WO2017184624A1 - Compounds and compositions for treating conditions associated with nlrp activity - Google Patents

Compounds and compositions for treating conditions associated with nlrp activity Download PDF

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Publication number
WO2017184624A1
WO2017184624A1 PCT/US2017/028167 US2017028167W WO2017184624A1 WO 2017184624 A1 WO2017184624 A1 WO 2017184624A1 US 2017028167 W US2017028167 W US 2017028167W WO 2017184624 A1 WO2017184624 A1 WO 2017184624A1
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WIPO (PCT)
Prior art keywords
alkyl
membered
hydroxy
optionally substituted
ring
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2017/028167
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English (en)
French (fr)
Inventor
Gary Glick
Shomir Ghosh
William R. Roush
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Innate Tumor Immunity Inc
Original Assignee
IFM Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by IFM Therapeutics Inc filed Critical IFM Therapeutics Inc
Priority to EP17720928.5A priority Critical patent/EP3445757B1/en
Priority to JP2019505347A priority patent/JP2019518071A/ja
Priority to AU2017254523A priority patent/AU2017254523B2/en
Priority to EP20208882.9A priority patent/EP3872070A1/en
Priority to ES17720928T priority patent/ES2855732T3/es
Priority to US16/094,499 priority patent/US11339136B2/en
Publication of WO2017184624A1 publication Critical patent/WO2017184624A1/en
Anticipated expiration legal-status Critical
Priority to US17/711,205 priority patent/US11760735B2/en
Ceased legal-status Critical Current

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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings

Definitions

  • 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).
  • a compound that modulates e.g., antagonizes
  • NLRP1 or NLRP3 or both NLRP1 and NLRP3 e.g., antagonizes
  • NLRP1/3 activity e.g., an increase, e.g.
  • 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).
  • 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 rhe
  • 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).
  • a compound that modulates e.g., antagonizes
  • NLRP1 or NLRP3 or both NLRP1 and NLRP3 e.g., antagonizes
  • NLRP1 or NLRP3 or both NLRP1 and NLRP3 e.g.,
  • 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-1 ⁇ and/or IL-18 by directly binding to NLRP1/3, or by inactivating, destabilizing, altering distribution, of NLRP1/3 or otherwise.
  • 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.
  • 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
  • one or more pharmaceutically acceptable excipients e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same.
  • methods for modulating e.g., agonizing, partially agonizing, antagonizing
  • NLRP1 or NLRP3 or both NLRP1 and NLRP3 activity 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.
  • methods of treatment of a disease in which NLRP1/3 signaling contributes to the pathology and/or symptoms and/or progression of the disease 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).
  • 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 of treatment 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.
  • 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
  • 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
  • the methods can further include identifying the subject.
  • 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.
  • API refers to an active pharmaceutical ingredient.
  • an “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.
  • 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.
  • 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.
  • 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.
  • pharmaceutically acceptable salt may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • 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.
  • 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.
  • 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
  • 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.
  • 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, tart
  • “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.
  • 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.
  • 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.
  • primate e.g., human
  • monkey cow, pig, sheep, goat
  • horse dog, cat, rabbit, rat
  • patient is used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
  • treat 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.
  • halo refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
  • alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • C 1-10 indicates 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.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
  • 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.
  • 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.
  • heterocyclic rings include five-membered, six- membered, and seven-membered heterocyclic rings.
  • 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.
  • cycloalkyls include five- membered, six-membered, and seven-membered rings. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl,.
  • 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.
  • heterocycloalkyls include five-membered, six- membered, and seven-membered heterocyclic rings.
  • Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.
  • hydroxy refers to an OH group.
  • amino refers to an NH 2 group.
  • oxo refers to O.
  • a curved line connecting two atoms indicates a chain of length as specified by the recited number or number range.
  • a chain connecting an atom“Atom 1” to an atomo“Atom 2” may be depicted as ,
  • atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • isotopes of carbon include 13 C and 14 C.
  • X 1 is O, S, or NH
  • X 2 is N or CR 9 ;
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, and C 1 -C 6 haloalkyl;
  • R 9 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, and C1-C6 haloalkyl;
  • R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl,or C 1 -C 6 alkyl optionally substituted with hydroxy
  • R 3 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy
  • R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 2 , R 3 , R 4 and R 5 is not hydrogen, and that R 2 and R 4 are not both hydroxymethyl;
  • 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,
  • 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;
  • n1 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;
  • n2 is from 1 to 10;
  • R 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;
  • R 10 is selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;
  • R 1 and R 10 taken 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
  • R 13 is C1-C6 alkyl
  • each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl,
  • R 15 is C1-C6 alkyl
  • the compound of formula I comprises ring A and ring B; X 3 is NH; X 2 is CH; and R 10 is H,
  • X 1 is O, S, or NH
  • X 2 is N or CR 9 ;
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, and C1-C6 haloalkyl;
  • R 9 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, and C 1 -C 6 haloalkyl;
  • R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl,or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 3 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy
  • R 4 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy
  • R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 2 , R 3 , R 4 and R 5 is not hydrogen, and that R 2 and R 4 are not both hydroxymethyl;
  • 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,
  • 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;
  • n1 is from 1 to 10;
  • 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;
  • n2 is from 1 to 10;
  • R 1 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl;
  • R 10 is selected from H, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl;
  • R 1 and R 10 taken 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
  • R 13 is C 1 -C 6 alkyl
  • each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl,
  • R 15 is C 1 -C 6 alkyl
  • the compound of formula I comprises ring A and ring B; X 3 is NH; X 2 is CH; and R 10 is H,
  • Y is not CH or CCl.
  • X 2 is N or CR 9 ;
  • X 3 is NH or O
  • X 3’ is O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO 11
  • R 8’ is selected from CN, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , and C1-C6 haloalkyl;
  • R 9 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, and C1-C6 haloalkyl;
  • R 2 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 2’ is hydrogen, halo, or C1-C6 alkyl optionally substituted with hydroxy; R 2’’ is hydrogen or C1-C6 alkyl;
  • R 3 is hydrogen, CN, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 3’ is hydrogen, halo, or C1-C6 alkyl optionally substituted with hydroxy
  • R 3’’ is hydrogen, CN, or C 1 -C 6 alkyl
  • R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 4’ is hydrogen, halo, or C1-C6 alkyl optionally substituted with hydroxy
  • R 4’’ is hydrogen or C 1 -C 6 alkyl
  • R 5 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 5’ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy
  • R 5’’ is hydrogen, CN, or C 1 -C 6 alkyl
  • 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,
  • 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,
  • ring A is a saturated carbocyclic ring
  • n1 is from 2 to 5;
  • n1 is from 1 to 10;
  • ring B is a saturated carbocyclic ring
  • n2 is from 2 to 5;
  • n2 is from 1 to 10;
  • R 1 is selected from H, unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
  • R 1’’ is selected from unsubstituted C1-C6 alkyl, C(O)C2-C6 alkyl, and C3-C6 cycloalkyl;
  • R 1’’’ is selected from C(R 19 )2OH
  • R 10 is selected from H, Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;
  • R 10’ is selected from H, Cl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;
  • R 10’’ is selected from Cl, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 3 -C 6 heterocycloalkyl;
  • R 1 and R 10 taken 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
  • R 13 is C1-C6 alkyl
  • each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, CO2R 15 and CONR 17 R 18 ;
  • each R 19 is the same and is selected from C1-C6 alkyl
  • R 20 is selected from H, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy
  • R 21 is selected from H, halo, or C 1 -C 6 alkyl substituted with hydroxy
  • R 1 or R 1’ when present, is C(R 19 )2OH; and (3)
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, and F;
  • R 8’ is selected from CN and CONR 11 R 12 ;
  • R 9 is selected from H
  • R 2 is hydrogen or C 1 -C 6 alkyl
  • R 2’ is C 1 -C 6 alkyl
  • R 3 is hydrogen, CN, C1-C6 alkoxy, or halo
  • R 3’ is hydrogen or halo
  • R 4 is hydrogen or C 1 -C 6 alkyl
  • R 4’ is C1-C6 alkyl
  • R 5 is hydrogen
  • R 5’ is hydrogen
  • R 4 and R 5 taken 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,
  • 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,
  • 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,
  • ring A is a saturated carbocyclic ring
  • n1 3;
  • n1 0;
  • ring B is a saturated carbocyclic ring
  • n2 is 3;
  • R 1’ is selected from C(R 19 )2OH and C3-C6 cycloalkyl
  • R 1’’ is selected from C 3 -C 6 cycloalkyl
  • R 1’’’ is selected from C(R 19 )2OH;
  • R 10 is selected from H, Cl, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
  • R 10 is optionally substituted with one or more substituents each independently selected from hydroxy;
  • R 10’’ is selected from C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
  • R 10’’ is optionally substituted with one or more hydroxy
  • R 10’’’ is selected from C1-C6 alkyl and C3-C6 cycloalkyl
  • each of R 11 and R 12 at each occurrence is independently selected from hydrogen
  • each R 19 is the same and is selected from C1-C6 alkyl
  • R 21 is selected from H or C 1 -C 6 alkyl substituted with hydroxy
  • R 1 or R 1’ when present, is C(R 19 ) 2 OH; and (3)
  • variables shown in the formulae herein are as follows: The groups X 1 and X 2
  • X 1 is O.
  • X 1 is S.
  • X 1 is NH
  • X 2 is CR 9 .
  • X 2 is CH.
  • X 2 is N.
  • X 1 is S and X 2 is CR 9 .
  • X 1 is O and X 2 is CH.
  • X 1 is S and X 2 is CH.
  • X 1 is O and X 2 is N.
  • X 1 is S and X 2 is N.
  • X 1 is NH and X 2 is N.
  • X 3 is NH
  • X 3 is O.
  • X 3 and R 2 taken together with the atoms connecting them form a four-to-seven-membered ring C of the formula Ring C
  • 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 R 16 .
  • A1 is N and A2 is CH2.
  • R 16 is H.
  • ring C is a heterocyclic ring containing one heteroatom selected from O, N and S.
  • X 3’ is O.
  • Y is CR 8 .
  • R 2 is hydrogen
  • R 2 is C1-C6 alkoxy.
  • R 2 is methoxy
  • R 2 is halo
  • R 2 is C1-C6 haloalkyl.
  • R 2 is CF 3 .
  • R 2 is C 1 -C 6 alkyl 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.
  • R 3 is hydrogen
  • R 3 is C1-C6 alkoxy.
  • R 3 is halo
  • R 3 is C1-C6 haloalkyl. In some embodiments of one or more formulae herein, R 3 is CF3.
  • R 3 is C 1 -C 6 alkyl optionally substituted with hydroxy.
  • R 3 is isopropyl
  • R 3 is methyl
  • R 3 is CN
  • R 4 is hydrogen
  • R 4 is C 1 -C 6 alkoxy.
  • R 4 is methoxy
  • R 4 is halo
  • R 4 is C1-C6 haloalkyl. In some embodiments of one or more formulae herein, R 4 is CF 3 .
  • R 4 is C1-C6 alkyl optionally substituted with hydroxy.
  • R 4 is isopropyl
  • R 4 is methyl
  • R 5 is hydrogen
  • R 5 is C 1 -C 6 alkoxy.
  • R 5 is methoxy
  • R 5 is halo
  • R 5 is C1-C6 haloalkyl. In some embodiments of one or more formulae herein, R 5 is CF 3 .
  • R 5 is C1-C6 alkyl optionally substituted with hydroxy.
  • each of R 2 and R 4 is hydrogen.
  • each of R 2 and R 4 is C 1 -C 6 alkyl optionally substituted with hydroxy.
  • R 5 is isopropyl
  • R 5 is methyl
  • 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.
  • each of R 2 and R 4 is methyl.
  • 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-C6 alkyl optionally substituted with hydroxy.
  • 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.
  • each of R 3 and R 5 is methyl.
  • 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-C6 alkyl optionally substituted with hydroxy.
  • each of R 3 and R 5 is hydrogen and each of R 2 and R 4 is isopropyl.
  • each of R 3 and R 5 is hydrogen and each of R 2 and R 4 is t-butyl.
  • each of R 3 and R 5 is hydrogen and each of R 2 and R 4 is methyl.
  • each of R 3 and R 5 is hydrogen and each of R 2 and R 4 is hydroxymethyl.
  • R 3 is halo and R 5 is H.
  • R 3 is CN and R 5 is H.
  • each of R 2 and R 4 is hydrogen and each of R 3 and R 5 is C1-C6 alkyl 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.
  • each of R 2 and R 4 is hydrogen and each of R 3 and R 5 is t-butyl.
  • each of R 2 and R 4 is hydrogen and each of R 3 and R 5 is methyl.
  • each of R 2 and R 4 is hydrogen and each of R 3 and R 5 is hydroxymethyl.
  • R 2 and R 3 taken together with the carbons connecting them form ring A.
  • R 4 and R 5 taken together with the carbons connecting them form ring B.
  • 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.
  • R 2 and R 3 taken together with the carbons connecting them form a five membered carbocyclic ring and R 4 and R 5 taken together with the carbons connecting them form a five membered carbocyclic ring.
  • R 2’ is hydrogen
  • R 2’ is halo
  • R 2’ is C 1 -C 6 alkyl optionally substituted with hydroxy.
  • R 2’ is isopropyl
  • R 2’ is methyl
  • R 3’ is hydrogen
  • R 3’ is C 1 -C 6 alkyl optionally substituted with hydroxy.
  • R 3’ is isopropyl. In some embodiments of one or more formulae herein, R 3’ is methyl.
  • R 4’ is hydrogen
  • R 4’ is halo
  • R 4’ is C1-C6 alkyl optionally substituted with hydroxy.
  • R 4’ is isopropyl
  • R 4’ is methyl
  • R 5’ is hydrogen
  • R 5’ is halo
  • R 5’ is C1-C6 alkyl optionally substituted with hydroxy.
  • 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 C 1 -C 6 alkyl optionally substituted with hydroxy.
  • R 5’ is isopropyl
  • R 5’ is methyl
  • 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.
  • each of R 2’ and R 4’ is methyl.
  • 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 C 1 -C 6 alkyl optionally substituted with hydroxy.
  • 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.
  • each of R 3’ and R 5’ is methyl.
  • 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 C 1 -C 6 alkyl optionally substituted with hydroxy.
  • 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.
  • each of R 3’ and R 5’ is hydrogen and each of R 2’ and R 4’ is methyl.
  • each of R 3’ and R 5’ is hydrogen and each of R 2’ and R 4’ is hydroxymethyl.
  • each of R 2’ and R 4’ is hydrogen and each of R 3’ and R 5’ is C1-C6 alkyl optionally substituted with hydroxy.
  • each of R 2’ and R 4’ is hydrogen and each of R 3’ and R 5’ is isopropyl.
  • each of R 2’ and R 4’ is hydrogen and each of R 3’ and R 5’ is t-butyl.
  • each of R 2’ and R 4’ is hydrogen and each of R 3’ and R 5’ is methyl.
  • each of R 2’ and R 4’ is hydrogen and each of R 3’ and R 5’ is hydroxymethyl.
  • R 4’ and R 5’ taken together with the carbons connecting them form ring B.
  • R 2’’ is hydrogen
  • R 2’’ is C1-C6 alkyl.
  • R 2’’ is isopropyl
  • R 2’’ is methyl
  • R 3’’ is hydrogen. In some embodiments of one or more formulae herein, R 3’’ is CN.
  • R 3’’ is C 1 -C 6 alkyl.
  • R 3’’ is isopropyl
  • R 3’’ is methyl
  • R 4’’ is hydrogen
  • R 4’’ is C 1 -C 6 alkyl.
  • R 4’’ is isopropyl
  • R 4’’ is methyl
  • R 5’’ is hydrogen
  • R 5’’ is CN
  • R 5’’ is C1-C6 alkyl.
  • 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 C 1 -C 6 alkyl. In some embodiments of one or more formulae herein, R 5’’ is isopropyl.
  • R 5’’ is methyl
  • 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-C6 alkyl. In some embodiments of one or more formulae herein, each of R 3’’ and R 5’’ is isopropyl.
  • 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 C 1 -C 6 alkyl.
  • each of R 3’’ and R 5’’ is hydrogen and each of R 2’’ and R 4’’ is isopropyl.
  • each of R 3’’ and R 5’’ is hydrogen and each of R 2’’ and R 4’’ is t-butyl.
  • 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 5’’ is C 1 -C 6 alkyl.
  • each of R 2’’ and R 4’’ is hydrogen and each of R 3’’ and R 5’’ is isopropyl.
  • each of R 2’’ and R 4’’ is hydrogen and each of R 3’’ and R 5’’ is t-butyl.
  • each of R 2’’ and R 4’’ is hydrogen and each of R 3’’ and R 5’’ is methyl.
  • ring A is a carbocyclic ring.
  • ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.
  • ring B is a carbocyclic ring.
  • ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.
  • ring A is a carbocyclic ring and n1 is 3.
  • ring A is a carbocyclic ring and n1 is 4.
  • ring A is a saturated carbocyclic ring.
  • ring B is a saturated carbocyclic ring.
  • ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 3.
  • ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 4.
  • ring B is a carbocyclic ring and n2 is 3.
  • ring B is a carbocyclic ring and n2 is 4.
  • ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 3.
  • ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 4.
  • ring A is the same as ring B. In some embodiments, ring A is In some embodiments, ring B is
  • ring B is
  • ring A is
  • ring B is
  • ring A is a heterocyclic ring of the formula
  • ring A is a heterocyclic ring of the formula .
  • the groups R 6 and R 7 and the variables n1, n2, m1 and m2 in ring A and ring B In some embodiments of one or more formulae herein, R 6 is H.
  • R 6 is C 1 -C 6 alkyl.
  • R 6 is C1-C6 alkoxy.
  • R 6 is methoxy
  • R 6 is NR 11 R 12 .
  • R 6 is oxo
  • n1 is 2.
  • n1 is 3.
  • n1 is 4.
  • n1 is 5.
  • n2 is 2.
  • n2 is 3.
  • n2 is 4.
  • n2 is 5.
  • m1 is 1.
  • m1 is 2.
  • m1 is 3.
  • m1 is 4. In some embodiments of one or more formulae herein, m2 is 1.
  • m2 is 2.
  • m2 is 3.
  • m2 is 4.
  • two R 6 taken 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.
  • each R 6 in each ring is H.
  • each R 6 in each ring is C 1 -C 6 alkyl. In some embodiments of one or more formulae herein, each R 7 in each ring is H.
  • each R 7 in each ring is C1-C6 alkyl. In some embodiments of one or more formulae herein, each R 6 in each ring is H and each R 7 in each ring is H.
  • each R 6 in each ring is H and each R 7 in each ring is C 1 -C 6 alkyl.
  • each R 6 in each ring is C 1 -C 6 alkyl and each R 7 in each ring is H.
  • each R 6 in each ring is C1-C6 alkyl and each R 7 in each ring is C 1 -C 6 alkyl.
  • the ring E In some embodiments of one or more formulae herein, is selected from
  • R 8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, C1-C6 haloalkoxy, and C1-C6 haloalkyl.
  • R 8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, and C1-C6 haloalkyl.
  • R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl and CONH 2 . In some embodiments of one or more formulae herein, R 8 is H.
  • R 8 is CN
  • R 8 is Cl
  • R 8 is F.
  • R 8 is CO 2 C 1 -C 6 alkyl.
  • R 8 is CO 2 C 3 -C 8 cycloalkyl.
  • R 8 is CONH2.
  • R 8 is CONR 11 R 12 .
  • R 8 is C 1 -C 6 alkyl.
  • R 8 is C1-C6 haloalkoxy.
  • R 8 is C1-C6 haloalkyl.
  • R 8 is CF 3 .
  • R 8’ is selected from CN, CO 2 C 1 -C 6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, and C1-C6 haloalkyl.
  • R 8’ is selected from CN, CO 2 C 1 -C 6 alkyl and CONH 2 .
  • R 8’ is CN
  • R 8’ is CO2C1-C6 alkyl.
  • R 8’ is CO 2 C 3 -C 8 cycloalkyl.
  • R 8’ is CONH2.
  • R 8’ is CONR 11 R 12 .
  • R 8’ is C 1 -C 6 alkyl.
  • R 8’ is C 1 -C 6 haloalkyl.
  • R 8’ is CF3.
  • R 9 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, and C1-C6 haloalkyl.
  • R 9 is H.
  • R 9 is CN
  • R 9 is Cl. In some embodiments of one or more formulae herein, R 9 is F.
  • R 9 is CO 2 C 1 -C 6 alkyl.
  • R 9 is CO 2 C 3 -C 8 cycloalkyl.
  • R 9 is CONH2.
  • R 9 is CONR 11 R 12 .
  • R 9 is C 1 -C 6 alkyl.
  • R 9 is C1-C6 haloalkyl.
  • R 9 is CF3.
  • the groups R 1 , R 1’ , R 1’’ , and R 1’’’ are CF3.
  • R 1 is C 1 -C 6 alkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 1 is C 1 -C 6 alkyl substituted with hydroxy.
  • R 1 is 2-hydroxy-2-propyl.
  • R 1 is C3-C6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 1 is C3-C6 cycloalkyl. In some embodiments of one or more formulae herein, R 1 is C3-C6 cycloalkyl substituted with hydroxy.
  • R 1 is 1-hydroxy-1-cyclopropyl. In some embodiments of one or more formulae herein, R 1 is 1-hydroxy-1-cyclobutyl. In some embodiments of one or more formulae herein, R 1 is 1-hydroxy-1-cyclopentyl. In some embodiments of one or more formulae herein, R 1 is C 3 -C 6 heterocycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 1 is C 3 -C 6 heterocycloalkyl. In some embodiments of one or more formulae herein, R 1 is C3-C6 heterocycloalkyl substituted with hydroxy.
  • R 1 is C(R 19 ) 2 OH or C(O)C 2 -C 6 alkyl.
  • R 1 is C(R 19 )2OH.
  • R 1 is C(O)C 2 -C 6 alkyl.
  • R 1 is propanoyl
  • R 1 is butanoyl
  • R 1’ is unsubstituted C1-C6 alkyl. In some embodiments of one or more formulae herein, R 1’ is C(R 19 )2OH.
  • R 1’ is 2-hydroxy-2-propyl.
  • R 1’ is C 3 -C 6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy or amino.
  • R 1’ is C 3 -C 6 cycloalkyl.
  • R 1’ is C 3 -C 6 cycloalkyl substituted with hydroxy.
  • R 1’ is 1-hydroxy-1-cyclopropyl. In some embodiments of one or more formulae herein, R 1’ is 1-hydroxy-1-cyclobutyl. In some embodiments of one or more formulae herein, R 1’ is 1-hydroxy-1-cyclopentyl. In some embodiments of one or more formulae herein, R 1’ is C(R 19 )2OH or C(O)C2-C6 alkyl.
  • R 1’ is C(R 19 ) 2 OH.
  • R 1’ is C(O)C2-C6 alkyl.
  • R 1’ is propanoyl
  • R 1’ is 2-hydroxypropanoyl.
  • R 1’ is butanoyl
  • R 1’’ is C 3 -C 6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy or amino.
  • R 1’’ is C 3 -C 6 cycloalkyl.
  • R 1’’ is C3-C6 cycloalkyl substituted with hydroxy. In some embodiments of one or more formulae herein, R 1’’ is 1-hydroxy-1-cyclopropyl. In some embodiments of one or more formulae herein, R 1’’ is 1-hydroxy-1-cyclobutyl. In some embodiments of one or more formulae herein, R 1’’ is 1-hydroxy-1-cyclopentyl. In some embodiments of one or more formulae herein, R 1’’ is C(O)C2-C6 alkyl.
  • R 1’’ is propanoyl
  • R 1’’ is 2-hydroxypropanoyl.
  • R 1’’ is butanoyl
  • R 1’’’ is C(R 19 )2OH.
  • R 1’’’ is 2-hydroxy-2-propyl.
  • the groups R 10 , R 10’ , R 10’’ , and R 10’’’ are 2-hydroxy-2-propyl.
  • R 10 is H.
  • R 10 is Cl
  • R 10 is C1-C6 alkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 10 is C1-C6 alkyl substituted with hydroxy.
  • R 10 is 2-hydroxy-2-propyl.
  • R 10 is C3-C6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 10 is C 3 -C 6 cycloalkyl.
  • R 10 is C3-C6 cycloalkyl substituted with hydroxy.
  • R 10 is 1-hydroxy-1-cyclopropyl. In some embodiments of one or more formulae herein, R 10 is 1-hydroxy-1-cyclobutyl. In some embodiments of one or more formulae herein, R 10 is 1-hydroxy-1-cyclopentyl. In some embodiments of one or more formulae herein, R 10 is C 3 -C 6 heterocycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 10 is C 3 -C 6 heterocycloalkyl. In some embodiments of one or more formulae herein, R 10 is C 3 -C 6 heterocycloalkyl substituted with hydroxy.
  • R 10’ is C3-C6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 10’ is C3-C6 cycloalkyl.
  • R 10’ is C3-C6 cycloalkyl substituted with hydroxy.
  • R 10’’ is Cl.
  • R 10’’ is C1-C6 alkyl optionally substituted with one or more substituents each independently selected from hydroxyl and amino.
  • R 10’’ is C1-C6 alkyl substituted with hydroxy.
  • R 10’’ is 2-hydroxy-2-propyl.
  • R 10’’ is C3-C6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy and amino.
  • R 10’’ is C3-C6 cycloalkyl.
  • R 10’’ is C3-C6 cycloalkyl substituted with hydroxy.
  • R 10’’ is 1-hydroxy-1-cyclopropyl. In some embodiments of one or more formulae herein, R 10’’ is 1-hydroxy-1-cyclobutyl. In some embodiments of one or more formulae herein, R 10’’ is 1-hydroxy-1-cyclopentyl. In some embodiments of one or more formulae herein, R 10’’ is C 3 -C 6 heterocycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 10’’ is C 3 -C 6 heterocycloalkyl. In some embodiments of one or more formulae herein, R 10’’ is C3-C6 heterocycloalkyl substituted with hydroxy.
  • R 10’’’ is Cl.
  • R 10’’’ is 2-hydroxy-2-propyl. In some embodiments of one or more formulae herein, R 10’’’ is C3-C6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 10’’’ is C3-C6 cycloalkyl.
  • R 10’’’ is C3-C6 cycloalkyl substituted with hydroxy.
  • R 10’’’ is 1-hydroxy-1-cyclopropyl. In some embodiments of one or more formulae herein, R 10’’’ is 1-hydroxy-1-cyclobutyl. In some embodiments of one or more formulae herein, R 10’’’ is 1-hydroxy-1-cyclopentyl. In some embodiments of one or more formulae herein, R 10’’’ is C 3 -C 6 heterocycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 10’’’ is C 3 -C 6 heterocycloalkyl. In some embodiments of one or more formulae herein, R 10’’’ is C3-C6 heterocycloalkyl substituted with hydroxy.
  • one of R 1 and R 10 is C1-C6 alkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo, and the other of R 1 and R 10 is C 3 -C 6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • one of R 1 and R 10 is 2-hydroxy-2- propyl and the other of R 1 and R 10 is 1-hydroxy-1-cyclobutyl. In some embodiments of one or more formulae herein, one of R 1 and R 10 is 2-hydroxy-2- propyl and the other of R 1 and R 10 is 1-hydroxy-1-cyclopentyl.
  • R 1 is H and R 10 is C 1 -C 6 alkyl substituted with hydroxy.
  • R 1 is C(R 19 ) 2 OH and R 10 is H. In some embodiments of one or more formulae herein, R 1 is 2-hydroxy-2-propyl and R 10 is Cl.
  • R 1 is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo, and the hydroxy, amino or oxo substituent is at the carbon of R 1 directly bonded to the five- membered heteroaryl ring of the formulae herein.
  • R 10 is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo, and the hydroxy, amino or oxo substituent is at the carbon of R 10 directly bonded to the five- membered heteroaryl ring of the formulae herein.
  • R 1 and R 10 taken together with the atoms connecting them form a three-membered carbocyclic ring.
  • R 1 and R 10 taken together with the atoms connecting them form a four-membered carbocyclic ring.
  • R 1 and R 10 taken together with the atoms connecting them form a five-membered carbocyclic ring.
  • R 1 and R 10 taken together with the atoms connecting them form a six-membered carbocyclic ring.
  • R 1 and R 10 taken together with the atoms connecting them form a seven-membered carbocyclic ring.
  • R 1 and R 10 taken together with the atoms connecting them form an eight-membered carbocyclic ring.
  • R 1 and R 10 taken together with the atoms connecting them form a three-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments of one or more formulae herein, R 1 and R 10 taken together with the atoms connecting them form a four-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.
  • R 1 and R 10 taken together with the atoms connecting them form a five-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.
  • R 1 and R 10 taken together with the atoms connecting them form a six-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.
  • R 1 and R 10 taken together with the atoms connecting them form a seven-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.
  • R 1 and R 10 taken together with the atoms connecting them form an eight-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.
  • R 1 and R 10 taken together with the atoms connecting them form a carbocyclic ring substituted with hydroxy.
  • R 1 and R 10 taken together with the atoms connecting them form a carbocyclic ring substituted with oxo.
  • R 1 and R 10 taken together with the atoms connecting them form a carbocyclic ring substituted with C1-C6 alkoxy.
  • R 1 and R 10 taken together with the atoms connecting them form a carbocyclic ring substituted with NR 11 R 12 .
  • R 1 and R 10 taken together with the atoms connecting them form a carbocyclic ring substituted with COOC1-C6 alkyl.
  • R 1 and R 10 taken together with the atoms connecting them form a carbocyclic ring substituted with CONR 11 R 12 .
  • R 10’ is unsubstituted C1-C6 alkyl
  • R 1’’ is C3-C6 cycloalkyl optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 1’’ is a C 3 -C 6 cycloalkyl substituted with hydroxy directly bonded to the five-membered heteroaryl ring of the formulae herein and R 10’ is H.
  • R 1’’ is 1-hydroxycyclopentyl and R 10’ is H.
  • R 1’’ is 1-hydroxycyclobutyl and R 10’ is H.
  • R 1’’ is 1-hydroxycyclopropyl and R 10’ is H. In some embodiments of one or more formulae herein, R 1’’ is C(O)C2-C6 alkyl and R 10’ is H.
  • R 1’’ is propanoyl and R 10’ is H.
  • the groups R 1’’’ and R 10’ are independently selected from
  • R 1’’’ is C(R 19 )2OH and R 10’ is H. In some embodiments of one or more formulae herein, R 1’’’ is C(R 19 )2OH and R 10’ is Cl. In some embodiments of one or more formulae herein, R 1’’’ is 2-hydroxy-2-propyl and R 10’ is H.
  • R 1’’’ is 2-hydroxy-2-propyl and R 10’ is Cl.
  • the groups R 1’ and R 10’ are 2-hydroxy-2-propyl and R 10’.
  • R 1’ is C(R 19 ) 2 OH and R 10’ is selected from H, Cl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;
  • R 1’ is C(R 19 ) 2 OH and R 10’ is H. In some embodiments of one or more formulae herein, R 1’ is 2-hydroxy-2-propyl and R 10’ is H.
  • R 1’ is C 3 -C 6 cycloalkyl optionally substituted with hydroxyl and R 10’ is H.
  • R 1’ is a C3-C6 cycloalkyl substituted with hydroxy directly bonded to the five-membered heteroaryl ring of the formulae herein and R 10’ is H.
  • R 1’ is 1-hydroxycyclopentyl and R 10’ is H.
  • R 1’ is 1-hydroxycyclobutyl and R 10’ is H.
  • R 1’ is 1-hydroxycyclopropyl and R 10’ is H.
  • the groups R 1 and R 10’’’ are
  • R 1 is selected from H
  • R 1 is selected from H
  • R 1 is H and R 10’’’ is a C 3 -C 6 cycloalkyl substituted with hydroxy directly bonded to the five-membered heteroaryl ring of the formulae herein.
  • R 1 is H and R 10’’’ is 1- hydroxycyclopentyl.
  • R 1 is H and R 10’’’ is 1- hydroxycyclobutyl.
  • R 1 is H and R 10’’’ is 1- hydroxycyclopropyl.
  • R 1 is C(R 19 )2OH and R 10’’’ is Cl. In some embodiments of one or more formulae herein, R 1 is 2-hydroxy-2-propyl and R 10’’’ is Cl.
  • R 1 is H and R 10’’’ is C1-C6 alkyl substituted with hydroxy.
  • R 1 is H and R 10’’’ is 2-hydroxy-2- propyl.
  • the groups R 1’ and R 10 are 2-hydroxy-2- propyl.
  • R 1’ is unsubstituted C1-C6 alkyl and R 10 is C1-C6 alkyl optionally substituted with hydroxy.
  • R 1’ is methyl and R 10 is 2- hydroxy-2-propyl.
  • R 1’ is C(R 19 )2OH and R 10 is H.
  • the groups R 1 and R 10’’ are
  • R 1 is selected from H
  • R 1 is C(R 19 ) 2 OH and R 10’’ is C 1 -C 6 alkyl optionally substituted with hydroxy.
  • R 1 is H and R 10’’ is C3-C6 cycloalkyl substituted with hydroxy.
  • the groups R 11 and R 12 are C3-C6 cycloalkyl substituted with hydroxy.
  • R 11 is hydrogen. In some embodiments of one or more formulae herein, R 11 is C1-C6 alkyl.
  • R 11 is CO 2 R 15 .
  • R 11 is CONR 17 NR 18 .
  • R 12 is hydrogen.
  • R 12 is C 1 -C 6 alkyl.
  • R 12 is CO 2 R 15 .
  • R 12 is CONR 17 NR 18 .
  • R 13 is C1-C6 alkyl.
  • R 15 is C1-C6 alkyl.
  • R 17 is hydrogen
  • R 17 is C 1 -C 6 alkyl.
  • R 18 is hydrogen
  • R 18 is C 1 -C 6 alkyl.
  • R 16 is hydrogen
  • R 16 is C 1 -C 6 alkyl.
  • R 16 is C1-C6 alkoxy.
  • R 16 is NR 11 R 12 .
  • R 16 is oxo
  • R 16 is The group R 19
  • each R 19 is the same and is selected from C1-C6 alkyl.
  • each R 19 is methyl.
  • each R 19 is ethyl.
  • each R 19 is 1-propyl. In some embodiments of one or more formulae herein, each R 19 is 2-propyl.
  • the groups R 20 and R 21 are
  • each R 20 is selected from H, halo, or C1-C6 alkyl optionally substituted with hydroxyl.
  • each R 20 is H.
  • each R 20 is halo.
  • each R 20 is C1-C6 alkyl optionally substituted with hydroxyl.
  • each R 20 is 2-hydroxy-2-propyl.
  • each R 21 is selected from H, halo, or C1-C6 alkyl substituted with hydroxyl.
  • each R 21 is H.
  • each R 21 is halo.
  • each R 21 is C1-C6 alkyl substituted with hydroxyl.
  • each R 21 is 2-hydroxy-2-propyl. Additional embodiments
  • R 2 and R 4 are each isopropyl; X 3 is NH; X 2 is CH; R 10 is H; and R 1 is optionally substituted C 1 -C 6 alkyl,
  • Y is not CH or CCl.
  • Y is not CH or CCl.
  • R 1 or R 1’ when present, is C(R 19 ) 2 OH; and (3) either of R 10’ or R 10’’’ , when present, is C(R 19 ) 2 OH; and (3) either of R 10’ or R 10’’ , when present, is C(R 19 ) 2 OH; and (3) either of R 10’ or R 10’’ , when present, is C(R 19 ) 2 OH; and (3) either of R 10’ or R 10’’’ , when present, is C(R 19 ) 2 OH; and (3) either of R 10’ or R 10’’’ , when present, is C(R 19 ) 2 OH; and (3) either of R 10’ or R 10’’’ , when present, is C(R 19 ) 2 OH; and (3) either of R 10’ or R 10’’’ , when present, is C(R 19 ) 2 OH; and (3) either of R 10’ or R 10’’’ , when present, is C(R 19 ) 2 OH; and (3) either of
  • the compound of any of the formulae herein is not a compound disclosed in any of Examples 1-150 of patent publication WO2001/019390, which are incorporated by reference herein.
  • the compound of any of the formulae herein is not a compound disclosed in any of Examples 1-130 of patent publication WO 98/32733, which are incorporated by reference herein.
  • the compound of any of the formulae herein is not a compound disclosed in any of the Examples at [00123] of patent publication WO2016/131098, which are incorporated by reference herein.
  • X 1 is O, S, or NH
  • X 2 is N or CR 9 ;
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl and CONH2;
  • R 9 is selected from H and C1-C6 alkyl
  • R 2 is hydrogen or C 1 -C 6 alkyl optionally substituted with hydroxy
  • R 3 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy
  • R 4 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy and is the same as R 2 ;
  • R 5 is hydrogen or C 1 -C 6 alkyl optionally substituted with hydroxy and is the same as R 3 ;
  • R 2 , R 3 , R 4 and R 5 is not hydrogen, and that R 2 and R 4 are not both hydroxymethyl;
  • each R 6 in each ring is the same and is H or C 1 -C 6 alkyl
  • each R 7 in each ring is the same and is H or C1-C6 alkyl
  • R 1 is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R 1 is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo;
  • R 10 is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R 10 is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo;
  • R 1 and R 10 taken together with the atoms connecting them form a five-membered, a six- membered, or a seven-membered carbocyclic or heterocyclic ring;
  • the compound of formula I comprises ring A and ring B; X 3 is NH; X 2 is CH; and R 10 is H,
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl and CONH2;
  • R 9 is selected from H and C 1 -C 6 alkyl
  • R 2 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy
  • R 3 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy
  • R 4 is hydrogen or C 1 -C 6 alkyl optionally substituted with hydroxy and is the same as R 2 ;
  • R 5 is hydrogen or C 1 -C 6 alkyl optionally substituted with hydroxy and is the same as R 3 ;
  • each R 6 in each ring is the same and is H or C 1 -C 6 alkyl
  • each R 7 in each ring is the same and is H or C 1 -C 6 alkyl
  • R 1 is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R 1 is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo;
  • R 10 is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein R 10 is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo;
  • R 1 and R 10 taken together with the atoms connecting them form a five-membered, a six- membered, or a seven-membered carbocyclic or heterocyclic ring;
  • the compound of Formula I is a compound of Formula Ia
  • X 1 is O, S, or NH
  • X 3 is NH or O
  • R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl and CONH 2 ;
  • R 2 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl,or C1-C6 alkyl optionally substituted with hydroxy;
  • R 3 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 4 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 2 , R 3 , R 4 and R 5 is not hydrogen, and that R 2 and R 4 are not both hydroxymethyl;
  • 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,
  • 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 1 to 10;
  • 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 1 to 10;
  • R 1 is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein R 1 is optionally substituted with hydroxy, amino or oxo;
  • R 10 is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R 10 is optionally substituted with hydroxy, amino or oxo;
  • R 1 and R 10 taken 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
  • NR 1 R 12 NR 13 , COOC1-C6 alkyl, and CONR 11 R 12 ;
  • R 13 is C1-C6 alkyl;
  • each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, CO 2 R 15 and CONR 17 R 18 ;
  • R 15 is C1-C6 alkyl
  • the compound of Formula I is a compound of Formula Ia
  • X 1 is O, S, or NH
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl and CONH2;
  • R 2 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy
  • R 3 is hydrogen or C 1 -C 6 alkyl optionally substituted with hydroxy
  • R 4 is hydrogen or C 1 -C 6 alkyl optionally substituted with hydroxy and is the same as R 2 ;
  • R 5 is hydrogen or C1-C6 alkyl optionally substituted with hydroxy and is the same as R 3 ;
  • each R 6 in each ring is the same and is H or C1-C6 alkyl
  • each R 7 in each ring is the same and is H or C 1 -C 6 alkyl
  • R 1 is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R 1 is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo;
  • R 10 is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein R 10 is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo;
  • R 1 and R 10 taken together with the atoms connecting them form a five-membered, a six- membered, or a seven-membered carbocyclic or heterocyclic ring.
  • the compound of Formula Ia is a compound of Formula Ia-i:
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl and CONH2;
  • R 2 is C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl,or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 3 is hydrogen;
  • R 4 is C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 5 is hydrogen;
  • R 1 is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein R 1 is optionally substituted with hydroxy, amino or oxo;
  • R 10 is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R 10 is optionally substituted with hydroxy, amino or oxo;
  • the compound of Formula Ia is a compound of Formula Ia-i:
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl and CONH2;
  • R 3 is C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl,or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 2 is hydrogen;
  • R 5 is C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 4 is hydrogen;
  • R 1 is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R 1 is optionally substituted with hydroxy, amino or oxo;
  • R 10 is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein R 10 is optionally substituted with hydroxy, amino or oxo;
  • the compound of Formula Ia is a compound of Formula Ia-i:
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl and CONH 2 ;
  • 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,
  • 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;
  • n1 is from 1 to 10;
  • 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;
  • n2 is from 1 to 10;
  • R 1 is selected from H, C 1 -C 6 alkyl and C 3 -C 6 cycloalkyl, wherein R 1 is optionally substituted with hydroxy, amino or oxo;
  • R 10 is selected from H, C1-C6 alkyl and C3-C6 cycloalkyl, wherein R 10 is optionally substituted with hydroxy, amino or oxo;
  • R 1 and R 10 taken together with the atoms connecting them form a five-membered, a six- membered, or a seven-membered carbocyclic or heterocyclic ring.
  • the compound of Formula Ia-i is a compound of Formula Ia-i(A)
  • R 8 is H, CN, F, CO2C1-C6 alkyl, or CONH 2 .
  • R 8 is H.
  • R 8 is CN.
  • R 8 is F.
  • R 8 is CO 2 C 1 -C 6 alkyl.
  • R 8 is CONH 2 .
  • R 2 and R 4 are each isopropyl.
  • the compound of Formula Ia-i is a compound of Formula Ia-i(B)
  • R 8 is H, CN, F, CO2C1-C6 alkyl, or CONH2.
  • R 8 is H.
  • R 8 is CN.
  • R 8 is F.
  • R 8 is CO2C1-C6 alkyl.
  • R 8 is CONH 2 .
  • R 2 and R 4 are each isopropyl.
  • the compound of Formula Ia-i is a compound of Formula Ia-i(C):
  • R 8 is H, CN, Cl or F.
  • R 8 is H.
  • R 8 is CN.
  • R 8 is Cl.
  • R 8 is F.
  • R 2 and R 4 are each isopropyl.
  • the compound of Formula Ia-i is a compound of Formula Ia-i(D)
  • R 8 is H, CN, Cl or F.
  • R 8 is H.
  • R 8 is CN.
  • R 8 is Cl.
  • R 8 is F.
  • R 2 and R 4 are each isopropyl.
  • the compound of Formula Ia-i(C) is a compound of Formula Ia- i(C1)
  • R 8 is H, CN, Cl or F.
  • R 8 is H.
  • R 8 is CN.
  • R 8 is Cl.
  • R 8 is F.
  • R 2 and R 4 are each isopropyl.
  • the compound of Formula Ia-i is a compound of Formula Ia-i(D1)
  • R 8 is H, CN, Cl or F.
  • R 8 is H.
  • R 8 is CN.
  • R 8 is Cl.
  • R 8 is F.
  • R 2 and R 4 are each isopropyl.
  • the compound of Formula Ia-i is a compound of Formula Ia-i(E)
  • R 8 is H, CN, F, CO2C1-C6 alkyl, or CONH 2 .
  • R 8 is H.
  • R 8 is CN.
  • R 8 is F.
  • R 8 is CO 2 C 1 -C 6 alkyl.
  • R 8 is CONH 2 .
  • R 2 and R 4 are each isopropyl.
  • the compound of Formula Ia-i is a compound of Formula Ia-i(F)
  • R 8 is H, CN, Cl or F.
  • R 8 is H.
  • R 8 is CN.
  • R 8 is Cl.
  • R 8 is F.
  • R 2 and R 4 are each isopropyl.
  • the compound of Formula Ia-i is a compound of Formula Ia-i(G)
  • R 8 is H, CN, Cl or F.
  • R 8 is H.
  • R 8 is CN.
  • R 8 is Cl.
  • R 8 is F.
  • R 2 and R 4 are each isopropyl.
  • the compound of Formula I is a compound of Formula Ia-ii
  • the compound of Formula I is a compound of Formula Ia-iii
  • R 1 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, wherein R 1 is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 1 is C 1 -C 6 alkyl optionally substituted with one or more hydroxy.
  • R 1 is C1-C6 alkyl substituted with hydroxy.
  • the hydroxy is at the carbon of R 1 directly bonded to the five- membered heteroaryl ring in Formulae Ia, Ia-i, Ia-i(A), Ia-i(C), Ia-i(C1), Ia-i(E), Ia-i(F), Ia-i(G), Ia-ii, Ia-iii, and Ib,
  • R 1 is 2-hydroxy-2-propyl.
  • R 10 is C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, wherein R 10 is optionally substituted with one or more substituents each independently selected from hydroxy, amino and oxo.
  • R 10 is C 1 -C 6 alkyl optionally substituted with one or more hydroxy.
  • R 10 is C1-C6 alkyl substituted with hydroxy.
  • the hydroxy is at the carbon of R 10 directly bonded to the five- membered heteroaryl ring in Formulae Ia, Ia-i, Ia-i(B), Ia-i(D), Ia-i(D1), Ia-i(E), Ia-i(F), Ia-i(G), Ia-ii, Ia-iii, and Ic,
  • R 10 is 2-hydroxy-2-propyl.
  • R 1 and R 10 taken 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
  • R 1 and R 10 taken together with the atoms connecting them form a five-membered carbocyclic ring.
  • R 1 and R 10 taken together with the atoms connecting them form a six- membered carbocyclic ring.
  • R 1 and R 10 taken together with the atoms connecting them form a five-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.
  • R 1 and R 10 taken together with the atoms connecting them form a five- membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.
  • ring A is a carbocyclic ring and n1 is 3.
  • ring A is a carbocyclic ring and n1 is 4.
  • ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 3.
  • ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 4.
  • ring B is a carbocyclic ring and n2 is 3.
  • ring B is a carbocyclic ring and n2 is 4.
  • ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 3.
  • ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 4.
  • the compound of Formula I is a compound of Formula Ib
  • the compound of Formula I is a compound of Formula Ic
  • the compound of Formula II is a compound of Formula IIa
  • X 2 is N or CR 9 ;
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;
  • R 9 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, and C1-C6 haloalkyl;
  • R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 3 is hydrogen, CN, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 5 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • 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,
  • ring A is a saturated carbocyclic ring; n1 is from 2 to 5;
  • n1 is from 1 to 10;
  • ring B is a saturated carbocyclic ring
  • n2 is from 2 to 5;
  • n2 is from 1 to 10;
  • R 1 is selected from H, unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
  • R 10 is selected from H, Cl, C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;
  • R 1 and R 10 taken 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
  • R 13 is C 1 -C 6 alkyl
  • each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl,
  • R 15 is C1-C6 alkyl
  • the compound of Formula II is a compound of Formula IIb
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, C1-C6 haloalkoxy, and C1-C6 haloalkyl;
  • R 9 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, and C 1 -C 6 haloalkyl;
  • R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 3 is hydrogen, CN, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 4 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 2 and R 3 taken together with the carbons connecting them form a four-membered to seven- membered ring A, or R 4 and R 5 taken together with the carbons connecting them form a four-membered to seven- membered ring B,
  • 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,
  • ring A is a saturated carbocyclic ring
  • n1 is from 2 to 5;
  • n1 is from 1 to 10;
  • ring B is a saturated carbocyclic ring
  • n2 is from 2 to 5;
  • n2 is from 1 to 10;
  • R 10’ is selected from H, Cl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;
  • R 13 is C1-C6 alkyl
  • each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl,
  • R 15 is C1-C6 alkyl
  • the compound of Formula II is a compound of Formula IIc
  • X 3 is NH or O
  • R 8’ is selected from CN, CO 11
  • R 9 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, and C1-C6 haloalkyl;
  • R 2’ is hydrogen, halo, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 2’’ is hydrogen or C 1 -C 6 alkyl
  • R 3’ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy
  • R 3’’ is hydrogen, CN, or C1-C6 alkyl
  • R 4’ is hydrogen, halo, or C 1 -C 6 alkyl optionally substituted with hydroxy
  • R 4’’ is hydrogen or C 1 -C 6 alkyl
  • R 5’ is hydrogen, halo, or C1-C6 alkyl optionally substituted with hydroxy
  • R 5’’ is hydrogen, CN, or C1-C6 alkyl
  • 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,
  • ring A is a saturated carbocyclic ring
  • n1 is from 2 to 5;
  • n1 is from 1 to 10;
  • ring B is a saturated carbocyclic ring
  • n2 is from 2 to 5; m2 is from 1 to 10;
  • R 6 taken 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;
  • R 1’’’ is selected from C(R 19 )2OH;
  • R 10’ is selected from H, Cl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocycloalkyl;
  • R 13 is C 1 -C 6 alkyl
  • each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl, CO2R 15 and CONR 17 R 18 ;
  • R 15 is C 1 -C 6 alkyl
  • each R 19 is the same and is selected from C 1 -C 6 alkyl
  • the compound of Formula II is a compound of Formula IId
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, C1-C6 haloalkoxy, and C1-C6 haloalkyl;
  • R 9 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, and C 1 -C 6 haloalkyl;
  • R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 3 is hydrogen, CN, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 4 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • 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,
  • ring A is a saturated carbocyclic ring
  • n1 is from 2 to 5;
  • n1 is from 1 to 10;
  • ring B is a saturated carbocyclic ring
  • n2 is from 2 to 5;
  • n2 is from 1 to 10;
  • R 6 taken 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; R 1’ is selected from unsubstituted C 9
  • R 10’ is selected from H, Cl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;
  • R 13 is C1-C6 alkyl; each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl,
  • R 15 is C 1 -C 6 alkyl
  • each R 19 is the same and is selected from C1-C6 alkyl
  • the compound of Formula II is a compound of Formula IIe
  • X 3 is NH or O
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;
  • R 9 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, and C1-C6 haloalkyl;
  • R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 3 is hydrogen, CN, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 4 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 5 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • 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,
  • ring A is a saturated carbocyclic ring; n1 is from 2 to 5;
  • n1 is from 1 to 10;
  • ring B is a saturated carbocyclic ring
  • n2 is from 2 to 5;
  • n2 is from 1 to 10;
  • R 1 is selected from H, unsubstituted C 1 -C 6 alkyl, C(R 19 ) 2 OH, C(O)C 2 -C 6 alkyl, and C 3 -C 6 cycloalkyl;
  • R 10’’’ is selected from Cl, C1-C6 alkyl substituted with hydroxy, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl;
  • R 13 is C 1 -C 6 alkyl
  • each of R 11 and R 12 at each occurrence is independently selected from hydrogen, C 1 -C 6 alkyl,
  • R 15 is C 1 -C 6 alkyl
  • each R 19 is the same and is selected from C 1 -C 6 alkyl; provided that if (1) R 1 is C(R 19 )2OH; and (2) R 10’’’ is not Cl; then s not
  • R 10’’’ is C 1 -C 6 alkyl substituted with hydroxy; then is not
  • the compound of Formula II is a compound of Formula IIf
  • X 3 is NH or O
  • X 3 is NH, X 3 and R 4 taken together with the atoms connecting them form a four-to- seven-membered heterocyclic ring optionally substituted with one or more R 16 ;
  • Y is N or CR 8 ;
  • R 8 is selected from H, CN, Cl, F, CO 2 C 1 -C 6 alkyl, CO 2 C 3 -C 8 cycloalkyl, CONR 11 R 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkoxy, and C 1 -C 6 haloalkyl;
  • R 9 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR 11 R 12 , C1-C6 alkyl, and C 1 -C 6 haloalkyl;
  • R 2 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • R 3 is hydrogen, CN, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 4 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
  • R 5 is hydrogen, C 1 -C 6 alkoxy, halo, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl optionally substituted with hydroxy;
  • 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,

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