′ is independently selected from the group consisting of: unbranched C₁-C₆alkyl and C₃-C₇cycloalkyl.

In some embodiments of the compound of Formula AA-5, each R^6′ is independently selected from the group consisting of: methyl, cyclopropyl, fluoro, and phenyl.

In some embodiments of the compound of Formula AA-5, each R^7′ is independently selected from the group consisting of: unbranched C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, CO—C₁-C₆alkyl; CONR⁸R⁹, and 4- to 6-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 4- to 6-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments of the compound of Formula AA-5, each R⁷is independently selected from the group consisting of: unbranched C₁-C₆alkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl.

In some embodiments of the compound of Formula AA-5, each R^7′ 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 R^6′ and R^7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-5, one pair of R^6′ and R^7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, hydroxymethyl, halo, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In certain embodiments of the compound of Formula AA-5 (when one pair of R^6′ and R^7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹), the C₄-C₈carbocyclic ring is a C₅carbocyclic ring optionally substituted with one or more oxo, CH₃, or hydroxy. For example, the C₅carbocyclic ring is substituted with one CH₃. For example, the C₅carbocyclic ring is geminally substituted with two CH₃.

In certain embodiments of the compound of Formula AA-5 (when one pair of R^6′ and R^7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹), the C₄-C₈carbocyclic ring is a C₇carbocyclic ring, wherein the C₇carbocyclic ring is a bicyclic spirocycle, wherein the bicyclic spirocycle comprises a 5-membered ring and a 3-membered ring.

In some embodiments, each of R^6′ and R^7′ is independently selected from the group consisting of: C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, halo, and C₆-C₁₀aryl; or

one pair of R^6′ and R^7′ on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

The group R³

In some embodiments, R³is selected from hydrogen, C₁-C₆alkyl, and

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wherein the C₁-C₂alkylene group is optionally substituted with oxo.

In some embodiments, R³is hydrogen.

In some embodiments, R³is other than hydrogen.

In some embodiments, R³is cyano.

In some embodiments, R³is hydroxy.

In some embodiments, R³is C₁-C₆alkoxy.

In some embodiments, R³is C₁-C₆alkyl.

In some embodiments, R³is methyl.

In some embodiments, R³is

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wherein the C₁-C₂alkylene group is optionally substituted with oxo.

In some embodiments, R³is —CH₂R¹⁴.

In some embodiments, R³is —C(O)R¹⁴. In certain of these embodiments, R³is CHO. In certain other of these embodiments, R³is C(O)C₁-C₆alkyl.

In some embodiments, R³is —CH₂CH₂R¹⁴.

In some embodiments, R³is —CHR¹⁴CH₃.

In some embodiments, R³is —CH₂C(O)R¹⁴.

In some embodiments, R³is —C(O)CH₂R¹⁴.

In some embodiments, R³is CO₂C₁-C₆alkyl (e.g., CO₂t-Bu).

The group R¹⁴

In some embodiments, R¹⁴is hydrogen, C₁-C₆alkyl, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶.

In some embodiments, R¹⁴is hydrogen or C₁-C₆alkyl.

In some embodiments, R¹⁴is hydrogen, 5- to 10-membered monocyclic or bicyclic heteroaryl or C₆-C₁₀monocyclic or bicyclic aryl, wherein each C₁-C₆alkyl, aryl or heteroaryl is optionally independently substituted with 1 or 2 R⁶.

In some embodiments, R¹⁴is hydrogen.

In some embodiments, R¹⁴is C₁-C₆alkyl.

In some embodiments, R¹⁴is methyl.

In some embodiments, R^1′ is 5- to 10-membered monocyclic or bicyclic heteroaryl optionally independently substituted with 1 or 2 R⁶.

In some embodiments, R^1′ is C₆-C₁₀monocyclic 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, R¹⁰is C₁-C₆alkyl.

In some embodiments, R¹⁰is methyl.

In some embodiments, R¹⁰is ethyl.

The groups R⁸and R⁹

In some embodiments, each of R⁸and R⁹at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, (C═NR¹³)NR¹¹R¹², S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², COR¹³, CO₂R¹³and CONR¹¹R¹²; wherein the C₁-C₆alkyl is optionally substituted with one or more hydroxy, halo, C₁-C₆alkoxy, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₇cycloalkyl or 3- to 7-membered heterocycloalkyl; or R⁸and R⁹taken 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 R⁸and R⁹at each occurrence is hydrogen,

In some embodiments, each R⁸at each occurrence is hydrogen and each R⁹at each occurrence is C₁-C₆alkyl.

In some embodiments, each R⁸at each occurrence is hydrogen and each R⁹at each occurrence is methyl.

In some embodiments, each R⁸at each occurrence is hydrogen and each R⁹at each occurrence is ethyl.

In some embodiments, each of R⁸and R⁹at each occurrence is methyl.

In some embodiments, each of R⁸and R⁹at each occurrence is ethyl.

In some embodiments, R⁸and R⁹taken together with the nitrogen they are attached to form a 3-membered ring.

In some embodiments, R⁸and R⁹taken together with the nitrogen they are attached to form a 4-membered ring.

In some embodiments, R⁸and R⁹taken together with the nitrogen they are attached to form a 5-membered ring.

In some embodiments, R⁸and R⁹taken 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, R⁸and R⁹taken 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, R⁸and R⁹taken together with the nitrogen they are attached to form a 7-membered ring.

In some embodiments, one of R⁸and R⁹is C(O)R¹³; R¹³is —(Z¹—Z²)_a1—Z₃; and al is 0.

In certain of these embodiments, the other one of R⁸and R⁹is hydrogen.

As a non-limiting example of the foregoing embodiments, NR⁸R⁹is selected from the group consisting of: NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In some embodiments, one of R⁸and R⁹is C(O)R¹³; R¹³is C₁-C₆alkyl.

In certain embodiments, NR⁸R⁹is selected from the group consisting of: NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, and NH(C═NR¹³)NR¹¹R¹².

The group R¹³

In some embodiments, R¹³is C₁-C₆alkyl.

In some embodiments, R¹³is methyl.

In some embodiments, R¹³is ethyl.

In some embodiments, R¹³is C₆-C₁₀aryl.

In some embodiments, R¹³is phenyl.

In some embodiments, R¹³is 5- to 10-membered heteroaryl.

In some embodiments, R¹³is —(Z¹—Z²)_a1—Z³.

In certain of these embodiments, a1 is 0. In certain embodiments, Z³is C₆-C₁₀aryl or 5- to 10-membered heteroaryl.

In some embodiments, R¹³is C₆-C₁₀aryl.

In some embodiments, R¹³is phenyl.

In some embodiments, R¹³is 5- to 10-membered heteroaryl.

In some embodiments, C(O)R¹³is selected from COC₁-C₆alkyl, CO—C₆-C₁₀aryl, and CO(5- to 10-membered heteroaryl).

The groups R¹¹and R¹²

In some embodiments, each of R¹¹and R¹²at each occurrence is independently selected from hydrogen and C₁-C₆alkyl.

In some embodiments, each of R¹¹and R¹²at each occurrence is hydrogen,

In some embodiments, each R¹¹at each occurrence is hydrogen and each R¹²at each occurrence is C₁-C₆alkyl.

In some embodiments, each R¹¹at each occurrence is hydrogen and each 10²at each occurrence is methyl.

In some embodiments, each R¹¹at each occurrence is hydrogen and each R¹²at each occurrence is ethyl.

In some embodiments, each of R¹¹and R¹²at each occurrence is methyl.

In some embodiments, each of R¹¹and R¹²at each occurrence is ethyl.

The Group R¹⁵

In some embodiments, R¹⁵is —(Z⁴—Z⁵)_a2—Z⁶.

In certain embodiments, a2 is 1-5.

In certain embodiments, the Z⁴group directly attached to R¹or R²is —O—.

In certain embodiments, each Z⁴is independently —O— or —NH—, provided that the Z⁴group directly attached to R¹or R²is —O—.

In certain embodiments, each Z⁴is —O—.

In certain embodiments, each Z⁵is independently C₂-C₆alkylene optionally substituted with one or more substituents independently selected from oxo, halo, and hydroxyl. In certain these embodiments, each Z⁵is independently C₂-C₄(e.g., C₂-C₃(e.g., C₂or C₃)) alkylene.

In certain embodiments, Z⁶is OH.

In certain embodiments, Z⁶is NHC(O)(C₁-C₆alkoxy).

In certain embodiments, Z⁶is C₆-C₁₀aryl.

In certain embodiments, Z⁶is C₁-C₆alkoxy.

In certain embodiments of R¹⁵, a2=1; and Z⁴is 0. In certain of these embodiments, Z⁵is C₂-C₄(e.g., C₂-C₃(e.g., C₂or C₃)) alkylene. In certain of the foregoing embodiments, Z⁶is selected from OH, NHC(O)(C₁-C₆alkoxy), and C₁-C₆alkoxy.

As non-limiting examples, R¹⁵is selected from:

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In certain embodiments of R¹⁵, a2=1; and each Z⁴is O. In certain of these embodiments, Z⁵is C₂-C₄(e.g., C₂-C₃(e.g., C₂or C₃)) alkylene. In certain of the foregoing embodiments, Z⁶is selected from OH, NHC(O)(C₁-C₆alkoxy), and C₁-C₆alkoxy. In certain other of the foregoing embodiments, Z⁶is C₆-C₁₀aryl (e.g., R¹⁵is

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In certain embodiments of R¹⁵, a2≥2 (e.g., a2 is 3 or 4); each Z⁴is O; and each Z⁵is ethylene. In certain of these embodiments Z⁶is OH. In certain other embodiments, Z⁶is NHC(O)(C₁-C₆alkoxy) (e.g., Boc). As a non-limiting example, R¹⁵is:

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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), R¹is 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 R²is halo (e.g., F). In certain other embodiments, n is 1; and R²is C₁-C₆alkyl 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), R¹is C₁-C₆alkyl 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 R²is halo (e.g., F). In certain other embodiments, n is 1; and R²is C₁-C₆alkyl 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, R¹is C₁-C₆alkyl optionally substituted with one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R¹is

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In certain of the foregoing embodiments, n is 1; and R²is C₁-C₆alkyl 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, R¹is 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, R²is 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; R¹is C₁-C₆alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); and R², when present, is C₁-C₆alkyl 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 R¹is C₁-C₆alkyl optionally substituted with 1-3 halo (e.g., fluoro).

In some embodiments, A is phenyl; m is 1; n is 0 or 1; and R¹is C₁-C₆alkyl 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 R¹is C₁-C₆alkyl 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-C₆alkyl (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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R⁷is selected from C₁-C₆alkyl (e.g., methyl, ethyl, or isopropyl), C₆-C₁₀aryl (e.g., phenyl), and C₃-C₁₀cycloalkyl (e.g., cyclopropyl); p is 0, 1, or 2; q is 0, 1, or 2; wherein each Y is independently selected from C₁-C₆alkyl (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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In some embodiments, the substituted ring B is

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In some embodiments, the substituted ring B is

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each R⁶is independently selected from C₁-C₆alkyl (e.g., isopropyl); each R⁷is 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 R⁶is independently selected from C₁-C₆alkyl (e.g., isopropyl); each R⁷is 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; R¹is C₁-C₆alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); R², when present, is C₁-C₆alkyl optionally substituted with hydroxyl (e.g., methyl, hydroxymethyl, or hydroxyethyl); the substituted ring B is

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In some embodiments, A is pyrazolyl (e.g., 3-pyrazolyl); m is 1; n is 0; R¹is C₁-C₆alkyl optionally substituted with 1-3 halo (e.g., fluoro); the substituted ring B is

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In some embodiments, A is phenyl; m is 1; n is 0 or 1; and R¹is C₁-C₆alkyl optionally substituted with NR⁸R⁹(e.g., dimethylamino); R², when present, is halo (e.g., fluoro); the substituted ring B is

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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; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is a pyrazolyl; m is 1; n is 1; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is an imidazolyl; m is 1; n is 1; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is a thiophenyl; m is 1; n is 1; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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wherein R^xis selected from the group consisting of H and C₁-C₆alkyl (e.g., methyl); Z¹is selected from the group consisting of O, NH, and —CH₂— optionally substituted with 1-2 R²⁰; Z²is selected from the group consisting of NH and —CH₂— optionally substituted with 1-2 R²⁰; Z³is 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; R²⁰is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C₁-C₆alkyl (e.g., methyl or ethyl) optionally substituted with one R²¹, C₁-C₆alkoxy (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 R²⁰on the same atom, taken together with the atom connecting them, independently forms a monocyclic C₃-C₄carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O)₂Ph; R²¹is selected from the group consisting of halo (e.g., fluoro), NR⁸R⁹, C₂-C₆alkynyl (e.g., ethynyl), and C₁-C₆alkoxy (e.g., methoxy); R⁸and R⁹at each occurrence is independently selected from hydrogen, C₁-C₆alkyl (e.g., methyl or ethyl), COR¹³, and CO₂R¹³; R¹³is selected from the group consisting of: C₁-C₆alkyl (e.g., methyl or t-butyl) and C₁-C₆haloalkyl (e.g., trifluoromethyl).

In some embodiments, the optionally substituted ring A is

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wherein Z⁴is selected from the group consisting of —CH₂—, —C(O)—, and NH; Z⁵is selected from the group consisting of O, NH, N—CH₃, and —CH₂—.

In some embodiments, the substituted ring B is

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R⁶is selected from C₁-C₆alkyl (e.g., methyl, ethyl, or isopropyl) and C₃-C₁₀cycloalkyl (e.g., cyclopropyl); R⁷is selected from C₁-C₆alkyl (e.g., methyl, ethyl, or isopropyl), C₁-C₆haloalkyl (e.g., trifluoromethyl) and C₃-C₁₀cycloalkyl (e.g., cyclopropyl or cyclobutyl); or R⁶and R⁷, taken together with the atoms connecting them, independently form a C₅carbocyclic ring optionally substituted with one or more C₁-C₆alkyl (e.g., methyl); q is 0, 1, or 2; each Y is independently selected from C₁-C₆alkyl (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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In some embodiments, the optionally substituted ring A is

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the substituted ring B is

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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;

R¹is C₁-C₆(e.g., C₂-C₄) alkyl optionally substituted with one or more substituents each independently selected from hydroxy and halo;

R²is halo or C₁-C₆alkyl optionally substituted with one or more hydroxy;

the substituted ring B is

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In certain embodiments of [4A], ring A is thiazolyl (e.g., thiazol-5-yl). In certain of these embodiments, R¹is 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, R¹is

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In certain of the foregoing embodiments, n is 1; and R²is C₁-C₆alkyl 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, R¹is C₁-C₆alkyl 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, R²is 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;

R¹is C₁-C₆(e.g., C₂-C₄) alkyl optionally substituted with one or more substituents each independently selected from hydroxy and halo;

R²is halo or C₁-C₆alkyl optionally substituted with one or more hydroxy; and

the substituted ring B is

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In certain embodiments of [4B], ring A is thiazolyl (e.g., thiazol-5-yl). In certain of these embodiments, R¹is 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, R¹is

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In certain of the foregoing embodiments, n is 1; and R²is C₁-C₆alkyl 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, R¹is C₁-C₆alkyl 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, R²is 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 R⁷is selected from C₁-C₆alkyl (e.g., methyl, ethyl, or isopropyl), and C₃-C₁₀cycloalkyl (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 R²is halo (e.g., F). In certain other embodiments, n is 1; and R²is C₁-C₆alkyl 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), R¹is C₁-C₆alkyl 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 R²is halo (e.g., F). In certain other embodiments, n is 1; and R²is C₁-C₆alkyl 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, R¹is C₁-C₆alkyl optionally substituted with one or more hydroxy (e.g., 1, 2, or 3 (e.g., 1 or 2)). For example, R¹is

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In certain of the foregoing embodiments, n is 1; and R²is C₁-C₆alkyl 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, R¹is 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, R²is 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; R¹is C₁-C₆alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); and R², when present, is C₁-C₆alkyl 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 R¹is C₁-C₆alkyl 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 R¹is C₁-C₆alkyl 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; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, 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; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, 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; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is

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wherein R¹is selected from the group consisting of H and C₁-C₆alkyl (e.g., methyl); Z¹is selected from the group consisting of O, NH, and —CH₂— optionally substituted with 1-2 R²⁰; Z²is selected from the group consisting of NH and —CH₂— optionally substituted with 1-2 R²⁰; Z³is 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; R²⁰is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C₁-C₆alkyl (e.g., methyl or ethyl) optionally substituted with one R²¹, C₁-C₆alkoxy (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 R²⁰on the same atom, taken together with the atom connecting them, independently forms a monocyclic C₃-C₄carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 O atom optionally substituted with OS(O)₂Ph; R²¹is selected from the group consisting of halo (e.g., fluoro), NR⁸R⁹, C₂-C₆alkynyl (e.g., ethynyl), and C₁-C₆alkoxy (e.g., methoxy); R⁸and R⁹at each occurrence is independently selected from hydrogen, C₁-C₆alkyl (e.g., methyl or ethyl), COR¹³, and CO₂R¹³; R¹³is selected from the group consisting of: C₁-C₆alkyl (e.g., methyl or t-butyl) and C₁-C₆haloalkyl (e.g., trifluoromethyl).

In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is

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wherein Z⁴is selected from the group consisting of —CH₂—, —C(O)—, and NH; Z⁵is 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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In some embodiments of the compound of Formula AA-1, the substituted ring B is

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In some embodiments of the compound of Formula AA-1, the substituted ring B is

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each R^6″ is independently selected from C₁-C₆alkyl (e.g., isopropyl); each R⁷is 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 R^6″ is independently selected from C₁-C₆alkyl (e.g., isopropyl); each R⁷is 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; R¹is C₁-C₆alkyl optionally substituted with hydroxy (e.g., 2-hydroxy-2-propyl); R², when present, is C₁-C₆alkyl optionally substituted with hydroxyl (e.g., methyl, hydroxymethyl, or hydroxyethyl); the substituted ring B is

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In some embodiments of the compound of Formula AA-1, A′ is pyrazolyl (e.g., 3-pyrazolyl); m is 1; n is 0; R¹is C₁-C₆alkyl optionally substituted with 1-3 halo (e.g., fluoro); the substituted ring B is

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In some embodiments of the compound of Formula AA-1, A′ is phenyl; m is 1; n is 0 or 1; R¹is C₁-C₆alkyl 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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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; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═N¹⁰, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, 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; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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 R¹and/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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, NR¹⁰CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, 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; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is

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In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is

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wherein Z⁴is selected from the group consisting of —CH₂—, —C(O)—, and NH; Z⁵is 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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In some embodiments of the compound of Formula AA-1, the optionally substituted ring A′ is

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wherein R¹is selected from the group consisting of H and C₁-C₆alkyl (e.g., methyl); Z¹is selected from the group consisting of O, NH, and —CH₂— optionally substituted with 1-2 R²⁰; Z²is selected from the group consisting of NH and —CH₂— optionally substituted with 1-2 R²⁰; Z³is 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; R²⁰is selected from the group consisting of hydroxy, halo (e.g., fluoro), oxo, C₁-C₆alkyl (e.g., methyl or ethyl) optionally substituted with one R²¹, C₁-C₆alkoxy (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 R²⁰on the same atom, taken together with the atom connecting them, independently forms a monocyclic C₃-C₄carbocyclic ring or a monocyclic 3- to 4-membered heterocyclic ring containing 1 0 atom optionally substituted with OS(O)₂Ph; R²¹is selected from the group consisting of halo (e.g., fluoro), NR⁸R⁹, C₂-C₆alkynyl (e.g., ethynyl), and C₁-C₆alkoxy (e.g., methoxy); R⁸and R⁹at each occurrence is independently selected from hydrogen, C₁-C₆alkyl (e.g., methyl or ethyl), COR¹³, and CO₂R¹³; Rⁿis selected from the group consisting of: C₁-C₆alkyl (e.g., methyl or t-butyl) and C₁-C₆haloalkyl (e.g., trifluoromethyl); and

the substituted ring B is

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R⁶is selected from C₁-C₆alkyl (e.g., methyl); R⁷is selected from C₁-C₆alkyl (e.g., isopropyl) and C₃-C₁₀cycloalkyl (e.g., cyclopropyl or cyclobutyl); or R⁶and R⁷, taken together with the atoms connecting them, independently form a C₅carbocyclic ring optionally substituted with one or more C₁-C₆alkyl (e.g., methyl); q is 0, 1, or 2; each Y is independently selected from C₁-C₆alkyl (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;

R¹is C₁-C₆(e.g., C₂-C₄) alkyl optionally substituted with one or more substituents each independently selected from hydroxy and halo;

R²is halo or C₁-C₆alkyl optionally substituted with one or more hydroxy; the substituted ring B is

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In certain embodiments of [4C], ring A′ is thiazolyl (e.g., thiazol-5-yl). In certain of these embodiments, R¹is 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, R¹is

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In certain of the foregoing embodiments, n is 1; and R²is C₁-C₆alkyl 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, R¹is C₁-C₆alkyl 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, R²is 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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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;

R¹is C₁-C₆(e.g., C₂-C₄) alkyl optionally substituted with one or more substituents each independently selected from hydroxy and halo;

R²is halo or C₁-C₆alkyl optionally substituted with one or more hydroxy; and

the substituted ring B is

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In certain embodiments of [4D], ring A′ is thiazolyl (e.g., thiazol-5-yl). In certain of these embodiments, R¹is 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, R¹is

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In certain of the foregoing embodiments, n is 1; and R²is C₁-C₆alkyl 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, R¹is C₁-C₆alkyl 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, R²is 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 R⁷is selected from C₁-C₆alkyl (e.g., methyl, ethyl, or isopropyl), and C₃-C₁₀cycloalkyl (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 R¹is C₁-C₆alkyl 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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In some embodiments of the compound of Formula AA-2, the substituted ring B is

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In some embodiments of the compound of Formula AA-2, the substituted ring B is

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each R⁶is independently selected from C₁-C₆alkyl (e.g., isopropyl); each R⁷is 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 R⁶is independently selected from C₁-C₆alkyl (e.g., isopropyl); each R⁷is 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; R¹is C₁-C₆alkyl 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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In some embodiments of the compound of Formula AA-3, A″ is thiophenyl (e.g., 2-thiophenyl); m″ is 1; n″ is 1; R^1′ is C₂-C₆alkyl optionally substituted with hydroxyl or oxo (e.g., 2-hydroxy-2-propyl); and R^2′ is C₂-C₆alkyl 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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In some embodiments of the compound of Formula AA-3, the substituted ring B is

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In some embodiments of the compound of Formula AA-3, the substituted ring B is

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each R⁶is independently selected from C₁-C₆alkyl (e.g., isopropyl); each R⁷is 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 R⁶is independently selected from C₁-C₆alkyl (e.g., isopropyl); each R⁷is 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; R^1′ is C₂-C₆alkyl optionally substituted with hydroxyl or oxo (e.g., 2-hydroxy-2-propyl); R^2′ is C₂-C₆alkyl optionally substituted with hydroxyl or oxo (e.g., 2-hydroxy-2-propyl); the substituted ring B is

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In some embodiments of the compound of Formula AA-3, the optionally substituted ring A″ is a thiophenyl; m is 1; n is 1; R¹and R²are on adjacent atoms, and taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-3, the substituted ring B is

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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); R¹is C₁-C₆alkyl optionally substituted with hydroxyl or oxo (e.g., methyl or 2-hydroxy-2-propyl); and R^2″ is methyl.

In some embodiments of the compound of Formula AA-4, the substituted ring B′ is

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each R⁶is independently selected from C₁-C₆alkyl (e.g., isopropyl); each R⁷is independently selected from halo (e.g., fluoro); p is 0 or 1.

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each R⁶is independently selected from C₁-C₆alkyl (e.g., isopropyl); each R⁷is 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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In some embodiments of the compound of Formula AA-5, the substituted ring B″ is

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R^7′ is selected from unbranched C₁-C₆alkyl (e.g., methyl or ethyl), C₆-C₁₀aryl (e.g., phenyl), and C₃-C₁₀cycloalkyl (e.g., cyclopropyl); p is 0, 1, or 2; q is 0, 1, or 2; wherein each Y is independently selected from C₁-C₆alkyl (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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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, NR¹⁰CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, NR¹⁰CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, NR¹⁰CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

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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one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹,═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, NR¹⁰CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments, the optionally substituted ring A is

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one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA, when ring A is phenyl, then R¹and R²are each independently selected from C₃-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, F, I, CN, NO₂, COC₁-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₂-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH-(C═NR¹³) NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;
- wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄or C₆-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA, when ring A is pyridyl, then R¹and R²are each independently selected from C₃-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, F, I, CN, NO₂, COC₁-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₂-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH-(C═NR¹³) NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, and 3- to 7-membered heterocycloalkyl,

wherein the C₃-C₆alkyl, C₁-C₆haloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;
- wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄or C₆-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA, when ring A is phenyl, then R¹and R²are each independently selected from C₃alkyl, C₅-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, F, I, CN, NO₂, COC₂-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₂-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;
- wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄or C₆-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹;
when ring A is pyridyl, then R¹and R²are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₂-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl,
wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;
- wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹; and R⁶and R⁷are each independently selected from a C₂-C₆alkyl, C₂-C₆haloalkyl, C₂-C₆alkoxy, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,
wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of the compound of Formula AA-1, when ring A′ is phenyl, then R¹and R²are each independently selected from C₃alkyl, C₅-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, F, I, CN, NO₂, COC₂-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₂-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH-(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl,

wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;

1wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄or C₆-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹; when ring A is pyridyl, then R¹and R²are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO—C₆-C₁₀aryl, CO(5- to 10-membered heteroaryl), CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₂-C₆alkyl, N(C₁-C₆alkyl)₂, NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, NHCOOC₁-C₆alkyl, NH—(C═NR¹³)NR¹¹R¹², CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, S(O₂)NR¹¹R¹², S(O)C₁-C₆alkyl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl, wherein the C₁-C₆alkyl, C₁-C₆haloalkyl, C₃-C₇cycloalkyl, and 3- to 7-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 5-membered heterocycloalkyl, 5-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl;
- wherein each C₁-C₆alkyl substituent and each C₁-C₆alkoxy substituent of the R¹or R²C₃-C₇cycloalkyl or of the R¹or R²3- 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R¹and R²on adjacent atoms, taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic 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-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy, OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, OS(O₂)C₆-C₁₀aryl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo, C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹; R^6″ is selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₁-C₆haloalkoxy, I, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R^6″ is optionally substituted with one or more substituents independently selected from hydroxy, Cl, Br, I, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R^6″ is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R^6″ 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
R⁷is selected from C₂-C₆alkyl, C₂-C₆haloalkyl, C₁-C₆haloalkoxy, I, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl, wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from hydroxy, halo, CN, oxo, C₁-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 3- to 7-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(3- to 7-membered heterocycloalkyl), NHCOC₂-C₆alkynyl, C₆-C₁₀aryloxy, and S(O₂)C₁-C₆alkyl; and wherein the C₁-C₆alkyl or C₁-C₆alkoxy that R⁶or R⁷is substituted with is optionally substituted with one or more hydroxyl, C₆-C₁₀aryl or NR⁸R⁹, or wherein R⁶or R⁷is 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-C₁₀aryl, 5- to 10-membered heteroaryl, NHCOC₆-C₁₀aryl, 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-C₆alkyl, and OC₁-C₆alkyl;
or one pair of R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, CH₂NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of Formula AA, Ring A is

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and R¹is C₁-C₆alkyl 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

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and R¹is C₁-C₆alkyl 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

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and R¹is C₁-C₆alkyl 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

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and R¹is C₁-C₆alkyl 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 R¹is C₁-C₆alkyl 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 R¹is C₁-C₆alkyl 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 R¹is C₁-C₆alkyl 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 R¹is C₁-C₆alkyl 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 R¹is C₁-C₆alkyl 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

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and R¹is C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹.

In some embodiments of Formula AA, Ring A is

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and R¹is C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹.

In some embodiments of Formula AA, Ring A is

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and R¹is C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹.

In some embodiments of Formula AA, Ring A is

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R¹is C₁-C₆alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl); and R²is halo.

In some embodiments of Formula AA, Ring A is

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R¹is C₁-C₆alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl); and R²is halo.

In some embodiments of Formula AA, Ring A is

embedded image

R¹is C₁-C₆alkyl substituted with one or more (e.g., from 1-2) hydroxy (e.g., 2-hydroxy-2-propyl or 1,2-dihydroxy-2-propyl); and R²is halo.

In some embodiments of Formula AA, Ring A is

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R¹is C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹; and R²is halo.

In some embodiments of Formula AA, Ring A is

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R¹is C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹; and R²is halo.

In some embodiments of Formula AA, Ring A is

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R¹is C₁-C₆alkyl substituted with one or more (e.g., one) NR⁸R⁹; and R²is halo.

In some embodiments of Formula AA, Ring A is

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and each of R¹and R²is C₁-C₆alkyl 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 R¹and R²is C₁-C₆alkyl 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 R¹and R²is C₁-C₆alkyl substituted with one or more (e.g., from 1-2) hydroxy. In certain of these embodiments, R²is hydroxy methyl.

In some embodiments of Formula AA, Ring A is

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and R¹is C₁-C₆alkyl optionally substituted with one or more halo (e.g., ethyl or difluoromethyl).

In some embodiments of Formula AA, Ring A is

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and R¹is C₁-C₆alkyl optionally substituted with one or more halo (e.g., ethyl or difluoromethyl).

In some embodiments of Formula AA, Ring A is:

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and and R¹is C₁-C₆alkyl optionally substituted with one or more halo (e.g., ethyl or difluoromethyl).

In some embodiments of Formula AA, Ring A is

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and R¹and R²taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic ring (e.g., C₅or C₆carbocyclic 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-C₆alkyl (e.g., methyl), C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy (e.g., methoxy, ethoxy, isopropoxyl), OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹(e.g., amino, methylamino, or dimethylamino), ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of Formula AA, Ring A is

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and each of R¹and R²is C₁-C₆alkyl 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 R¹and R²is C₁-C₆alkyl 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 R¹and R²taken together with the atoms connecting them, independently form one monocyclic or bicyclic C₄-C₁₂carbocyclic ring (e.g., C₅or 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-C₆alkyl (e.g., methyl), C₂-C₆alkenyl, C₂-C₆alkynyl, C₁-C₆alkoxy (e.g., methoxy, ethoxy, isopropoxyl), OC₃-C₁₀cycloalkyl, NR⁸R⁹, ═NR¹⁰, CN, COOC₁-C₆alkyl, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, 3- to 10-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and CONR⁸R⁹, wherein the C₁-C₆alkyl, C₁-C₆alkoxy, S(O₂)C₆-C₁₀aryl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, C₃-C₁₀cycloalkyl, and 3- to 10-membered heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, halo (e.g., fluoro), C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₁₀cycloalkyl, C₁-C₆alkoxy, oxo, NR⁸R⁹(e.g., amino, methylamino, or dimethylamino), ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹.

In some embodiments of Formula AA, the substituted ring B is

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In certain of these embodiments, the R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇(e.g., C₄or 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹. For example, the R⁶and R⁷on 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 R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇(e.g., C₄or 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹):

the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In certain of these embodiments, the remaining R⁶is C₆-C₁₀aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C₁-C₆alkyl, and C₁-C₆alkoxy. For example, R⁶is 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-C₆alkyl, and C₁-C₆alkoxy.

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 R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In certain of these embodiments, one R⁶is C₆-C₁₀aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C₁-C₆alkyl, and C₁-C₆alkoxy. For example, R⁶is 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-C₆alkyl, and C₁-C₆alkoxy.

In certain embodiments (when the substituted ring B is

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and one R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl):

the remaining R⁶and R⁷are independently selected from the group consisting of cyano, halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₃-C₇cycloalkyl.

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 R⁶and R⁷on 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹. For example, the R⁶and R⁷on 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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the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁸, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

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 R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In certain embodiments (when the substituted ring B is

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and one R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl):

the remaining R⁶and each R⁷are independently selected from the group consisting of cyano, halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₃-C₇cycloalkyl.

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 R⁶and R⁷on 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹. For example, the R⁶and R⁷on 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 R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇(e.g., C₄or 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-C₆alkyl, C₁-C₆alkoxy, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹):

the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

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(e.g., R⁷is 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 R^6″ and R⁷on 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-C₆alkyl, C₁-C₆alkoxy, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹. For example, the R^6″ and R⁷on 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 R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇(e.g., C₄or 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹):

the remaining R^6″ is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In certain of these embodiments, the remaining R^6″ is C₆-C₁₀aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C₁-C₆alkyl, and C₁-C₆alkoxy. For example, R^6″ 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-C₆alkyl, and C₁-C₆alkoxy.

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 R^6″ is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In certain of these embodiments, one R^6″ is C₆-C₁₀aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C₁-C₆alkyl, and C₁-C₆alkoxy. For example, R^6″ 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-C₆alkyl, and C₁-C₆alkoxy.

In certain embodiments (when the substituted ring B is

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and one R^6″is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl):

the remaining R^6″and R⁷are independently selected from the group consisting of halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₃-C₇cycloalkyl.

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 R^6″and R⁷on 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹. For example, the R^6″ and R⁷on 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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the remaining R^6″ is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

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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In certain embodiments (when the substituted ring B is

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and one R^6″ is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl):

the remaining R^6″ and each R⁷are independently selected from the group consisting of halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₃-C₇cycloalkyl.

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 R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇(e.g., C₄or 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹. For example, the R^6″ and R⁷on 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 R^6″ and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇(e.g., C₄or 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-C₆alkyl, C₁-C₆alkoxy, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹):

the remaining R^6″ is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

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(e.g., R⁷is 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 embodiments (when the substituted ring B is selected from:

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the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

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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In certain embodiments (when the substituted ring B is

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the remaining R⁶and R⁷are independently selected from the group consisting of cyano, halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₃-C₇cycloalkyl.

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 embodiments (when the substituted ring B is

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the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

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 R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In certain embodiments (when the substituted ring B is

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and one R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl):

the remaining R⁶and each R⁷are independently selected from the group consisting of cyano, halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₃-C₇cycloalkyl.

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 R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇(e.g., C₄or 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹. For example, the R⁶and R⁷on 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 R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇(e.g., C₄or 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹):

the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

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(e.g., R⁷is 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 embodiments (when the substituted ring B is selected from:

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the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

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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In certain embodiments (when the substituted ring B is

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the remaining R⁶and R⁷are independently selected from the group consisting of cyano, halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₃-C₇cycloalkyl.

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 embodiments (when the substituted ring B

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the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

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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In certain embodiments (when the substituted ring B is

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the remaining R⁶and each R⁷are independently selected from the group consisting of cyano, halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₃-C₇cycloalkyl.

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 embodiments (when the substituted ring B is is

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the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

As a non-limiting example of the foregoing embodiments, substituted ring B is selected from:

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(e.g., R⁷is 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

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In certain embodiments (when the substituted ring B′ is

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the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

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 R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In certain embodiments (when the substituted ring B′ is

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and one R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl):

the remaining R⁶and each R⁷are independently selected from the group consisting of cyano, halo, C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₃-C₇cycloalkyl.

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 embodiments (when the substituted ring B′ is is

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the remaining R⁶is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

As a non-limiting example of the foregoing embodiments, substituted ring B′ is selected from:

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(e.g., R⁷is 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 R^6′and R^7′ on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇(e.g., C₄or 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹. For example, the R^6′and R^7′ 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 R^6′and R^7′ on adjacent atoms, taken together with the atoms connecting them, independently form C₄-C₇(e.g., C₄or 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, C₆-C₁₀aryl, and CONR⁸R⁹):

the remaining R^6′ is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In certain of these embodiments, the remaining R^6′ is C₆-C₁₀aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C₁-C₆alkyl, and C₁-C₆alkoxy. For example, R^6′ 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-C₆alkyl, and C₁-C₆alkoxy.

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 R^6′ is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl.

In certain of these embodiments, one R^6′ is C₆-C₁₀aryl or 5- to 10-membered heteroaryl optionally substituted with a substituent selected from halo, CN, C₁-C₆alkyl, and C₁-C₆alkoxy. For example, R^6′ 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-C₆alkyl, and C₁-C₆alkoxy.

In certain embodiments (when the substituted ring B″ is

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and one R^6′ is C₆-C₁₀aryl 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-C₆alkyl, C₁-C₆alkoxy, NR⁸R⁹, ═NR¹⁰, COOC₁-C₆alkyl, CONR⁸R⁹, 4- to 6-membered heterocycloalkyl, C₆-C₁₀aryl, 5- to 10-membered heteroaryl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(4- to 6-membered heterocycloalkyl), NHCOC₁-C₆alkyl, NHCOC₆-C₁₀aryl, NHCO(5- to 10-membered heteroaryl), NHCO(4- to 6-membered heterocycloalkyl), and NHCOC₂-C₆alkynyl):

the remaining R^6′ and R⁷are independently selected from the group consisting of CN, halo, unbranched C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₃-C₇cycloalkyl.

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

X¹is selected from CH, CR′, CR², N, NH, NR¹, NR², and S;

X²is selected from CH, CR′, CR², N, NH, NR¹, NR², and S;

X³is selected from CH, CR′, CR², N, NH, NR¹, NR², and S;

X⁴is selected from CH, CR′, CR², N, NH, NR¹, NR², and S;

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is aromatic and charge neutral;

X¹, X², X³, and X⁴collectively comprise from 0-2 R¹and from 0-2 R², wherein the sum of R¹and R²is 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 R⁷are as defined previously herein.

In some embodiments of Formula BB, X¹is CR¹or CR².

In some embodiments of Formula BB, X¹is CH.

In some embodiments of Formula BB, X²is N.

In some embodiments of Formula BB, X²is CH.

In some embodiments of Formula BB, X²is CR¹or CR².

In some embodiments of Formula BB, X³is CR¹or CR².

In some embodiments of Formula BB, X³is NR¹or NR².

In some embodiments of Formula BB, X⁴is N.

In some embodiments of Formula BB, X⁴is S.

In some embodiments of Formula BB, X¹is CR¹, X²is CR¹, X³is NR², and X⁴is N.

In some embodiments of Formula BB-1, X¹is CR¹X²is CH, X³is NR², and X⁴is N.

In some embodiments of Formula BB-1, X¹is CH, X²is CR¹X³is NR², and X⁴is N.

In some embodiments of Formula BB, X¹is CR¹, X²is N, X³is CR², and X⁴is S.

In some embodiments of Formula BB, X¹is CH, X²is N, X³is CR², and X⁴is S.

In some embodiments of Formula BB, X¹is S, X²is CR¹X³is CR², and X⁴is CR¹.

In some embodiments of Formula BB, X¹is S, X²is CR¹X³is CH, and X⁴is CR².

In some embodiments of Formula BB, X¹is CR¹, X²is NR², X³is N, and X⁴is CR¹.

In some embodiments of Formula BB, R¹and R²are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and C(O)R¹³(e.g., C₁-C₆alkyl, C₁-C₆haloalkyl, and halo),

wherein the C₁-C₆alkyl is optionally substituted with one or more substituents each independently selected from hydroxy or R¹⁵(e.g., hydroxyl);

or one pair of R¹and R²on 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 R¹and/or R²), and

rein the heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, C₁-C₆alkoxy, and NR⁸R⁹.

In some embodiments of Formula BB, R¹and R²are 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 R¹and R²on 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 R¹and/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, R¹and R²are 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, R¹and R²are 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, R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₆-C₁₀aryl, CO₂C₁-C₆alkyl, and C₃-C₁₀cycloalkyl, wherein R⁶and R⁷are each optionally substituted with one or more sub stituents independently selected from halo and C₁-C₆alkyl;

or at least one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₄-C₈carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more substituents independently selected from hydroxy, oxo, and C₁-C₆alkyl.

In some embodiments of Formula BB, R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, CO₂C₁-C₆alkyl, and C₃-C₁₀cycloalkyl, wherein R⁶and R⁷are each optionally substituted with one or more sub stituents independently selected from halo and C₁-C₆alkyl;

In some embodiments of Formula BB, R⁶and R⁷are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO₂Et, and cyclopropyl,

wherein R⁶and R⁷are each optionally substituted with one or more sub stituents independently selected from fluoro and methyl;

or at least one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₅carbocyclic 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, R⁶and R⁷are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl;

or at least one pair of R⁶and R⁷on adjacent atoms, taken together with the atoms connecting them, independently form at least one C₅carbocyclic ring, wherein the carbocyclic ring is optionally independently substituted with one or more methyl.

In some embodiments of Formula BB, R⁶and R⁷are each independently selected from methyl and trifluoromethyl;

In some embodiments, the compound of Formula AA is a compound of Formula BB-1

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wherein

J¹and J²are 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-C₆alkyl;

o is 0 or 1 and p is 0 or 1, wherein the sum of o and p is 1 or 2;

X¹is selected from CH and CR¹; and

X², X³, X⁴, R⁶, and R⁷are as defined previously herein.

In some embodiments of Formula BB-1, X¹is CH.

In some embodiments of Formula BB-1, X¹is CR¹.

In some embodiments of Formula BB-1, X²is N.

In some embodiments of Formula BB-1, X²is CH.

In some embodiments of Formula BB-1, X²is CR¹or CR².

In some embodiments of Formula BB-1, X³is CR¹or CR².

In some embodiments of Formula BB-1, X³is NR¹or NR².

In some embodiments of Formula BB-1, X⁴is N.

In some embodiments of Formula BB-1, X⁴is S.

In some embodiments of Formula BB-1, X¹is CR¹X²is CR¹, X³is NR², and X⁴is N.

In some embodiments of Formula BB-1, X¹is CR¹X²is CH, X³is NR², and X⁴is N.

In some embodiments of Formula BB-1, X¹is CH, X²is CR¹, X³is NR², and X⁴is N.

In some embodiments of Formula BB, X¹is CR¹, X²is N, X³is CR², and X⁴is S.

In some embodiments of Formula BB-1, X¹is CH, X²is N, X³is CR², and X⁴is S.

In some embodiments of Formula BB-1, X¹is S, X²is CR¹X³is CR², and X⁴is CR¹.

In some embodiments of Formula BB, X¹is S, X²is CR¹, X³is CH, and X⁴is CR².

In some embodiments of Formula BB-1, X¹is CR¹, X²is NR², X³is N, and X⁴is CR¹.

In some embodiments of Formula BB-1, R¹and R²are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and C(O)R¹³(e.g., C₁-C₆alkyl, C₁-C₆haloalkyl, and halo), wherein the C₁-C₆alkyl is optionally substituted with one or more substituents each independently selected from hydroxyl or R¹⁵(e.g., hydroxyl);

or one pair of R¹and R²on 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

wherein the heterocyclic ring is optionally independently substituted with one or more substituents each independently selected from hydroxy, C₁-C₆alkoxy, and NR⁸R⁹.

In some embodiments of Formula BB-1, R¹and R²are 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 R¹and R²on 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

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, R¹and R²are 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, R¹and R²are 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, R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₆-C₁₀aryl, CO₂C₁-C₆alkyl, and C₃-C₁₀cycloalkyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from halo and C₁-C₆alkyl;

In some embodiments of Formula BB-1, R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, CO₂C₁-C₆alkyl, and C₃-C₁₀cycloalkyl,

wherein R⁶and R⁷are each optionally substituted with one or more sub stituents independently selected from halo and C₁-C₆alkyl;

In some embodiments of Formula BB-1, R⁶and R⁷are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO₂Et, and cyclopropyl,

wherein R⁶and R⁷are each optionally substituted with one or more sub stituents independently selected from fluoro and methyl;

In some embodiments of Formula BB-1, R⁶and R⁷are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl;

In some embodiments of Formula BB-1, R⁶and R⁷are each independently selected from methyl and trifluoromethyl;

In some embodiments of Formula BB-1, J¹is selected from the group consisting of —CH₂—,

embedded image

—CHR—, —C(═O)—, and —CR₂; and J²is —CH₂—. In any of these embodiments, R is C₁-C₆alkyl (e.g., methyl).

In some embodiments of Formula BB-1, J¹is selected from the group consisting of —CH₂— and —CR₂—; and J²is —CH₂—. In any of these embodiments, R is C₁-C₆alkyl (e.g., methyl).

In some embodiments of Formula BB-1, R is C₁-C₆alkyl (e.g., methyl).

In certain embdoiments, J¹is —CH₂—; and J²is —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 J³are 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-C₆alkyl;

X¹is selected from CH and CR¹;

X²is selected from N, CH, CR¹and CR²;

R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

In some embodiments of Formula BB-1a, X²is N.

In some embodiments of Formula BB-1a, X²is CH.

In some embodiments of Formula BB-1a, X²is CR¹or CR².

In some embodiments of Formula BB-1b, X¹is selected from CH;

In some embodiments of Formula BB-1b, X¹is selected from CR¹;

In some embodiments of Formula BB-1a and/or Formula BB-1b, each R¹is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and C(O)R¹³(e.g., C₁-C₆alkyl, C₁-C₆haloalkyl, and halo),

wherein the C₁-C₆alkyl 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 R¹is 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 R¹is 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 R¹is independently selected fromethyl, 1,2-dihydroxy-2-propyl, and fluoro.

In some embodiments of Formula BB-1a, the R¹connected to carbon is halo; X²is CH; and the R¹connected to nitrogen is C₁-C₃alkyl. For example, the R¹connected to carbon is fluoro; X²is CH; and the R¹connected to nitrogen is ethyl.

In some embodiments of Formula BB-1b, X¹is CH; and R¹is C₁-C₃alkyl optionally substituted with one or more hydroxyl. For example, X¹is CH; and R¹is 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 R²is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and C(O)R¹³(e.g., C₁-C₆alkyl, C₁-C₆haloalkyl, and halo),

wherein the C₁-C₆alkyl 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 R²is 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 R²is 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 R²is independently selected fromethyl, 1,2-dihydroxy-2-propyl, and fluoro.

In some embodiments of Formula BB-1a, R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₆-C₁₀aryl, CO₂C₁-C₆alkyl, and C₃-C₁₀cycloalkyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from halo and C₁-C₆alkyl.

In some embodiments of Formula BB-1a, R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, CO₂C₁-C₆alkyl, and C₃-C₁₀cycloalkyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from halo and C₁-C₆alkyl.In some embodiments of Formula BB-1a, R⁶and R⁷are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO₂Et, and cyclopropyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from fluoro and methyl.

In some embodiments of Formula BB-1a, R⁶and R⁷are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl.

In some embodiments of Formula BB-1a, R⁶and R⁷are each independently selected from methyl and trifluoromethyl. For example, R⁶is methyl; and R⁷is trifluoromethyl.

In some embodiments of Formula BB-1a, J¹and J²are independently selected from —CH₂—, —CHR—, and —CR₂—.

In some embodiments of Formula BB-1a, J¹is selected from —CH₂—, —CHR—, and —CR₂—; and J²is —CH₂—.

In some embodiments of Formula BB-1a, J¹is selected from —CH₂— and —CR₂—; and J²is —CH₂—.

In some embodiments of Formula BB-1b, J¹and J³are 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-C₆alkyl (e.g., methyl).

In some embodiments of Formula BB-1b, J¹and J³are independently selected from the group consisting of —CH₂— and —CR₂—.

In some embodiments of Formula BB-1b, one or two of J¹and J³is other than CH₂.

In some embodiments of Formula BB-1b, J¹is

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—CHR—, —CR₂—, or —C(═O)— (e.g.,

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—CHR—, —CR₂—); and J³is CH₂.

In some embodiments of Formula BB-1a and/or Formula BB-1b, R is C₁-C₆alkyl (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-C₆alkyl;

R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy, halo, CN, NO₂, COC₁-C₆alkyl, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, OCOC₁-C₆alkyl, OCOC₆-C₁₀aryl, OCO(5- to 10-membered heteroaryl), OCO(3- to 7-membered heterocycloalkyl), C₆-C₁₀aryl, 5- to 10-membered heteroaryl, NH₂, NHC₁-C₆alkyl, N(C₁-C₆alkyl)₂, CONR⁸R⁹, SF₅, SC₁-C₆alkyl, S(O₂)C₁-C₆alkyl, C₃-C₁₀cycloalkyl and 3- to 10-membered heterocycloalkyl, and C₂-C₆alkenyl,

In some embodiments of Formula BB-1a-i and/or Formula BB-1b-i, each R¹is independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, halo, and C(O)R¹³(e.g., C₁-C₆alkyl, C₁-C₆haloalkyl, and halo)

wherein the C₁-C₆alkyl 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 R¹is 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 R¹is 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 R¹is independently selected fromethyl, 1,2-dihydroxy-2-propyl, and fluoro.

In some embodiments of Formula BB-1a-i, the R¹connected to carbon is halo; and the le connected to nitrogen is C₁-C₃alkyl.

In some embodiments of Formula BB-1b-i, R¹is C₁-C₃alkyl optionally substituted with one or more hydroxyl.

In some embodiments of Formula BB-1a-i, R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, C₆-C₁₀aryl, CO₂C₁-C₆alkyl, and C₃-C₁₀cycloalkyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from halo and C₁-C₆alkyl.

In some embodiments of Formula BB-1a-i, R⁶and R⁷are each independently selected from C₁-C₆alkyl, C₁-C₆haloalkyl, CO₂C₁-C₆alkyl, and C₃-C₁₀cycloalkyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from halo and C₁-C₆alkyl.

In some embodiments of Formula BB-1a-i, R⁶and R⁷are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, phenyl, CO₂Et, and cyclopropyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from fluoro and methyl.

In some embodiments of Formula BB-1a-i, R⁶and R⁷are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl,

wherein R⁶and R⁷are each optionally substituted with one or more substituents independently selected from fluoro and methyl.

In some embodiments of Formula BB-1a-i, R⁶and R⁷are each independently selected from methyl, ethyl, isopropyl, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, and cyclopropyl.

In some embodiments of Formula BB-1a-i, R⁶and R⁷are 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), R⁶is 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.

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

101a

141bb

101b

142

102

142a

102a

142b

102b

143

103

143a

103aa

143b

103ab

144

103ba

145

103bb

145a

104

145b

104a

146

104b

147

105

147a

105a

147b

105b

148

106

148a

106a

148b

106b

149

107

149a

107a

149b

107b

150

110

150

111

150b

112

151

113

152

114

153

114a

153a

114b

153b

115

154

116

154a

116a

154b

116b

155

117

155a

117a

155b

117b

156

118

156a

118a

156b

118b

157

119

157a

119a

157b

119b

158

120

158a

120a

158b

120b

159

121

159a

121a

159b

121b

160

122

160a

122a

160b

122b

161

123

161a

124

161b

124a

162

124b

162aa

125

162ab

125a

162ba

125b

162bb

126

163

126a

163a

126b

163b

127

164

127a

164a

127b

164b

128

165

128a

165a

128b

165b

129

166

129aa

167

129ab

167a

129ba

167b

129bb

168

130

168a

130a

168aa

130b

168ab

131

168b

131a

168ba

131aab

168bb

131b

169a

131c

169b

131d

170

131e

171

131f

172

131g

172a

132

172b

132a

173

132b

173a

133

173b

133a

174

133b

174a

134

174b

134aa

175

134ab

175a

134ba

175b

134bb

176

135

177

136

178

136a

179

136b

180

137

180a

137a

180b

137b

181

138

182

139

183

140

183a

140a

183b

140aa

183c

140ab

183d

140b

184a

140ba

184b

140bb

184c

141

184d

141a

201

141aa

201a

141ab

141b

141ba

and pharmaceutically acceptable salts thereof.

In some embodiments, provided herein is a compound that is selected from the following:

185b

185

185a

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

embedded image

421

302

422

303

423

304

424

305

425

306

426

307

427

308

428

309

429

311

430

312

431

313

432

314

433

315

434

316

435

317

436

318

437

319

438

320

439

321

440

322

441

323

442

324

443

325

444

326

445

327

446

328

447

330

449

331

450

332

451

333

452

334

453

335

454

336

455

337

456

338

457

339

458

340

459

341

460

342

461

343

462

344

463

345

464

346

465

347

466

348

467

349

468

350

469

351

470

352

471

353

472

354

473

355

474

356

475

357

476

358

477

359

478

360

479

361

480

362

481

363

482

364

483

365

484

366

485

367

486

368

487

369

488

370

489

371

490

372

491

373

492

374

493

375

494

376

495

377

496

378

497

379

498

380

499

381

500

382

501

383

502

384

503

385

504

386

505

387

506

388

507

389

508

390

509

391

510

392

511

393

512

394

513

395

514

396

515

397

516

398

517

399

518

400

519

401

520

402

521

403

522

404

523

405

524

406

525

407

526

408

527

409

528

410

529

411

530

412

531

413

532

414

533

415

534

416

535

417

536

418

537

419

538

420

539

540

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

115a

115b

140c

170a

170b

171a

171b

171c

171d

176a

176b

181a

181b

182a

182b

201b

201c

201d

201e

201f

304a

304b

306a

306b

601

601a

601b

602

602a

602b

603

604

604a

604b

605

605a

605b

605c

605d

605e

605f

605g

605h

607

607a

607b

608

608a

608b

608c

608d

609

610

610a

610b

611

611a

611b

612

612a

612b

613

613a

613b

614

614a

614b

615

615a

615b

616

616a

616b

617

617a

617b

618

618a

618b

619

620

620a

620b

621

621a

621b

622

622a

622b

623

623a

623b

624

624a

624b

625

625a

625b

626

626a

626b

627

628

628a

628b

629

630

630a

630b

631

631a

631b

632

632a

632b

633

633a

633b

634

634a

634b

635

636a

636b

636c

637

637a

637b

638

638a

638b

639

639a

639b

640

640a

640b

640c

641

642

642a

642b

643

643a

643b

644

644a

644b

645

645a

645b

646a

647

647a

647b

648

648a

648b

649

649a

649b

650

650a

650b

651

651a

651b

652

652a

652b

653

653a

653b

654

654a

654b

655

655a

655b

656

656a

656b

656c

656d

657

657a

657b

658

658a

658b

659

659a

659b

660

660a

660b

660c

660d

661

661a

661b

662

662a

662b

662c

662d

662e

663

663a

663b

664

664a

664b

665

667

667a

667b

668

668a

668b

668c

668d

669

669a

669b

670

670a

670b

671

671a

671b

671c

671d

672

673

673a

673b

674

674a

674b

675

675a

675b

676

676a

676b

677

678

678a

678b

679

680

680a

680b

681

681a

681b

682

682a

682b

683

683a

683b

684

684a

684b

685

685a

685b

686

686a

686b

687

687a

687b

688

688a

688b

689

689a

689b

690

690a

690b

691

691a

691b

692

692a

692b

693

694

694a

694b

695

695a

695b

696

697a

697b

698a

698b

699a

699b

699c

700a

700b

701a

701b

702

703

704

705a

705b

706

707

708

709

710

711

712

713

716a

716b

717

718a

719

720a

720b

720c

721a

721b

721c

722

723a

723b

723c

724

725a

726

726a

726b

727

727a

727b

728

728a

728b

729

729a

729b

730

730a

730b

731

731a

731b

732a

733

734

735

736

737

738

739

739a

739b

739c

739d

740

740a

740b

741

741a

741b

742

742a

742b

743

743a

743b

743c

743d

744

744a

744b

744c

744d

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

801b

802

802a

802b

802c

802d

803

803a

803b

804

804a

804b

805

805a

805b

806

806a

806b

807

807a

807b

808

808a

808b

809

809a

809b

810

811a

811b

811

811a

811b

812

812a

812b

813

813a

813b

814

814a

814b

814c

814d

815

815a

815d

816

816a

816b

816c

816d

817

817a

817b

817c

817d

818

818a

818b

819

819a

819b

820

820a

820b

820c

820d

821

821a

821b

822

822a

822b

823

823a

823b

824

824a

824b

825

825a

825b

826

826a

826b

827

827a

827b

828

828a

828b

828c

828d

829

829a

829b

829c

829d

830

830a

830b

831

831a

831b

832

832a

832b

833

833a

833b

834

834a

834b

835

835a

835b

836

836a

836b

837

837a

837b

838

838a

838b

839

839a

839b

840

840a

840b

841

841a

841b

842

842a

842b

843

843a

843b

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

901b

902

902a

902b

903

903a

903b

904

904a

904b

905

905a

905b

906

907

907a

907b

908

908a

909

910

911

911a

911b

912

912a

912b

913

914

914a

914b

915

915a

915b

916

916a

916b

917

917a

917b

918

918a

918b

919

920

920a

920b

921

921a

921b

922

922a

922b

923

923a

923b

924

924a

924b

925

926

926a

926b

927

928

929

930

931

932

933a

934a

934b

935a

935b

935c

935d

935e

936a

936b

936c

937a

937b

937c

937d

937e

937f

938a

938b

938c

939a

939b

940a

940b

941a

941b

941c

941d

942a

942b

942c

943a

943b

944a

944b

945a

945b

946a

946b

947a

947b

948a

948b

949a

950a

951a

952a

953a

954a

955a

956a

957a

958a

959a

960a

961a

962a

963a

964a

965a

966a

967a

1041a

967b

968

969

969a

969b

970

970a

970b

971

971a

971b

972

973

974

974a

974b

975

975a

975b

976

976a

976b

977

977a

977b

978

978a

978b

979

979a

979b

980

980a

980b

981a

981b

981c

982a

983

983a

983b

984

984a

984b

985

985a

985b

986

987

987a

987b

988

989

990

991

992

992a

993

994

994a

995

996

997

998

998a

999

999a

1000

1000a

1001

1001a

1002

1002a

1003

1003a

1004

1004a

1005

1005a

1006

1006a

1007

1007a

1008

1008a

1009

1009a

1010

1010a

1011

1011a

1012

1013

1013a

1014

1014a

1015

1015a

1016

1016a

1017

1017a

1018

1018a

1019

1019a

1020

1020a

1021

1022

1022a

1023

1024

1025

1025a

1026

1026a

1027

1028

1029

1029a

1030

1031

1032

1033

1034

1034a

1035

1036

1037

1038

1039

1040

1041

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

1100a

1101a

1100b

1101b

1100c

1101c

1100d

1101d

1101e

1102

1103

1102a

1103a

1102b

1103b

1104

1105

1104a

1105a

1104b

1105b

1106

1107

1106a

1107a

1106b

1107b

1108

1109

1108a

1109a

1108b

1109b

1110

1111

1110a

1110b

1112

1113

1113a

1113b

1114

1115a

1115b

1116a

1116b

1117a

1117b

1118

1119

1004b

1007b

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-CH₃KIH, 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 1×10⁻⁵M (e.g., less than 0.5×10⁻⁵M, less than 1×10⁻⁶M, less than 0.5×10⁻⁶M, less than 1×10⁻⁷M, less than 0.5×10⁻⁷M, less than 1×10⁻⁸M, less than 0.5×10⁻⁸M, less than 1×10⁻⁹M, less than 0.5×10⁻⁹M, less than 1×10⁻¹⁰M, less than 0.5×10⁻¹¹M, less than 1×10^{−1 1}M, less than 0.5×10⁻¹¹M, or less than 1×10⁻¹²M), 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 K_Dof about 1×10⁻¹²M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, about 0.5×10⁻⁶M, about 1×10⁻⁷M, about 0.5×10⁻⁷M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, about 1×10⁻⁹M, about 0.5×10⁻⁹M, about 1×10⁻¹⁰M, about 0.5×10⁻¹⁰M, about 1×10⁻¹¹M, or about 0.5×10⁻¹¹M (inclusive); about 0.5×10⁻¹¹M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, about 0.5×10⁻⁶M, about 1×10⁻⁷M, about 0.5×10⁻⁷M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, about 1×10⁻⁹M, about 0.5×10⁻⁹M, about 1×10⁻¹⁰M, about 0.5×10⁻¹⁰M, or about 1×10⁻¹¹M (inclusive); about 1×10⁻¹¹M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, about 0.5×10⁻⁶M, about 1×10⁻⁷M, about 0.5×10⁻⁷M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, about 1×10⁻⁹M, about 0.5×10⁻⁹M, about 1×10⁻¹⁰M, or about 0.5×10⁻¹⁰M (inclusive); about 0.5×10⁻¹⁰M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, about 0.5×10⁻⁶M, about 1×10⁻⁷M, about 0.5×10⁻⁷M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, about 1×10⁻⁹M, about 0.5×10⁻⁹M, or about 1×10⁻¹⁰M (inclusive); about 1×10⁻¹⁰M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, about 0.5×10⁻⁶M, about 1×10⁻⁷M, about 0.5×10⁻⁷M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, about 1×10⁻⁹M, or about 0.5×10⁻⁹M (inclusive); about 0.5×10⁻⁹M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, about 0.5×10⁻⁶M, about 1×10⁻⁷M, about 0.5×10⁻⁶M, about 1×10⁻⁸M, about 0.5×10⁻⁸M, or about 1×10⁻⁹M (inclusive); about 1×10⁻⁹M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, about 0.5×10⁻⁶M, about 1×10⁻⁷M, about 0.5×10⁻⁷M, about 1×10⁻⁸M, or about 0.5×10⁻⁸M (inclusive); about 0.5×10⁻⁸M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, about 0.5×10⁻⁶M, about 1×10⁻⁷M, about 0.5×10⁻⁷M, or about 1×10⁻⁸M (inclusive); about 1×10⁻⁸M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, about 0.5×10⁻⁶M, about 1×10⁻⁷M, or about 0.5×10⁻⁷M (inclusive); about 0.5×10⁻⁷M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, about 0.5×10⁻⁶M, or about 1×10⁻⁷M (inclusive); about 1×10⁻⁷M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, about 1×10⁻⁶M, or about 0.5×10⁻⁶M (inclusive); about 0.5×10⁻⁶M to about 1×10⁻⁵M, about 0.5×10⁻⁵M, or about 1×10⁻⁶M (inclusive); about 1×10⁻⁶M to about 1×10⁻⁵M or about 0.5×10⁻⁵M (inclusive); or about 0.5×10⁻⁵M to about 1×10⁻⁵M (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 K_offof about 1×10⁻⁶s⁻¹to about 1×10⁻³s⁻¹, about 0.5×10⁻³s⁻¹, about 1×10⁻⁴s⁻¹, about 0.5×10⁻⁴s⁻¹, about 1×10⁻⁵s⁻¹, or about 0.5×10⁻⁵s⁻¹(inclusive); about 0.5×10⁻⁵s⁻¹to about 1×10⁻³s⁻¹, about 0.5×10⁻³s⁻¹, about 1×10⁻⁴s⁻¹, about 0.5×10⁻⁴s⁻¹, or about 1×10⁻⁵s⁻¹(inclusive); about 1×10⁻⁵s⁻¹to about 1×10⁻³s⁻¹, about 0.5×10⁻³s⁻¹, about 1×10⁻⁴s⁻¹, or about 0.5×10⁻⁴s⁻¹(inclusive); about 0.5×10⁻⁴s⁻¹to about 1×10⁻³s⁻¹, about 0.5×10⁻³s⁻¹, or about 1×10⁻⁴s⁻¹(inclusive); about 1×10-4 s⁻¹to about 1×10⁻³s⁻¹, or about 0.5×10⁻³s⁻¹(inclusive); or about 0.5×10⁻⁵s⁻¹to about 1×10⁻³s⁻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 K_onof about 1×10²M⁻¹s⁻¹to about 1×10⁶M⁻¹s⁻¹, about 0.5×10⁶M⁻¹s⁻¹, about 1×10⁵M⁻¹s⁻¹, about 0.5×10⁵M⁻¹s⁻¹, about 1×10⁴M⁻¹s⁻¹, about 0.5×10⁴M⁻¹s⁻¹, about 1×10³M⁻¹s⁻¹, or about 0.5×10³M⁻¹s⁻¹(inclusive); about 0.5×10³M⁻¹s⁻¹to about 1×10⁶M⁻¹s⁻¹, about 0.5×10⁶M⁻¹s⁻¹, about 1×10⁵M⁻¹s⁻¹, about 0.5×10⁵M⁻¹s⁻¹, about 1×10⁴M⁻¹s⁻¹, about 0.5×10⁴M⁻¹s⁻¹, or about 1×10³M⁻¹s⁻¹(inclusive); about 1×10³M⁻¹s⁻¹to about 1×10⁶M⁻¹s⁻¹, about 0.5×10⁶M⁻¹s⁻¹, about 1×10⁵M⁻¹s⁻¹, about 0.5×10⁵M⁻¹s⁻¹, about 1×10⁴M⁻¹s⁻¹, or about 0.5×10⁴M⁻¹s⁻¹(inclusive); about 0.5×10⁴M⁻¹s⁻¹to about 1×10⁶M⁻¹s⁻¹, about 0.5×10⁶M⁻¹s⁻¹, about 1×10⁵M⁻¹s⁻¹, about 0.5×10⁵M⁻¹s⁻¹, or about 1×10⁴M⁻¹s⁻¹(inclusive); about 1×10⁴M⁻¹s⁻¹to about 1×10⁶M⁻¹s⁻¹, about 0.5×106 M⁻¹s⁻¹, about 1×10⁵M⁻¹s⁻¹, or about 0.5×105 M⁻¹s⁻¹(inclusive); about 0.5×10⁵M⁻¹s⁻¹to about 1×10⁶M⁻¹s⁻¹, about 0.5×10⁶M⁻¹s⁻¹, or about 1×10⁵M⁻¹s⁻¹(inclusive); about 1×10⁵M⁻¹s⁻¹to about 1×10⁶M⁻¹s⁻¹, or about 0.5×10⁶M⁻¹s⁻¹(inclusive); or about 0.5×10⁶M⁻¹s⁻¹to about 1×10⁶M⁻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 (CH_5126766), 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 0.005 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 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.

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 SO₂was 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 SO₂was 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 Na₂SO₄and 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 SO₂was 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 NH₃was 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 SO₂was 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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

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 Na₂SO₄and 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 Na₂SO₄and 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 SO₂gas 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 SO₂in 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 NH₃gas 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 NH₃gas 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 SO₂in 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 SO₂was 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 BH₃in 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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

NH₃gas 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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.Na₂SO₃at 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 Na₂SO₄and 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 Na₂SO₄and 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. Na₂CO₃solution. The resulting solution was extracted with 3×150 mL of EtOAc, the combined organic layer was dried over anhydrous Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 NH_3.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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 NH₃at 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 NH₃in 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 NH₃at 0° C. for 15 min. The solution was washed with brine (2×100 mL), dried over Na₂SO₄and 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 Na₂SO₄and 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. NaHCO₃and 5.0 L of brine. The organic layer was dried over Na₂SO₄and 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 NaHCO₃and 1 ×500 mL of H₂O. The resulting mixture was washed with 1×500 mL of NaCl (aq.). The mixture was dried over anhydrous Na₂SO₄and 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 NH₃in 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 Na₂SO₄and 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 NH₃in 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 NH₃in 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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: NH₂at 6.91 (s, 2H) has correlations with N-Et's CH₂at 4.35-4.16 (m, 2H) and CH₃at 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 C₁₈OBD, 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 BF3⁻Et₂O (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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 Na₂SO₄and 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 SO₂bubbled 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 NH₃bubbled 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 CH₂at 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 Na₂SO₄and 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 Na₂SO₄and 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 CH₂at 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 Na₂SO₄and 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 Na₂SO₄and 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 CH₂at 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 Na₂SO₄and 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

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N′-((5-fluoro-2,4-diisopropylpyridin-3-yl)carbamoyl)-2-(2-hydroxypropan-2-yl)thiazole-5-sulfonimidamide (Scheme 1A)

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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)

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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

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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)

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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)

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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

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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

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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

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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

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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

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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)

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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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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
1^stand 2^ndpeaks 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
3^edand 4^thpeaks 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

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(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

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(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

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(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

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(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

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(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

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(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

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(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
1^st, 2^nd, 3^ed peak (three isomers) CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH₃•MeOH)
449

180
131a

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(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
4^th, 5^thpeaks (two isomers) CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH₃•MeOH)
449

181
131aab

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(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
6^thpeak CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
EtOH in Hex (8 mM NH₃•MeOH)
449

182
131c

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(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
1^stperk from Ex. 179; CHIRALPAK IE, 2*25 cm, 5 um
EtOH in Hex (8 mM NH₃•MeOH)
449

183
131d

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(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
2^ndperk from Ex. 179; CHIRALPAK IE, 2*25 cm, 5 um
EtOH in Hex (8 mM NH₃•MeOH)
449

184
131e

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(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
3^edperk from Ex. 179; CHIRALPAK IE, 2*25 cm, 5 um
EtOH in Hex (8 mM NH₃•MeOH)
449

185
131f

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(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
1^stperk from Ex. 180; CHIRALPAK AD-H-TC001 SFC, 2*25 cm, 5 um
MeOH (2 mM NH₃—MeOH) in CO₂
449

186
131g

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(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
2^ndperk resulted from Ex. 180 CHIRALPAK AD-H-TC001 SFC, 2*25 cm, 5 um
MeOH (2 mM NH₃—MeOH) in CO₂
449

187
121a

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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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- 4-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (8 mM NH₃•MeOH)
422

216
154b

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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- 4-sulfonimidamide
CHIRALPAK IC, 2*25 cm, 5 um
EtOH in Hex (8 mM NH₃•MeOH)
422

217
120a

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(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

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(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

embedded image

(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

embedded image

(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

embedded image

(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
1^stpeak Column, CHIRALPAK IG, 20*250 mm, 5 um
EtOH in MTBE (10 mM NH₃—MeOH)
411

224
184b

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(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 2^ndand 3^rdpeaks 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

embedded image

(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

embedded image

(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

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)thiophene- 2-sulfonimidamide
CHIRAL ART Cellulose-SB, 2*25 cm, 5 um
IPA in Hex (8 mM NH₃•MeOH)
435

230
175b

embedded image

(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

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-3- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
MeOH (2 mM NH₃—MeOH) in CO₂
423

232
180b

embedded image

(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 NH₃in this chiral chromatographic solvent and similar solvents were adjusted by adding 2 M NH₃in methanol to the desired NH₃concentration. In this case, the resulting concentration of NH₃in 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. U_eqis defined as ⅓

of the trace of the orthogonalised U_IJtensor.

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

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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 NH₃⁻MeOH); 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)

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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)

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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

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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

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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)pyridine-3- sulfonimidamide
444

300
683

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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

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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

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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-3- sulfonimidamide
444

303
704

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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

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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)-1- phenyl-1H-pyrazole-3- sulfonimidamide
495

305
663

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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)-1- phenyl-1H-pyrazole-3- sulfonimidamide
509

306
651

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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

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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

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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

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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

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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

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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- methoxypropan-2- yl)thiazole-5- sulfonimidamide
494

312
615

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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)-1- isopropyl-1H-pyrazole-3- sulfonimidamide
475

313
620

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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

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N′-((4-cyclopropyl-6- methylpyrimidin-2- yl)carbamoyl)-5-(2- hydroxypropan-2- yl)thiazole-2- sulfonimidamide
397

315
690

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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-4- sulfonimidamide
423

327
637

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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-4- sulfonimidamide
425

328
633

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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-3- (2-hydroxypropan-2- yl)benzenesulfonimidamide
415

329
625

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N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e] pyridin-8-yl)carbamoyl)-3- (2-hydroxypropan-2- yl)benzenesulfonimidamide
415

330
622

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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

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1-Isopropyl-N′-((3-methyl- 2-(trifluoromethyl)-6,7- dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole- 3-sulfonimidamide
431

332
617

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1-(Difluoromethyl)-N′-((3- methyl-2-(trifluoromethyl)- 6,7-dihydro-5H- cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole- 4-sulfonimidamide
439

333
614

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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

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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

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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

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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

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2-(2-Hydroxypropan-2-yl)- N′-((2-isopropyl-6,7- dihydro-5H- cyclopenta[b]pyridin-3- yl)carbamoyl)thiazole-5- sulfonimidamide
424

338
685

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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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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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)thiazole-2- sulfonimidamide
CHIRALPAK IG, 20*250 mm, 5 um
10% EtOH in MTBE (0.1% FA)
436

434
626a

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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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-4- sulfonimidamide
CHIRALPAK IG, 5*25 cm, 5 um
5% IPA in MTBE (10 mM NH₃—MeOH)
423

447
637b

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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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)

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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

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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

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3-(N′-((3,3-dimethyl- 1,2,3,5,6,7- hexahydrodicyclopenta [b,e]pyridin-8- yl)carbamoyl) sulfamidimidoyl)-N- methylbenzenesulfonamide
478

547
721c

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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

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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

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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

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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

(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 Na₂SO₄and 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 BCl₃in 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 Na₂SO₄and 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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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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

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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

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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

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1-(Difluoromethyl)-4-fluoro-N′- ((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
415

736

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1-Ethyl-4-fluoro-N′-((1,2,3,5,6,7- hexahydrodicyclopenta[b,e]pyridin-8- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
393

737

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N′-((2,3-dicyclopropyl-6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)carbamoyl)-1- (difluoromethyl)-4-fluoro-1H-pyrazole-3- sulfonimidamide
455

738

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N′-((3,5-dimethyl-2,6- bis(trifluoromethyl)pyridin-4- yl)carbamoyl)-4-(2-hydroxypropan-2- yl)thiophene-2-sulfonimidamide
505

739

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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

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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

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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

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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

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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

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1-Ethyl-4-fluoro-N′-((3-phenyl-6,7- dihydro-5H-cyclopenta[b]pyridin-4- yl)carbamoyl)-1H-pyrazole-3- sulfonimidamide
429

746

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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

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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

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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

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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

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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

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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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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
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

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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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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

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(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
1^stpeak and 2^ndpeak, Chiralpak ID, 2*25 cm, um
20% EtOH in Hex (0.1% FA)
449

822
1101b

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(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
3^rdpeak, Chiralpak ID, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449

823
1101c

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(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
4^thpeak, Chiralpak ID, 2*25 cm, 5 um
20% EtOH in Hex (0.1% FA)
449

824
1101d

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(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

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(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

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(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

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(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

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(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

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(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 IC₅₀of 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 #
IC₅₀in 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.

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

COMPOUNDS AND COMPOSITIONS FOR TREATING CONDITIONS ASSOCIATED WITH NLRP ACTIVITY

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

International Classifications

Abstract

Description

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PCT Information

Provisional Applications (13)