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) NLRP1 or NLRP3 or both NLRP1 and 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 NLRP1/3 activity (e.g., an increase, e.g., a condition, disease or disorder associated with NLRP1/3 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.

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.

The NLRP1 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as generalized vitiligo associated with autoimmune disease (autoimmune thyroid disease, latent autoimmune diabetes in adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus, and Addison's disease).

NLRP1 and NLRP3 can form a complex and they have 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, diseases caused by viral infection such as HIV and AIDS, autoimmune diseases such as rheumatoid arthritis, systemic Lupus erythematosus, autoimmune thyroiditis; Addison's disease, and pernicious anemia, cancer, and aging.

In light of the above, it would be desirable to provide compounds that modulate (e.g., antagonize) NRLP1/3, wherein the compounds inhibit NLRP3 or NLRP1 or both NLRP3 and NLRP1.

SUMMARY

This disclosure features chemical entities (e.g., a compound that modulates (e.g., antagonizes) NLRP1 or NLRP3 or both NLRP1 and 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 NLRP1 or NLRP3 or both NLRP1 and NLRP3 activity, also referred to herein “NLRP1/3” activity (e.g., an increase, e.g., a condition, disease or disorder associated with NLRP1/3 signaling).

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

An “antagonist” of NLRP1/3 includes compounds that inhibit the ability of NLRP1/3 to induce the production of IL-10 and/or IL-18 by directly binding to NLRP1/3, or by inactivating, destabilizing, altering distribution, of NLRP1/3 or otherwise.

In one aspect, compounds of Formula I, or a pharmaceutically acceptable salt thereof, are featured:

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

In one aspect, compounds of Formula II, or a pharmaceutically acceptable salt thereof, are featured:

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wherein the variables shown in Formula I can be as defined anywhere herein.

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) NLRP1 or NLRP3 or both NLRP1 and NLRP3 activity are featured that include contacting NLRP1 or NLRP3 or both NLRP1 and 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 NLRP1 or NLRP3 or both NLRP1 and NLRP3 (also referred to herein as “NLRP1/3”), as well as in vivo methods.

In a further aspect, methods of treatment of a disease in which NLRP1/3 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 NLRP1/3 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 diseases such as rheumatoid arthritis, systemic Lupus erythematosus, autoimmune thyroiditis; Addison's disease, and 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, each of the applications from which this application claims priority, and any attached appendices, are incorporated herein by reference in their entireties. In case of conflict between the present specification and any subject matter incorporated by reference herein, the present specification, including definitions, will control

As used herein, the term “NLRP1/3” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP 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 NLRP1/3 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, P A, 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, F L, 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 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, 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, tert-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, such as 3 to 8 carbons, such as 3 to 7 carbons, which may be optionally substituted. 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. Examples of heterocyclic rings include five-membered, six-membered, and seven-membered heterocyclic rings.

The term “cycloalkyl” as used herein includes an aromatic or nonaromatic cyclic 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 aromatic or nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring 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 “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, a curved line connecting two atoms indicates a chain of length as specified by the recited number or number range. For example, a chain connecting an atom “Atom 1” to an atomo “Atom 2” may be depicted as

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where the number outside the parenthetical indicates the number or range of numbers in the chain.

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 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.

DETAILED DESCRIPTION

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

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or a pharmaceutically acceptable salt thereof, wherein:

- X¹is O, S, or NH;
- X²is N or CR⁹;
- X³is NH or O;
- or when X³is NH, X³and R²taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R¹⁶; or when X³is NH, X³and R⁴taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R¹⁶;
- Y is N or CR⁸;
- R⁸is selected from H, CN, Cl, F, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, CONR¹¹R¹², C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R⁹is selected from H, CN, Cl, F, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, CONR¹¹R¹², C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R²is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- R³is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- R⁴is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- R⁵is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- provided that at least one of R², R³, R⁴and R⁵is not hydrogen, and that R²and R⁴are not both hydroxymethyl;
- or R²and R³taken together with the carbons connecting them form a four-membered to seven-membered ring A,
- or R⁴and R⁵taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- or R²and R³taken together with the carbons connecting them form a four-membered to seven-membered ring A and R⁴and R⁵taken together with the carbons connecting them form a four-membered to seven-membered ring B, wherein ring A is

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- and ring B is

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- wherein
- ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;
- n1 is from 2 to 5;
- m1 is from 1 to 10;
- wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;
- n2 is from 2 to 5;
- m2 is from 1 to 10;
- wherein each R⁶in each ring is the same or different and is selected from H, C₁-C₆alkyl, C₁-C₆alkoxy, NR¹¹R¹², oxo, and ═NR¹³;
- or two R⁶taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;
- R¹is selected from H, C₁-C₆alkyl, C₃-C₆cycloalkyl and C₃-C₆heterocycloalkyl; wherein R¹is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹², ═NR³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R¹⁰is selected from H, C₁-C₆alkyl, C₃-C₆cycloalkyl and C₃-C₆heterocycloalkyl;
- wherein R¹⁰is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- or R¹and R¹⁰taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R¹³is C₁-C₆alkyl;
- each of R¹¹and R¹²at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, CO₂R¹⁵and CONR¹⁷R¹⁸;
- R¹⁵is C₁-C₆alkyl;
- each of R⁷and R¹⁸at each occurrence is independently selected from hydrogen and C₁-C₆alkyl; each R¹⁶is the same or different and is selected from H, C₁-C₆alkyl, C₁-C₆alkoxy, NR¹¹R¹², oxo, and ═NR³;
- provided that if the compound of formula I comprises ring A and ring B; X³is NH; X²is CH; and R¹⁰is H,
- then (i) if X¹is 0 and R¹is C₁-C₆alkyl optionally substituted with hydroxy, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, or CONR¹¹R¹², then Y is not N, CF, CCl or CH, (ii) if X¹is O and R¹is C₁-C₆alkyl substituted with oxo, then Y is not CH, and (iii) if X¹is S, then Y is not CH;
- and provided that if R²and R⁴are each isopropyl; X³is NH; X²is CH; R¹⁰is H; and R¹is C₁-C₆alkyl optionally substituted with hydroxy, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, or CONR¹¹R¹²,
- then Y is not CH or CCl.

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

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- or a pharmaceutically acceptable salt thereof, wherein:
- X¹is O, S, or NH;
- X²is N or CR⁹;
- X³is NH or O;
- or when X³is NH, X³and R²taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R¹⁶;
- or when X³is NH, X³and R⁴taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R¹⁶; Y is N or CR⁸;
- R⁸is selected from H, CN, Cl, F, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, CONR¹¹R¹², C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R⁹is selected from H, CN, Cl, F, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, CONR¹¹R¹², C₁-C₆alkyl, and C₁-C₆haloalkyl;
- R²is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- R³is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- R⁴is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- R⁵is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- provided that at least one of R², R³, R⁴and R⁵is not hydrogen, and that R²and R⁴are not both hydroxymethyl;
- or R²and R³taken together with the carbons connecting them form a four-membered to seven-membered ring A,
- or R⁴and R⁵taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- or R²and R³taken together with the carbons connecting them form a four-membered to seven-membered ring A and R⁴and R⁵taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- wherein ring A is

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- and ring B is

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- wherein
- ring A is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;
- n1 is from 2 to 5;
- m1 is from 1 to 10;
- wherein ring B is a carbocyclic ring or a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;
- n2 is from 2 to 5;
- m2 is from 1 to 10;
- wherein each R⁶in each ring is the same or different and is selected from H, C₁-C₆alkyl, C₁-C₆alkoxy, NR¹¹R¹², oxo, and ═NR¹³;
- or two R⁶taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;
- R¹is selected from H, C₁-C₆alkyl, C₃-C₆cycloalkyl, and C₃-C₆heterocycloalkyl;
- wherein R¹is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R¹⁰is selected from H, C₁-C₆alkyl, C₃-C₆cycloalkyl, and C₃-C₆heterocycloalkyl; wherein R¹⁰is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹², ═NR^L3, COOC₁-C₆alkyl, and CONR¹¹R¹²; or R¹and R¹⁰taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R¹³is C₁-C₆alkyl;
- each of R¹and R¹²at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, CO₂R¹⁵and CONR¹⁷R¹⁸;
- R¹⁵is C₁-C₆alkyl;
- each of R¹⁷and R¹⁸at each occurrence is independently selected from hydrogen and C₁-C₆alkyl;
- each R¹⁶is the same or different and is selected from H, C₁-C₆alkyl, C₁-C₆alkoxy, NR¹¹R¹², oxo, and ═NR¹³;
- provided that if the compound of formula I comprises ring A and ring B; X³is NH; X²is CH; and R¹⁰is H,
- then (i) if X¹is 0 and R¹is C₁-C₆alkyl substituted with hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹²,
- ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹², then Y is not N, CF, CCl or CH, and (ii) if X¹is S, then Y is not CH;
- and provided that if R²and R⁴are each isopropyl; X³is NH; X²is CH; R¹⁰is H; and R¹is C₁-C₆alkyl optionally substituted with hydroxy, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, or CONR¹¹R¹²,
- then Y is not CH or CC.

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

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or a pharmaceutically acceptable salt thereof, wherein Formula II is selected from

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is selected from

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- X²is N or CR⁹;
- X³is NH or O;
- X³is O;
- or when X³is NH, X³and R²taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R^1″; or when X³is NH, X³and R⁴taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R¹⁶; Y is N or CR⁸;
- R⁸is selected from H, CN, Cl, F, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, CONR¹¹R¹², C₁-C₆alkyl, C₁-C₆haloalkoxy, and C₁-C₆haloalkyl;
- R^8′ is selected from CN, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, CONR¹¹R¹², and C₁-C₆haloalkyl;
- R⁹is selected from H, CN, Cl, F, CO₂C₁-C₆alkyl, CO₂C₃-C₈cycloalkyl, CONR¹¹R¹², C₁-C₆alkyl, and C₁-C₆haloalkyl;
  - R²is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- R^2′ is hydrogen, halo, or C₁-C₆alkyl optionally substituted with hydroxy;
- R^2″is hydrogen or C₁-C₆alkyl;
- R³is hydrogen, CN, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- R^3′ is hydrogen, halo, or C₁-C₆alkyl optionally substituted with hydroxy;
- R^3″is hydrogen, CN, or C₁-C₆alkyl;
- R⁴is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- R^4′ is hydrogen, halo, or C₁-C₆alkyl optionally substituted with hydroxy;
- R^4″is hydrogen or C₁-C₆alkyl;
- R⁵is hydrogen, C₁-C₆alkoxy, halo, C₁-C₆haloalkyl, or C₁-C₆alkyl optionally substituted with hydroxy;
- R^5′ is hydrogen, halo, or C₁-C₆alkyl optionally substituted with hydroxy;
- R^5″is hydrogen, CN, or C₁-C₆alkyl;
- or R²and R³taken together with the carbons connecting them form a four-membered to seven-membered ring A,
- or R^2′ and R^3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A,
- or R⁴and R⁵taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- or R^4′and R^5′taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- or R²and R³taken together with the carbons connecting them form a four-membered to seven-membered ring A and R⁴and R⁵taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- or R^2′ and R^3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A and R^4′ and R^5′ taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- wherein ring A is

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- and ring B is

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- wherein
- ring A is a saturated carbocyclic ring;
- n1 is from 2 to 5;
- m1 is from 1 to 10;
- wherein ring B is a saturated carbocyclic ring;
- n2 is from 2 to 5;
- m2 is from 1 to 10;
- wherein each R⁶in each ring is the same or different and is selected from H, C₁-C₆alkyl, C₁-C₆alkoxy, NR¹¹R¹², oxo, and ═NR¹³;
- or two R⁶taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;
- R¹is selected from H, unsubstituted C₁-C₆alkyl, C(R¹⁹)₂OH, C(O)C₂-C₆alkyl, and C₃-C₆cycloalkyl;
- wherein each C(O)C₂-C₆alkyl and C₃-C₆cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R^1′is selected from unsubstituted C₁-C₆alkyl, C(R¹⁹)₂OH, C(O)C₂-C₆alkyl, and C₃-C₆cycloalkyl;
- wherein each C(O)C₂-C₆alkyl and C₃-C₆cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R^1″ is selected from unsubstituted C₁-C₆alkyl, C(O)C₂-C₆alkyl, and C₃-C₆cycloalkyl; wherein each C(O)C₂-C₆alkyl and C₃-C₆cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R^1′″is selected from C(R¹⁹)₂OH;
- R¹⁰is selected from H, Cl, C₁-C₆alkyl, C₃-C₆cycloalkyl and C₃-C₆heterocycloalkyl;
- wherein R¹⁰is optionally substituted with one or more substituents each independently selected from hydroxy, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R^10′ is selected from H, Cl, C₃-C₆cycloalkyl and C₃-C₆heterocycloalkyl; wherein R^10′ is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹², ═NR³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R^10″is selected from Cl, C₁-C₆alkyl, C₃-C₆cycloalkyl, and C₃-C₆heterocycloalkyl; wherein R^10″is optionally substituted with one or more substituents each independently selected from hydroxy, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R^10′″is selected from Cl, C₁-C₆alkyl substituted with hydroxy, C₃-C₆cycloalkyl, and C₃-C₆heterocycloalkyl;
- wherein the C₃-C₆cycloalkyl, and C₃-C₆heterocycloalkyl above are each optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- or R¹and R¹⁰taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C₁-C₆alkoxy, NR¹¹R¹², ═NR¹³, COOC₁-C₆alkyl, and CONR¹¹R¹²;
- R¹³is C₁-C₆alkyl;
- each of R¹¹and R¹²at each occurrence is independently selected from hydrogen, C₁-C₆alkyl, CO₂R¹⁵and CONR¹⁷R¹⁸;
- R¹⁵is C₁-C₆alkyl;
- each of R¹⁷and R¹⁸at each occurrence is independently selected from hydrogen and C₁-C₆alkyl;
- each R¹⁶is the same or different and is selected from H, C₁-C₆alkyl, C₁-C₆alkoxy, NR¹¹R¹², oxo, and ═NR³;
- each R¹⁹is the same and is selected from C₁-C₆alkyl;
- R²⁰is selected from H, halo, or C₁-C₆alkyl optionally substituted with hydroxy;
- R²¹is selected from H, halo, or C₁-C₆alkyl substituted with hydroxy; provided that if (1) Formula II is

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and if (2) R^10′ is H or C₃-C₆heterocycloalkyl; then

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is not

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and provided that if: (1) Formula II is

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and (2) either of R¹or R^1′, when present, is C(R¹⁹)₂OH; and (3) either of R^10′ or R^10′″, when present, is not Cl; then

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is not

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and provided that if: (1) Formula II is

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and (2) R^10′″is C₁-C₆alkyl substituted with hydroxy; then

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is not

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

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or a pharmaceutically acceptable salt thereof, wherein Formula II is selected from

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is selected from

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- Y is N or CR⁸;
- R⁸is selected from H, CN, Cl, and F;
- R^8″ is selected from CN and CONR¹¹R¹²;
- R⁹is selected from H;
- R²is hydrogen or C₁-C₆alkyl;
- R^2′ is C₁-C₆alkyl;
- R³is hydrogen, CN, C₁-C₆alkoxy, or halo;
- R^3′ is hydrogen or halo;
- R⁴is hydrogen or C₁-C₆alkyl;
- R^4′ is C₁-C₆alkyl;
- R⁵is hydrogen;
- R^5′ is hydrogen;
- or R²and R³taken together with the carbons connecting them form a four-membered to seven-membered ring A,
- or R^2′ and R^3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A,
- or R⁴and R⁵taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- or R^4′ and R^5′ taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- or R²and R³taken together with the carbons connecting them form a four-membered to seven-membered ring A and R⁴and R⁵taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- or R^2′ and R^3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A and R^4′ and R^5′taken together with the carbons connecting them form a four-membered to seven-membered ring B,
- wherein ring A is

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- and ring B is

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- wherein
- ring A is a saturated carbocyclic ring;
- n1 is 3;
- m1 is 0;
- wherein ring B is a saturated carbocyclic ring;
- n2 is 3;
- m2 is 0;
- R¹is selected from H;
- R^1′is selected from C(R¹⁹)₂OH and C₃-C₆cycloalkyl;
- wherein the C₃-C₆cycloalkyl above is optionally substituted with one or more hydroxy;
- R^1″is selected from C₃-C₆cycloalkyl;
- wherein the C₃-C₆cycloalkyl above is optionally substituted with one or more hydroxy;
- R^1′″is selected from C(R¹⁹)₂OH;
- R¹⁰is selected from H, Cl, C₁-C₆alkyl, and C₃-C₆cycloalkyl;
- wherein R¹⁰is optionally substituted with one or more substituents each independently selected from hydroxy;
- R^10′ is selected from H or C₁;
- R^10″is selected from C₁-C₆alkyl, and C₃-C₆cycloalkyl;
- wherein R^10″is optionally substituted with one or more hydroxy;
- R^10′″is selected from C₁-C₆alkyl and C₃-C₆cycloalkyl;
- wherein R^10′″is optionally substituted with one or more hydroxy;
- each of R¹¹and R²at each occurrence is independently selected from hydrogen;
- each R¹⁹is the same and is selected from C₁-C₆alkyl;
- R²⁰is selected from H or C₁-C₆alkyl optionally substituted with hydroxy;
- R²¹is selected from H or C₁-C₆alkyl substituted with hydroxy;
- provided that if: (1) Formula II is

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and (2) either of R¹or R^1′, when present, is C(R¹⁹)₂OH; and (3) either of R^10′or R^10′″, when present, is not Cl; then

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is not

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and provided that if: (1) Formula II is

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and if (2) R^10′″is C₁-C₆alkyl substituted with hydroxy; then

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is not or

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

The groups X¹and X²

In some embodiments of one or more formulae herein, X¹is O.

In some embodiments of one or more formulae herein, X¹is S.

In some embodiments of one or more formulae herein, X¹is NH.

In some embodiments of one or more formulae herein, X²is CR⁹.

In some embodiments of one or more formulae herein, X²is CH.

In some embodiments of one or more formulae herein, X²is N.

In some embodiments of one or more formulae herein, X¹is O and X²is CR⁹.

In some embodiments of one or more formulae herein, X¹is S and X²is CR⁹.

In some embodiments of one or more formulae herein, X¹is O and X²is CH.

In some embodiments of one or more formulae herein, X¹is S and X²is CH.

In some embodiments of one or more formulae herein, X¹is O and X²is N.

In some embodiments of one or more formulae herein, X¹is S and X²is N.

In some embodiments of one or more formulae herein, X¹is NH and X²is N.

The groups X³and X^3′

In some embodiments of one or more formulae herein, X³is NH.

In some embodiments of one or more formulae herein, X³is O.

In some embodiments, X³and R²taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R¹⁶.

In some embodiments, X³and R⁴taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R¹⁶.

In some embodiments, X³and R²taken together with the atoms connecting them form a four-to-seven-membered ring C of the formula

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wherein q1 is 0, 1, 2 or 3; A1 is N; A2 is O, NH, or CH₂, provided that A1 and A2 are not both heteroatoms; and ring C is optionally substituted with 1 to 8 R¹⁶.

In some embodiments of ring C, Al is N and A2 is CH₂.

In some embodiments of ring C, R¹⁶is H.

In some embodiments, ring C is a heterocyclic ring containing one heteroatom selected from O, N and S.

In some embodiments, ring C is a heterocyclic ring containing two heteroatoms each independently selected from O, N and S.

In some embodiments of one or more formulae herein, X^3′ is O.

The Group Y

In some embodiments of one or more formulae herein, Y is CR⁸.

In some embodiments of one or more formulae herein, Y is N.

The Groups R², R⁴, R³and R⁵

In some embodiments of one or more formulae herein, R²is hydrogen.

In some embodiments of one or more formulae herein, R²is C₁-C₆alkoxy.

In some embodiments of one or more formulae herein, R²is methoxy.

In some embodiments of one or more formulae herein, R²is halo.

In some embodiments of one or more formulae herein, R²is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R²is CF₃.

In some embodiments of one or more formulae herein, R²is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R²is isopropyl.

In some embodiments of one or more formulae herein, R²is methyl.

In some embodiments of one or more formulae herein, R³is hydrogen.

In some embodiments of one or more formulae herein, R³is C₁-C₆alkoxy.

In some embodiments of one or more formulae herein, R³is methoxy.

In some embodiments of one or more formulae herein, R³is halo.

In some embodiments of one or more formulae herein, R³is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R³is CF₃.

In some embodiments of one or more formulae herein, R³is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R³is isopropyl.

In some embodiments of one or more formulae herein, R³is methyl.

In some embodiments of one or more formulae herein, R³is CN.

In some embodiments of one or more formulae herein, R⁴is hydrogen.

In some embodiments of one or more formulae herein, R⁴is C₁-C₆alkoxy.

In some embodiments of one or more formulae herein, R⁴is methoxy.

In some embodiments of one or more formulae herein, R⁴is halo.

In some embodiments of one or more formulae herein, R⁴is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R⁴is CF₃.

In some embodiments of one or more formulae herein, R⁴is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R⁴is isopropyl.

In some embodiments of one or more formulae herein, R⁴is methyl.

In some embodiments of one or more formulae herein, R⁵is hydrogen.

In some embodiments of one or more formulae herein, R⁵is C₁-C₆alkoxy.

In some embodiments of one or more formulae herein, R⁵is methoxy.

In some embodiments of one or more formulae herein, R⁵is halo.

In some embodiments of one or more formulae herein, R⁵is C₁-C₆haloalkyl.

In some embodiments of one or more formulae herein, R⁵is CF₃.

In some embodiments of one or more formulae herein, R⁵is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R²and R⁴is hydrogen.

In some embodiments of one or more formulae herein, each of R²and R⁴is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R⁵is isopropyl.

In some embodiments of one or more formulae herein, R⁵is methyl.

In some embodiments of one or more formulae herein, each of R²and R⁴is isopropyl.

In some embodiments of one or more formulae herein, each of R²and R⁴is t-butyl.

In some embodiments of one or more formulae herein, each of R²and R⁴is methyl.

In some embodiments of one or more formulae herein, each of R²and R⁴is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R³and R⁵is hydrogen.

In some embodiments of one or more formulae herein, each of R³and R⁵is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R³and R⁵is isopropyl.

In some embodiments of one or more formulae herein, each of R³and R⁵is t-butyl.

In some embodiments of one or more formulae herein, each of R³and R⁵is methyl.

In some embodiments of one or more formulae herein, each of R³and R⁵is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R³and R⁵is hydrogen and each of R²and R⁴is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R³and R⁵is hydrogen and each of R²and R⁴is isopropyl.

In some embodiments of one or more formulae herein, each of R³and R⁵is hydrogen and each of R²and R⁴is t-butyl.

In some embodiments of one or more formulae herein, each of R³and R⁵is hydrogen and each of R²and R⁴is methyl.

In some embodiments of one or more formulae herein, each of R³and R⁵is hydrogen and each of R²and R⁴is hydroxymethyl.

In some embodiments of one or more formulae herein, R³is halo and R⁵is H.

In some embodiments of one or more formulae herein, R³is CN and R⁵is H.

In some embodiments of one or more formulae herein, each of R²and R⁴is hydrogen and each of R³and R⁵is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R²and R⁴is hydrogen and each of R³and R⁵is isopropyl.

In some embodiments of one or more formulae herein, each of R²and R⁴is hydrogen and each of R³and R⁵is t-butyl.

In some embodiments of one or more formulae herein, each of R²and R⁴is hydrogen and each of R³and R⁵is methyl.

In some embodiments of one or more formulae herein, each of R²and R⁴is hydrogen and each of R³and R⁵is hydroxymethyl.

In some embodiments of one or more formulae herein, R²and R³taken together with the carbons connecting them form ring A.

In some embodiments of one or more formulae herein, R⁴and R⁵taken together with the carbons connecting them form ring B.

In some embodiments of one or more formulae herein, R²and R³taken together with the carbons connecting them form ring A and R⁴and R⁵taken together with the carbons connecting them form ring B.

In some embodiments of one or more formulae herein, R²and R³taken together with the carbons connecting them form a five membered carbocyclic ring and R⁴and R⁵taken together with the carbons connecting them form a five membered carbocyclic ring.

The groups R^2′, R^4′, R^3′ and R^5′

In some embodiments of one or more formulae herein, R^2′ is hydrogen.

In some embodiments of one or more formulae herein, R^2′ is halo.

In some embodiments of one or more formulae herein, R^2′is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R^2′is isopropyl.

In some embodiments of one or more formulae herein, R^2′ is methyl.

In some embodiments of one or more formulae herein, R^3′ is hydrogen.

In some embodiments of one or more formulae herein, R^3′ is halo.

In some embodiments of one or more formulae herein, R^3′ is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R^3′ is isopropyl.

In some embodiments of one or more formulae herein, R^3′ is methyl.

In some embodiments of one or more formulae herein, R^4′ is hydrogen.

In some embodiments of one or more formulae herein, R^4′ is halo.

In some embodiments of one or more formulae herein, R^4′ is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R^4′ is isopropyl.

In some embodiments of one or more formulae herein, R^4′ is methyl.

In some embodiments of one or more formulae herein, R^5′is hydrogen.

In some embodiments of one or more formulae herein, R^5′is halo.

In some embodiments of one or more formulae herein, R^5′ is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R^2′ and R^4′ is hydrogen.

In some embodiments of one or more formulae herein, each of R^2′ and R^4′ is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R^5′is isopropyl.

In some embodiments of one or more formulae herein, R^5′is methyl.

In some embodiments of one or more formulae herein, each of R^2′ and R^4′ is isopropyl.

In some embodiments of one or more formulae herein, each of R^2′ and R^4′ is t-butyl.

In some embodiments of one or more formulae herein, each of R^2′ and R^4′ is methyl.

In some embodiments of one or more formulae herein, each of R^2′ and R^4′ is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′is hydrogen.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′ is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′is isopropyl.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′is t-butyl.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′ is methyl.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′ is hydrogen and each of R^2′and R^4′ is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′ is hydrogen and each of R^2′and R^4′ is isopropyl.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′ is hydrogen and each of R^2′and R^4′ is t-butyl.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′ is hydrogen and each of R^2′and R^4′ is methyl.

In some embodiments of one or more formulae herein, each of R^3′ and R^5′ is hydrogen and each of R^2′and R^4′ is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R^2′ and R^4′ is hydrogen and each of R^3′ and R^5′ is C₁-C₆alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R^2′and R^4′ is hydrogen and each of R^3′ and R^5′ is isopropyl.

In some embodiments of one or more formulae herein, each of R^2′and R^4′ is hydrogen and each of R^3′ and R^5′ is t-butyl.

In some embodiments of one or more formulae herein, each of R^2′and R^4′ is hydrogen and each of R^3′ and R^5′ is methyl.

In some embodiments of one or more formulae herein, each of R^2′and R^4′ is hydrogen and each of R^3′ and R^5′ is hydroxymethyl.

In some embodiments of one or more formulae herein, R^2′and R^3′ taken together with the carbons connecting them form ring A.

In some embodiments of one or more formulae herein, R^4′ and R^5′ taken together with the carbons connecting them form ring B.

In some embodiments of one or more formulae herein, R^2′and R^3′ taken together with the carbons connecting them form ring A and R^4′ and R^5′ taken together with the carbons connecting them form ring B.

The groups R^2″, R^4″, R^3″ and R^5″

In some embodiments of one or more formulae herein, R^2″is hydrogen.

In some embodiments of one or more formulae herein, R^2″is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^2″is isopropyl.

In some embodiments of one or more formulae herein, R^2″is methyl.

In some embodiments of one or more formulae herein, R^3″is hydrogen.

In some embodiments of one or more formulae herein, R^3″is CN.

In some embodiments of one or more formulae herein, R^3″is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^3″is isopropyl.

In some embodiments of one or more formulae herein, R^3″is methyl.

In some embodiments of one or more formulae herein, R^4″is hydrogen.

In some embodiments of one or more formulae herein, R^4″is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^4″is isopropyl.

In some embodiments of one or more formulae herein, R^4″is methyl.

In some embodiments of one or more formulae herein, R^5″ is hydrogen.

In some embodiments of one or more formulae herein, R^5″ is CN.

In some embodiments of one or more formulae herein, R^5′is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, each of R^2″and R^4″is hydrogen.

In some embodiments of one or more formulae herein, each of R^2″and R^4″is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R^5″ is isopropyl.

In some embodiments of one or more formulae herein, R^5″ is methyl.

In some embodiments of one or more formulae herein, each of R^2″and R^4″is isopropyl.

In some embodiments of one or more formulae herein, each of R^2″and R^4″is t-butyl.

In some embodiments of one or more formulae herein, each of R^2″and R^4″is methyl.

In some embodiments of one or more formulae herein, each of R^3″ and R^5″ is hydrogen.

In some embodiments of one or more formulae herein, each of R^3″ and R^5″ is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, each of R^3″ and R^5″is isopropyl.

In some embodiments of one or more formulae herein, each of R^3″ and R^5″ is t-butyl.

In some embodiments of one or more formulae herein, each of R^3″ and R^5″ is methyl.

In some embodiments of one or more formulae herein, each of R^3″ and R^5″is hydrogen and each of R^2″and R^4″is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, each of R^3″ and R^5″ is hydrogen and each of R^2″and R^4″is isopropyl.

In some embodiments of one or more formulae herein, each of R^3″ and R^5″is hydrogen and each of R^2″and R^4″is t-butyl.

In some embodiments of one or more formulae herein, each of R^3″ and R^5″is hydrogen and each of R^2″and R^4″is methyl.

In some embodiments of one or more formulae herein, each of R^2″and R^4″is hydrogen and each of R^3″ and R^3″is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, each of R^2″and R^4″is hydrogen and each of R^3″ and R^5″is isopropyl.

In some embodiments of one or more formulae herein, each of R^2″and R^4″is hydrogen and each of R^3″ and R^5″is t-butyl.

In some embodiments of one or more formulae herein, each of R^2″and R^4″is hydrogen and each of R^3″ and R^5″is methyl.

Rings A and B

In some embodiments of one or more formulae herein, ring A is a carbocyclic ring.

In some embodiments of one or more formulae herein, ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments of one or more formulae herein, ring B is a carbocyclic ring.

In some embodiments of one or more formulae herein, ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, ring A is a carbocyclic ring and n1 is 3.

In some embodiments, ring A is a carbocyclic ring and n1 is 4.

In some embodiments, ring A is a saturated carbocyclic ring.

In some embodiments, ring B is a saturated carbocyclic ring.

In some embodiments, ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 3.

In some embodiments, ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 4.

In some embodiments, ring B is a carbocyclic ring and n2 is 3.

In some embodiments, ring B is a carbocyclic ring and n2 is 4.

In some embodiments, ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 3.

In some embodiments, ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 4.

In some embodiments, ring A is the same as ring B.

In some embodiments, ring A is

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In some embodiments, ring B is

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In some embodiments, ring B is

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and is the same as ring A.

In some embodiments, ring A is

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In some embodiments, ring B is

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and is the same as ring A.

In some embodiments, ring A is a heterocyclic ring of the formula

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In some embodiments, ring A is a heterocyclic ring of the formula

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The Groups R⁶and R⁷and the Variables n1, n2, m1 and m2 in Ring a and Ring B

In some embodiments of one or more formulae herein, R⁶is H.

In some embodiments of one or more formulae herein, R⁶is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, R⁶is C₁-C₆alkoxy.

In some embodiments of one or more formulae herein, R⁶is methoxy.

In some embodiments of one or more formulae herein, R⁶is NR¹¹R¹².

In some embodiments of one or more formulae herein, R⁶is oxo.

In some embodiments of one or more formulae herein, R⁶is ═NR¹³.

In some embodiments of one or more formulae herein, n1 is 2.

In some embodiments of one or more formulae herein, n1 is 3.

In some embodiments of one or more formulae herein, n1 is 4.

In some embodiments of one or more formulae herein, n1 is 5.

In some embodiments of one or more formulae herein, n2 is 2.

In some embodiments of one or more formulae herein, n2 is 3.

In some embodiments of one or more formulae herein, n2 is 4.

In some embodiments of one or more formulae herein, n2 is 5.

In some embodiments of one or more formulae herein, m1 is 1.

In some embodiments of one or more formulae herein, m1 is 2.

In some embodiments of one or more formulae herein, m1 is 3.

In some embodiments of one or more formulae herein, m1 is 4.

In some embodiments of one or more formulae herein, m2 is 1.

In some embodiments of one or more formulae herein, m2 is 2.

In some embodiments of one or more formulae herein, m2 is 3.

In some embodiments of one or more formulae herein, m2 is 4.

In some embodiments of one or more formulae herein, two R⁶taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments of one or more formulae herein, each R⁶in each ring is H.

In some embodiments of one or more formulae herein, each R⁶in each ring is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, each R⁷in each ring is H.

In some embodiments of one or more formulae herein, each R⁷in each ring is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, each R⁶in each ring is H and each R⁷in each ring is H.

In some embodiments of one or more formulae herein, each R⁶in each ring is H and each R⁷in each ring is C₁-C₆alkyl.

In some embodiments of one or more formulae herein, each R⁶in each ring is C₁-C₆alkyl and each R⁷in each ring is H.

In some embodiments of one or more formulae herein, each R⁶in each ring is C₁-C₆alkyl and each R⁷in each ring is C₁-C₆alkyl.

The ring E