WO2021026257A1 - Prodrugs of alox-15 inhibitors and methods of using the same - Google Patents
Prodrugs of alox-15 inhibitors and methods of using the same Download PDFInfo
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- WO2021026257A1 WO2021026257A1 PCT/US2020/045046 US2020045046W WO2021026257A1 WO 2021026257 A1 WO2021026257 A1 WO 2021026257A1 US 2020045046 W US2020045046 W US 2020045046W WO 2021026257 A1 WO2021026257 A1 WO 2021026257A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- ioaryl
- solvate
- compound
- pharmaceutically acceptable
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 17
- 239000000651 prodrug Substances 0.000 title abstract description 20
- 229940002612 prodrug Drugs 0.000 title abstract description 20
- 239000003112 inhibitor Substances 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 1170
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims description 1175
- 239000012453 solvate Substances 0.000 claims description 1153
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 661
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 567
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 534
- 229910052736 halogen Inorganic materials 0.000 claims description 257
- 150000002367 halogens Chemical class 0.000 claims description 226
- 125000004076 pyridyl group Chemical group 0.000 claims description 84
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 80
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 67
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 64
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 64
- 125000005843 halogen group Chemical group 0.000 claims description 63
- 125000001544 thienyl group Chemical group 0.000 claims description 63
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 49
- 125000002541 furyl group Chemical group 0.000 claims description 44
- 125000002883 imidazolyl group Chemical group 0.000 claims description 43
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 41
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 9
- 201000010099 disease Diseases 0.000 abstract description 6
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- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 299
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- -1 -CN radical Chemical class 0.000 description 88
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- 125000001246 bromo group Chemical group Br* 0.000 description 15
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- 125000004446 heteroarylalkyl group Chemical group 0.000 description 15
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- 238000013461 design Methods 0.000 description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C305/00—Esters of sulfuric acids
- C07C305/22—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings
- C07C305/24—Esters of sulfuric acids having oxygen atoms of sulfate groups bound to carbon atoms of six-membered aromatic rings of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
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Definitions
- Human ALOX-15 (15-lipoxygenase) protein is highly expressed in circulating blood eosinophils, airway epithelial cells and esophageal squamous epithelial cells.
- ALOX- 15 inhibitors are a druggable target for treating eosinophilic airway diseases, such as asthma, chronic rhinosinusitis, nasal polyposis, and allergic rhinitis and eosinophilic diseases of the gastro-intestinal tract, such as eosinophilic esophagitis and eosinophilic gastroenteritis.
- prodrugs of ALOX-15 inhibitors are also disclosed herein. Also disclosed herein are methods for synthesizing such prodrugs and methods for using such prodrugs in the treatment of diseases wherein ALOX-15 inhibition provides therapeutic benefit to the patient having the disease. Further described are pharmaceutical formulations that include a prodrug of an ALOX- 15 inhibitor.
- Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and C2-9heteroaryl;
- Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci-6alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- X is a bond, Ci- 6 alkyl, C2-6alkenyl, or C2-6alkynyl;
- Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and C2-9heteroaryl;
- Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci-6alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , -N(R 6 )2, - C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- each R 14 is independently selected from H and Ci ⁇ alkyl; each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl; eac N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -OC(0)R 8 , wherein Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C
- R 17 is -C(0)OR 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, or Ci- 9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 is -C(0)OR 6 , -C(0)N(R 6 ) 2 , N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0) 2 R 8 , or - S(0) 2 N(R 6 ) 2 ; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and C2-9heteroaryl;
- Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , -N(R 6 )2, - C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0)
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- R 16 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , -S(0) 2 R 8 , or -S(0) 2 N(R 6 ) 2 ;
- R 17 is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, or Ci- 9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , -S(0) 2 R 8 , or -S(0) 2 N(R 6 ) 2 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and C 2-9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci. 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- R 16 and R 17 are independently selected from H, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , - N(R 6 ) 2 , -C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -0C(0)R 8 , wherein Ci
- R 18 is Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- X is Ci- 6 alkyl
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and C 2-9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- R 16 and R 17 are independently selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 and R 19 are independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl;
- R 20 is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, or Ci- 9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- X is Ci- 6 alkyl
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and C 2-9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and Ci- 9 heteroaryl, wherein Ci-6alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9hetero
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, -Ci- 6 alkyl-C 6 -ioaryl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 alkoxy, Ci- ehaloalkoxy, -OR 11 , -SR 11 , -N(R U ) 2 , -C(0)0R u , -C(0)N(R u ) 2 , -C(0)C(0)N(R u ) 2 , - 0C(0)N(R u ) 2 , -N(R 12 )C(0)N(R u ) 2 , -N(R 12 )C(0)0R
- each R 14 is independently selected from H and Ci ⁇ alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 .
- R 16 and R 17 are independently selected from C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 and R 19 are independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl;
- R 20 is C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- X is -C(0)N(R 19 )- or -N(R 19 )C(0)-;
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and C 2-9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -Ci ⁇ alkyl-C 6 -ioaryl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci.
- each R 10 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 11 is independently selected from H, Ci- 6 alkyl, Ci ⁇ haloalkyl, C 2-6
- each R 14 is independently selected from H and Ci ⁇ alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 .
- R 18 is selected from H and Ci ⁇ alkyl
- R 19 is selected from H and Ci ⁇ alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- Ring A is selected from C3- 6 cycloalkyl, C2- 9 heterocycloalkyl, C 6 -ioaryl, and C2- 9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 2 is selected from H, Ci. 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -Ci ⁇ alkyl-C 6 -ioaryl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 alkoxy, Ci- ehaloalkoxy, -OR 11 , -SR 11 , -N(R U ) 2 , -C(0)0R u , -C(0)N(R u ) 2 , -C(0)C(0)N(R u ) 2 , - 0C(0)N(R u ) 2 , -N(R 12 )C(0)N(R u ) 2 , -N(R 12 )C(0)0R u ,
- each R 14 is independently selected from H and Ci ⁇ alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2.6 alkenyl, C 2.6 alkynyl, C3-6cycloalkyl, C 2 .
- Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; each R 18 is independently selected from H and Ci ⁇ alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- X is Ci-ioalkyl
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and C 2-9 heteroaryl
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- each R 10 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 11 is independently selected from H, Ci- 6 alkyl, Ci ⁇ haloalkyl, C 2-6 alkenyl, C 2-6 alkyl
- each R 1 is independently selected from -P(0)(OH) 2 , -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 ,
- Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and C2-9heteroaryl;
- Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
- R 3 is selected from Ci- 6 alkyl or -Ci-6alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C 3 -
- Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 .9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2 .
- each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 . 9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2 ⁇ alkenyl, C 2 .
- each R 9 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- -ioaryl, C 6 -ioaryl, Ci-9heteroaryl, -OR 11 , - 13 ), -C(0)C(0)N(R 12 )(R 13 ), - 0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )C(0)R 15 , - N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0) 2 R 15 , -C(0)R 15 , -S(0) 2 R 15 , -C(0)R 15 , -S(0) 2 R 15 , -C(0)R 15 , -S(0) 2 R 15 , -C(0)R 15 , -
- each R 14 is independently selected from H and Ci ⁇ alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 .
- each R 16 is independently selected from halogen, -CN, Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -C(0)R 8 , -S(0) 2 R 8 , -C(0)R 8 , -S
- R 17 is selected from H, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 . 9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , - C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -0C(0)R 8 , wherein Ci- 6
- a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (II), (Da), (lib), (III), (Ilia), (mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
- a pharmaceutically acceptable salt or solvate thereof comprising a compound of Formula (I), (la), (lb), (II), (Da), (lib), (III), (Ilia), (mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila
- Also described herein is a method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (Mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or solvate thereof.
- a method of treating an eosinophilic airway disease in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Da), (lib), (III), (Ilia), (Mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic airway disease is selected from asthma, chronic rhinosinusitis, nasal polyposis, and allergic rhinitis.
- Also described herein is a method of treating an eosinophilic disease of the gastro intestinal tract in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (Mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or solvate thereof.
- a method of treating an eosinophilic disease of the gastro-intestinal tract in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic disease of the gastro-intestinal tract is selected from eosinophilic esophagitis and eosinophilic gastritis.
- ALOX15 is one of five (ALOX5/12/12B/15/15B) human lipoxygenases and is involved in the metabolism of arachidonic acid and other polyunsaturated fatty acid substrates.
- 15-HETE is its major arachidonic acid-derived metabolite, which is then further metabolized to eoxins, 5- oxo-15-hydroxy-ETE and other metabolites.
- ALOX15 metabolites are largely pro-inflammatory and have been shown to induce airway epithelial injury and promote goblet cell hyperplasia/mucus hypersecretion (15-HETE), increase vascular permeability (eoxin C4) and are potent eosinophil chemoattractants (5-oxo-15-hydroxy-ETE).
- ALOX15 is highly expressed in circulating blood eosinophils, airway epithelial cells and esophageal squamous epithelial cells and is induced in vitro by IL-13, a central mediator of the Th2 response.
- therapies as described herein designed to inhibit the production of ALOX15 protein delivered locally to the nasal epithelium, via inhalation to the airway, orally or systemically can be efficacious in treating eosinophilic diseases of the upper and lower airway, including nasal polyposis, chronic rhinosinusitis, allergic rhinitis and asthma; and eosinophilic diseases of the gastro-intestinal tract, including eosinophilic esophagitis and eosinophilic gastroenteritis.
- Ci-C x includes C 1 -C 2 , C 1 -C 3 . . . Ci-C x. Ci-C x refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents). [0021] "Amino" refers to the -NH 2 radical.
- Cyano refers to the -CN radical.
- Niro refers to the -NO 2 radical.
- Oxa refers to the -O- radical.
- Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g ., C 1 -C 15 alkyl).
- an alkyl comprises one to thirteen carbon atoms (e.g., C 1 -C 13 alkyl).
- an alkyl comprises one to ten carbon atoms (e.g., C 1 -C 10 alkyl).
- an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl).
- an alkyl comprises one to six carbon atoms (e.g., C 1 -C 6 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C 1 -C 5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C 1 -C 4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C 1 -C 3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C 1 -C 2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl).
- an alkyl comprises five to fifteen carbon atoms (e.g., C 5 -C 15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cx alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C 2 -C 5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C 3 -C 5 alkyl).
- the alkyl group is selected from methyl, ethyl, 1 -propyl (//-propyl), 1 -methyl ethyl (Ao-propyl), 1 -butyl (//-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (Ao-butyl), 1,1 -dimethyl ethyl (/e/7-butyl), and 1 -pentyl (//-pentyl).
- the alkyl is attached to the rest of the molecule by a single bond.
- an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -0C(0)R a , -N(R a ) 2 , -C(0)R a , -C(0)0R a , -C(0)N(R a ) 2 , - N(R a )C(0)0R f , -0C(0)-NR a R f , -N(R a )C(0)R f , -N(R a )S(0) t R f (where t is 1 or 2), -S(0) t 0R a (where t is 1 or 2), -S(0) t R f (where t is 1 or 2), and -S(0) t N
- Alkoxy refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
- alkenyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In other embodiments, an alkenyl comprises two to ten carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to six carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms.
- alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like.
- an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , - SR a , -OC(0)-R f , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -C(0)N(R a ) 2 , -N(R a )C(0)OR f , -OC(O)- nR a R f , -N(R a )C(0)R f , -N(R a )S(0) t R f (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t R f (where t is 1 or 2), and -S(0) t t
- Alkynyl refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms.
- an alkynyl comprises two to ten carbon atoms.
- an alkynyl comprises two to eight carbon atoms.
- an alkynyl has two to four carbon atoms.
- the alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.
- an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(0)R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , - C(0)N(R a ) 2 , -N(R a )C(0)OR f , -OC(0)-NR a R f , -N(R a )C(0)R f , -N(R a )S(0) t R f (where t is 1 or 2), - S(0) t OR a (where t is 1 or 2), -S(0) t R f (where t is 1 or 2), and -S(0) t N(R a
- Aryl refers to a radical derived from an aromatic monocyclic or multi cyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
- the aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory.
- the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.
- aryl or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -0C(0)-R a , -R b -0C(0)-0R a , -R b -0C(0)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C (0)R a , -R b -C(0)0R a , -R b -C(0)0R a
- Aryloxy refers to a radical bonded through an oxygen atom of the formula -O-aryl, where aryl is as defined above.
- Aralkyl refers to a radical of the formula -R c -aryl where R c is an alkylene chain as defined above, for example, methylene, ethylene, and the like.
- the alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain.
- the aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
- Aralkyloxy refers to a radical bonded through an oxygen atom of the formula -O- aralkyl, where aralkyl is as defined above.
- alkenyl refers to a radical of the formula -R d -aryl where R d is an alkenylene chain as defined above.
- the aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group.
- the alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
- Aralkynyl refers to a radical of the formula -R e -aryl, where R e is an alkynylene chain as defined above.
- the aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group.
- the alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
- Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms.
- a cycloalkyl comprises three to ten carbon atoms.
- a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl is attached to the rest of the molecule by a single bond.
- Cycloalkyls are saturated, (i.e., containing single C-C bonds only) or partially unsaturated (i.e., containing one or more double bonds or triple bonds.)
- monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
- a cycloalkyl comprises three to eight carbon atoms (e.g., C 3 -C 8 cycloalkyl).
- a cycloalkyl comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl).
- a partially unsaturated cycloalkyl is also referred to as "cycloalkenyl.”
- monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
- Polycyclic cycloalkyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl,
- cycloalkyl is meant to include cycloalkyl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(0)-R a , -R b -OC(0)-OR a , -R b -OC(0)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C (0)R a , -R b -C (0)R a , -R b -C
- Halo or “halogen” refers to bromo, chloro, fluoro, or iodo substituents.
- Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.
- Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.
- the alkyl part of the fluoroalkyl radical are optionally substituted as defined above for an alkyl group.
- Haloalkoxy refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above.
- Heterocycloalkyl refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which include fused, spiro, or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocycloalkyl radical is partially or fully saturated. In some embodiments, the heterocycloalkyl is attached to the rest of the molecule through any atom of the ring(s).
- heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -o
- heterocycloalkyl is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -R b -OR a , -R b -OC(0)-R a , -R b -OC(0)-OR a , -R b -OC(0)-N(R a ) 2 , -R b -N(R a ) 2 , -R b -C (0)R a , -R b -C(0)OR a , -
- Heteroaryl refers to a radical derived from a 5- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur.
- the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory.
- Heteroaryl includes fused or bridged ring systems.
- the heteroatom(s) in the heteroaryl radical is optionally oxidized.
- heteroaryl is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroaryl alkyl, -R b -OR a , -R b -0C(0)-R a , -R b -0C(0)-0R a , -R b -0C(0)-N(R a ) 2 , -R b -OR a , -R b -0C(0)-R a , -R b -0C(0)-0R a , -R b -0C(0)-N(R a ) 2
- A-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical.
- An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- C -heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical.
- a C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
- Heteroaryloxy refers to radical bonded through an oxygen atom of the formula -O- heteroaryl, where heteroaryl is as defined above.
- Heteroarylalkyl refers to a radical of the formula -R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain.
- the heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
- Heteroarylalkoxy refers to a radical bonded through an oxygen atom of the formula - 0-R c -heteroaryl, where R c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom.
- the alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain.
- the heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
- a "tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible.
- the compounds presented herein exist as tautomers.
- a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH.
- Optional or “optionally” means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not.
- the term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, Ci-C 6 alkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2- alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di -substituted amino groups (e
- “Pharmaceutically acceptable salt” includes both acid and base addition salts.
- a pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms.
- Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
- “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc.
- acetic acid trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, / oluenesulfonic acid, salicylic acid, and the like.
- Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like.
- salts of amino acids such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)).
- Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
- “Pharmaceutically acceptable base addition salt” refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A/ A'-dibenzyl ethyl enedi ami ne, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine,
- treatment or “treating” or “palliating” or “ameliorating” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit.
- therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated.
- a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder.
- the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
- a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not.
- the prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility.
- An example, without limitation, of a prodrug is a compound described herein, which is administered as an phosphonooxymethyl derivative (the “prodrug”), but then is metabolically hydrolyzed to provide the active entity.
- a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound.
- compounds described herein are cleaved by an esterase. In some embodiments, compounds described herein are cleaved by a phosphatase.
- Prodrugs described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, sulfonamides, amides, phosphoramidates and sulfonate esters. See for example Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al. , Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H.
- compositions comprising these compounds are useful for the treatment of an eosinophilic airway disease including, but not limited to, asthma, chronic rhinosinusitis, nasal polyposis and allergic rhinitis.
- an eosinophilic airway disease including, but not limited to, asthma, chronic rhinosinusitis, nasal polyposis and allergic rhinitis.
- compositions comprising these compounds are useful for the treatment of an eosinophilic disease of the gastro-intestinal tract including, but not limited to, eosinophilic esophagitis and eosinophilic gastritis.
- Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and C2-9heteroaryl;
- Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl;
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6alkyl-N(R 10 )2.
- R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6alkyl-NH2.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6alkyl-N(H)CH3.
- R 1 is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is Ci- 6 alkyl.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-ealkyl-NFh.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6 alkyl-N(H)CH 3.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is Ring A is C 2-9 heteroaryl.
- Ring A is C 2-9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C 2 - cheteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- Ring A is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is Ring B is C2-9heteroaryl.
- R 1 is Ring B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
- Ring B is C2-9heterocycloalkyl.
- n is 0, 1, or 2.
- n is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is 1.
- n is 0.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein p is 2.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, 2, or 3.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, or 2.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein q is 2.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 16 and R 17 are each independently selected from halogen, -CN, Ci- 6 alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR 6 , -SR 6 , -N(R 6 )2, -C(0)0R 6 , -C(0)N(R 6 ) 2 , - 0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , - S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -0C(0)R 8 , wherein Ci- 6 alkyl
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen and unsubstituted Ci- 6 alkyl.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from -F, -Cl, or -Br.
- p is 0.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0.
- a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is H.
- R 2 is Ci- 6 alkyl.
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; or a pharmaceutically acceptable salt or solvate thereof.
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl
- R 3 is selected from Ci-6alkyl or -Ci- 6 alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S
- R 5 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9hetero
- Ring A is C2-9heteroaryl.
- a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is C2- 9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- [0077] is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
- a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof wherein R 3 is Ci ⁇ alkyl.
- n is 0, 1, or 2.
- n is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
- n is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- X is a bond, Ci-6alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and C 2-9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- R 17 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, or Ci. 9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0) 2 R 8 , or - S(0) 2 N(R 6 ) 2 ; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof. [0084] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond, Ci ⁇ alkyl, or C2-6alkenyl.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6alkyl-N(R 10 )2.
- R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6alkyl-NH2.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6alkyl-N(H)CH3.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is Ci- 6 alkyl.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-ealkyl-NFh.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6 alkyl-N(H)CH 3.
- Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2-
- 9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- pyridinyl pyrimidinyl
- pyrazinyl pyridazinyl
- pyridazinyl a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is C2-9heterocycloalkyl.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is C2-9heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.
- n is 0, 1, or 2.
- n is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- each R 16 is independently selected from halogen, -CN, Ci- 6 alkyl, C3- ecycloalkyl, C 2.9 heterocycloalkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , - S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -OC(0)R 8 , wherein Ci- 6 alkyl, C3-6cycl
- iheterocycloalkyl are optionally substituted with one, two, or three R 9
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein each R 16 is independently selected from halogen and Ci- 6 alkyl optionally substituted with one, two, or three R 9 .
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein each R 16 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- each R 16 are each independently selected from -F, -Cl, or -Br.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is -C(0)OR 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , C 6 -ioaryl, or Ci- iheteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 17 is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 17 is -C(0)OR 6 , -C(0)R 8 , C 6 -ioaryl, or Ci-cheteroaryl.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C 6 -ioaryl or Ci-9heteroaryl.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C 6 -ioaryl or Ci-9heteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is Ci-9heteroaryl, wherein Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein Ci-9heteroaryl is selected from benzothiophenyl, benzofuranyl, indolyl, benzimidazolyl, furopyridinyl, furopyrimidinyl, furopyrazinyl, benzooxazolyl, and benzoisoxazolyl.
- Ci-9heteroaryl is selected from benzothiophenyl, benzofuranyl, benzooxazolyl, and benzoisoxazolyl.
- Ci-9heteroaryl is benzothiophenyl or benzofuranyl.
- Ci-9heteroaryl is benzothiophenyl or benzofuranyl.
- Ci- 9heteroaryl is benzofuranyl.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)OR 6 , -C(0)N(R 6 ) 2 , N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , - S(0) 2 R 8 , or -S(0) 2 N(R 6 ) 2 .
- R 18 is -S(0) 2 R 8 , -N(R 7 )S(0) 2 R 8 , or N(R 7 )C(0)R 8 .
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -N(R 7 )S(0) 2 R 8 .
- R 2 is Ci- 6 alkyl.
- X is a bond, Ci ⁇ alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 hetero
- R 17 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, or Ci- 9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R 9 ; and R 18 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0) 2 R 8 , or - S(0) 2 N(R 6 ) 2 ; or a pharmaceutically acceptable salt or solvate thereof.
- a compound of Formula (Ha), or a pharmaceutically acceptable salt or solvate thereof wherein X is a bond, Ci- 6 alkyl, or C 2 ⁇ alkenyl.
- a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is -C(0)OR 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , C 6 -ioaryl, or Ci- 9 heteroaryl, wherein C 6 -ioaryl and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 .
- R 17 is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R 17 is -C(0)OR 6 , -C(0)R 8 , C 6 -ioaryl, or Ci- 9 heteroaryl.
- Ci- 9 heteroaryl is benzothiophenyl, benzofuranyl, indolyl, benzimidazolyl, furopyridinyl, furopyrimidinyl, furopyrazinyl, benzooxazolyl, or benzoisoxazolyl.
- Ci- 9 heteroaryl is benzothiophenyl, benzofuranyl, benzooxazolyl, or benzoisoxazolyl.
- Ci-cheteroaryl is benzothiophenyl or benzofuranyl.
- Ci-9heteroaryl is benzofuranyl.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)OR 6 , -C(0)N(R 6 ) 2 , N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , - S(0) 2 R 8 , or -S(0) 2 N(R 6 ) 2 .
- R 18 is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R 18 is -S(0) 2 R 8 , -N(R 7 )S(0) 2 R 8 , or N(R 7 )C(0)R 8 .
- a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -N(R 7 )S(0) 2 R 8 .
- R 2 is Ci- 6 alkyl.
- Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and C2-9heteroaryl;
- X is a bond, Ci ⁇ alkyl, C2-6alkenyl, or C2-6alkynyl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl
- R 3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , -N(R 6 )2, - C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- R 17 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, or Ci- 9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0) 2 R 8 , or - S(0) 2 N(R 6 ) 2 ; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- Ring A is C 2 -9heteroaryl.
- a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is C 2 -9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- X is a bond, Ci- 6 alkyl, or C 2 ⁇ alkenyl.
- [00112] is a compound of Formula (Hb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is -C(0)OR 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , C 6 -ioaryl, or Ci- iheteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 17 is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 17 is -C(0)OR 6 , -C(0)R 8 , C 6 -ioaryl, or Ci- iheteroaryl.
- a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C 6 -ioaryl or Ci-9heteroaryl.
- a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C 6 -ioaryl or Ci-9heteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is Ci- 9heteroaryl, wherein Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof wherein Ci-9heteroaryl is benzothiophenyl, benzofuranyl, indolyl, benzimidazolyl, furopyridinyl, furopyrimidinyl, furopyrazinyl, benzooxazolyl, or benzoisoxazolyl.
- Ci-9heteroaryl is benzothiophenyl, benzofuranyl, benzooxazolyl, or benzoisoxazolyl.
- Ci-9heteroaryl is benzothiophenyl or benzofuranyl.
- Ci-9heteroaryl is benzothiophenyl or benzofuranyl.
- Ci-9heteroaryl is benzofuranyl.
- a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , N(R 7 )C(0)R 8 , - N(R 7 )S(0) 2 R 8 , -S(0) 2 R 8 , or -S(0) 2 N(R 6 ) 2.
- R 18 is -S(0) 2 R 8 , - N(R 7 )S(0) 2 R 8 , or N(R 7 )C(0)R 8 .
- a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -N(R 7 )S(0) 2 R 8 .
- R 2 is Ci- 6 alkyl.
- Ring A is selected from C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and C 2 -9heteroaryl;
- Ring B is selected from C 2 -9heterocycloalkyl and C 2 -9heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3- 6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8
- R 16 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , -S(0) 2 R 8 , or -S(0) 2 N(R 6 ) 2 ;
- R 17 is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, or Ci- 9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , -S(0) 2 R 8 , or -S(0) 2 N(R 6 ) 2 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- a compound of Formula (PI), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is - C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-ealkyl-NFF.
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(H)CH3.
- R 1 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- OC(0)R 3 and R 3 is Ci- 6 alkyl.
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- OC(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl- OC(0)R 3 and R 3 is -Ci-ealkyl-NFh.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl- OC(0)R 3 and R 3 is -Ci- 6 alkyl-N(H)CH .
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , , , furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2-
- 9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- [00121] in some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is Ci- 6 alkyl.
- R 1 Ring B is C2-9heteroaryl.
- R 1 is a compound of aceutically acceptable salt or solvate thereof, wherein R 1 is ing B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
- 9heterocycloalkyl In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C2-
- 9heterocycloalkyl selected from pyrrolidinyl, piped dinyl, morpholinyl, and piperazinyl.
- n is 0, 1, or 2.
- n is 1.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 16 is selected from is -C(0)OR 6 , -C(0)R 8 , or -S(0) 2 R 8 . In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, R 16 is selected from is -C(0)OR 6 or -C(0)R 8 . In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, R 16 is selected from is -C(0)R 8 .
- R 16 is selected from is -C(0)R 8 , wherein R 8 is C 6 -ioaryl or Ci-cheteroaryl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, R 16 is selected from is -C(0)R 8 , wherein R 8 is C 6 -ioaryl or Ci-9heteroaryl, wherein C 6 -ioaryl or Ci-9heteroaryl are optionally substituted with one, two, or three R 9 . In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, R 16 is selected from is -C(0)R 8 , wherein R 8 is phenyl.
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C2-9heterocycloalkyl, C 6 -ioaryl, or Ci- 9heteroaryl, wherein C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 17 is C 6 -ioaryl or Ci-9heteroaryl.
- a compound of Formula (PI), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C 6 -ioaryl or Ci-9heteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C 6 -ioaryl, wherein C 6 -ioaryl are optionally substituted with one, two, or three R 9 .
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three R 9 .
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three halo or Ci ⁇ alkyl.
- R 17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
- [00128] is a compound of Formula (PI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 18 is -C(0)N(R 6 ) 2 , -C(0)R 8 , -S(0) 2 R 8 , or - S(0) 2 N(R 6 ) 2 .
- R 18 is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 18 is -C(0)OR 6 , -C(0)R 8 , or -S(0) 2 R 8 .
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three R 9 .
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three halo or Ci- 6 alkyl.
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three halo.
- a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
- [00130] is a compound of Formula (III) having the structure of Formula (Ilia):
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- each R 11 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl; each R 12 is independently selected from H and Ci- 6 alkyl; each R 13 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, and Ci- 9
- R 16 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , -S(0) 2 R 8 , or -S(0) 2 N(R 6 ) 2 ;
- R 17 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0) 2 R 8 , or - S(0) 2 N(R 6 ) 2 ; or a pharmaceutically acceptable salt or solvate thereof.
- R 16 is selected from is -C(0)0R 6 , -C(0)R 8 , or -S(0) 2 R 8 . In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, R 16 is selected from is -C(0)0R 6 or -C(0)R 8 . In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, R 16 is selected from is -C(0)R 8 .
- R 16 is selected from is -C(0)R 8 , wherein R 8 is C 6 -ioaryl or Ci-9heteroaryl.
- R 16 is selected from is -C(0)R 8 , wherein R 8 is C 6 -ioaryl or Ci-9heteroaryl, wherein C 6 -ioaryl or Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 16 is selected from is -C(0)R 8 , wherein R 8 is phenyl.
- a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C2-9heterocycloalkyl, C 6 -ioaryl, or Ci- 9heteroaryl, wherein C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 17 is C 6 -ioaryl or Ci-9heteroaryl.
- a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C 6 -ioaryl or Ci-9heteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C 6 -ioaryl, wherein C 6 -ioaryl are optionally substituted with one, two, or three R 9 .
- R 17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
- a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)N(R 6 ) 2 , -C(0)R 8 , -S(0) 2 R 8 , or - S(0) 2 N(R 6 ) 2.
- R 18 is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 18 is -C(0)0R 6 , -C(0)R 8 , or -S(0) 2 R 8 .
- a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three R 9 .
- a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three halo or Ci- 6 alkyl.
- a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three halo.
- a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
- R 2 is Ci ⁇ alkyl.
- [00135] is a compound of Formula (III) having the structure of Formula (Bib): Formula (Illb); wherein:
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 5 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 hetero
- each R 10 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 11 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9he
- R 16 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , -S(0) 2 R 8 , or -S(0) 2 N(R 6 ) 2 ;
- R 17 is C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, or Ci-9heteroaryl, wherein C3-
- R 18 is -C(0)0R 6 , -C(0)N(R 6 ) 2 , -C(0)R 8 , -S(0) 2 R 8 , or -S(0) 2 N(R 6 ) 2 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- Ring A is C2-9heteroaryl.
- a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- [00138] is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is Ci- 6 alkyl.
- nib is a compound of Formula (nib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2.
- n is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
- n is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 16 is selected from is -C(0)OR 6 , -C(0)R 8 , or -S(0) 2 R 8 .
- R 16 is selected from is -C(0)OR 6 or -C(0)R 8 .
- R 16 is selected from is -C(0)R 8 .
- R 16 is selected from is -C(0)R 8 , wherein R 8 is C 6 -ioaryl or Ci-9heteroaryl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, R 16 is selected from is -C(0)R 8 , wherein R 8 is C 6 -ioaryl or Ci-9heteroaryl, wherein C 6 -ioaryl or Ci-9heteroaryl are optionally substituted with one, two, or three R 9 . In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, R 16 is selected from is -C(0)R 8 , wherein R 8 is phenyl.
- a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is C2-9heterocycloalkyl, C 6 -ioaryl, or Ci- 9heteroaryl, wherein C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 17 is C 6 -ioaryl or Ci-9heteroaryl.
- R 17 is C 6 -ioaryl or Ci-9heteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 17 is C 6 -ioaryl, wherein C 6 -ioaryl are optionally substituted with one, two, or three R 9 .
- R 17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
- a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)N(R 6 ) 2 , -C(0)R 8 , -S(0) 2 R 8 , or - S(0) 2 N(R 6 ) 2.
- R 18 is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 18 is -C(0)0R 6 , -C(0)R 8 , or -S(0) 2 R 8 .
- a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three R 9 .
- R 18 is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three halo or Ci- 6 alkyl.
- a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three halo.
- R 18 is -C(0)R 8 , wherein R 8 is phenyl optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
- R 2 is Ci- 6 alkyl.
- R 2 is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CFF.
- Ring A is selected from C3- 6 cycloalkyl, C2- 9 heterocycloalkyl, C 6 -ioaryl, and C2- 9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 2 is selected from H, Ci. 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -Ci ⁇ alkyl-C 6 -ioaryl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 alkoxy, Ci- ehaloalkoxy, -OR 11 , -SR 11 , -N(R U ) 2 , -C(0)0R u , -C(0)N(R u ) 2 , -C(0)C(0)N(R u ) 2 , - 0C(0)N(R u ) 2 , -N(R 12 )C(0)N(R u ) 2 , -N(R 12 )C(0)0R u ,
- each R 14 is independently selected from H and Ci ⁇ alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2.6 alkenyl, C 2.6 alkynyl, C3-6cycloalkyl, C 2.
- R 16 and R 17 are independently selected from H, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2. 6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , - N(R 6 ) 2 , -C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -0C(0)R 8 , wherein Ci
- R 18 is Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2. 9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is - C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6 alkyl-N(R 10 ) 2.
- R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6 alkyl-NH 2.
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(H)CH3.
- R 1 is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is Ci- 6 alkyl.
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci-ealkyl-NFfc.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci- 6 alkyl-N(H)CH .
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , , , furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2-
- 9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Ring B is C2-9heteroaryl. In some embodiments is a compound of
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is C2- iheterocycloalkyl.
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is C2- iheterocycloalkyl selected from pyrrolidinyl, piped dinyl, morpholinyl, and piperazinyl.
- n is 0, 1, or 2.
- n is 1. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- n is 1 and R 4 is unsubstituted Ci- 6 alkyl.
- R 16 and R 17 are independently selected from H, halogen, Ci- 6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)0R 6 , wherein Ci- 6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are unsubstituted.
- R 16 and R 17 are independently selected from H, halogen, Ci- 6 alkyl, C 3 - 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)0R 6 , wherein Ci- 6 alkyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from H, halogen, or Ci ⁇ alkyl, wherein Ci- 6 alkyl is unsubstituted.
- R 16 and R 17 are independently selected from H, halogen, or Ci- 6 alkyl, wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- R 16 is H.
- R 17 is H. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, R 16 and R 17 are H.
- R 18 is Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6 cycloalkyl, C 2-9 heterocycloalkyl.
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is selected from Ci ⁇ alkyl, C 2 - 6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, and C 2-9 heterocycloalkyl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three R 9 .
- R 18 is Ci- 6 alkyl or C 2-6 alkenyl.
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is Ci- 6 alkyl or C 2-6 alkenyl, wherein Ci- 6 alkyl and C 2-6 alkenyl are optionally substituted with one, two, or three R 9 .
- R 18 is Ci ⁇ alkyl, wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- R 18 is C 2-6 alkenyl, wherein C 2 - 6 alkenyl is optionally substituted with one, two, or three R 9 .
- a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is H.
- R 2 is Ci- 6 alkyl.
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 9 is independently selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci- 6 alkyl-C 6 -ioaryl, C 6 -ioaryl, Ci-9heteroaryl, - OR 11 , -SR 11 , -N(R 12 )(R 13 ), -C(0)0R 12 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), - 0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )C(0)R 15 ,
- each R 12 is independently selected from H and Ci- 6 alkyl
- each R 13 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, C3-6cycloalkyl, C 2 .
- each R 14 is independently selected from H and Ci- 6 alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, C3-6cycloalkyl, C 2 .
- R 18 is Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 .9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 . cheterocydoalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; or a pharmaceutically acceptable salt or solvate thereof.
- R 18 is Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6 cycloalkyl, or C 2-9 heterocycloalkyl.
- a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is Ci- 6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three R 9 .
- R 18 is Ci- 6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three R 9 .
- R 18 is Ci- 6 alkyl or C 2-6 alkenyl.
- a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is Ci- 6 alkyl or C 2-6 alkenyl, wherein Ci- 6 alkyl and C 2-6 alkenyl are optionally substituted with one, two, or three R 9 .
- a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is Ci- 6 alkyl, wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- R 18 is C 2-6 alkenyl, wherein C 2-6 alkenyl is optionally substituted with one, two, or three R 9 .
- R 2 is Ci- 6 alkyl.
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl;
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 5 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 hetero
- each R 10 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 11 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 al
- R 18 is Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- Ring A is C 2-9 heteroaryl.
- a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is C 2-9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C 2-9 heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- [00163] is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
- n is 0, 1, or 2.
- n is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
- n is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 18 is Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6 cycloalkyl, C 2-9 heterocycloalkyl.
- a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is Ci- 6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 3-6 cycloalkyl are optionally substituted with one, two, or three R 9 .
- R 18 is Ci- 6 alkyl or C 2-6 alkenyl.
- a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is Ci- 6 alkyl or C 2-6 alkenyl, wherein Ci- 6 alkyl and C 2-6 alkenyl are optionally substituted with one, two, or three R 9 .
- a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 is Ci- 6 alkyl, wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- R 18 is C 2-6 alkenyl, wherein C 2-6 alkenyl is optionally substituted with one, two, or three R 9 .
- R 2 is Ci- 6 alkyl.
- X is Ci- 6 alkyl
- Ring A is selected from C3- 6 cycloalkyl, C2- 9 heterocycloalkyl, C 6 -ioaryl, and C2- 9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 2 is selected from H, Ci. 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -Ci ⁇ alkyl-C 6 -ioaryl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 alkoxy, Ci- ehaloalkoxy, -OR 11 , -SR 11 , -N(R U ) 2 , -C(0)0R u , -C(0)N(R u ) 2 , -C(0)C(0)N(R u ) 2 , - 0C(0)N(R u ) 2 , -N(R 12 )C(0)N(R u ) 2 , -N(R 12 )C(0)0R u ,
- each R 14 is independently selected from H and Ci ⁇ alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2.6 alkenyl, C 2.6 alkynyl, C3-6cycloalkyl, C 2.
- R 16 and R 17 are independently selected from C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 and R 19 are independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl;
- R 20 is C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- [00170] is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein X is methyl, ethyl, or propyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein X is ethyl.
- [00171] is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -P(0)(OH) 2.
- a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6 alkyl-N(R 10 ) 2.
- R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6alkyl-NH2.
- a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6alkyl-N(H)CH3.
- R 1 is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is Ci- 6 alkyl.
- a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-ealkyl-NFF.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(H)CH3.
- [00173] is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is Ring A is C2-9heteroaryl.
- Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2-aminoethyl
- Ring A is C2-a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-
- 9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- [00175] is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is Ci ⁇ alkyl.
- a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is Ring B is C2-9heteroaryl. In some embodiments is a compound of
- Ring B is C2-9heterocycloalkyl.
- n is 0, 1, or 2.
- n is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is 1.
- n is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- n is 1 and R 4 is unsubstituted Ci- 6 alkyl.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci-9heteroaryl.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci-9heteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from C 6 -ioaryl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R 16 and R 17 are independently selected from C 6 -ioaryl, wherein C 6 -ioaryl is optionally substituted with one, two, or three R 9 . In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R 16 and R 17 are independently selected from phenyl.
- R 16 and R 17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from Ci-9heteroaryl.
- R 16 and R 17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole.
- Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.
- Ci- 9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R 9 .
- R 16 may be pyrazinyl.
- R 17 may be thiophenyl.
- [00181] is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 18 and R 19 are independently selected from H and Ci- 6 alkyl.
- R 18 and R 19 are independently selected from H and Ci- 6 alkyl.
- R 18 is H.
- R 19 is H.
- R 19 is Ci- 6 alkyl.
- a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof wherein R 19 is methyl, ethyl, propyl, butyl, or pentyl.
- R 19 is substituted methyl, ethyl, propyl, butyl, or pentyl.
- a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof wherein R 19 is methyl or ethyl.
- [00182] is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R 20 is C 3-6 cycloalkyl or C 2-9 heterocycloalkyl.
- R 20 is C 3-6 cycloalkyl or C 2-9 heterocycloalkyl, wherein C 3-6 cycloalkyl or C 2 - 9 heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- R 20 is C 2-9 heterocycloalkyl.
- R 20 is C 2-9 heterocycloalkyl, wherein C 2-9 heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof wherein R 2 is H.
- R 2 is Ci- 6 alkyl.
- X is Ci- 6 alkyl
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 9 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -Ci- 6 alkyl-C 6 -ioaryl, C 6 -ioaryl, Ci- 9 heteroaryl, - OR 11 , -SR 11 , -N(R 12 )(R 13 ), -C(0)0R 12 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), - 0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )C(0)R 15 , -
- each R 12 is independently selected from H and Ci- 6 alkyl
- each R 13 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, C3-6cycloalkyl, C 2 .
- each R 14 is independently selected from H and Ci- 6 alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, C3-6cycloalkyl, C 2 .
- R 16 and R 17 are independently selected from C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 and R 19 are independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; and R 20 is C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, or Ci-9heteroaryl, wherein C3-
- 6 cycloalkyl, C 2 .9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; or a pharmaceutically acceptable salt or solvate thereof.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci- 9heteroaryl.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci- 9heteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from C 6 -ioaryl.
- R 16 and R 17 are independently selected from C 6 -ioaryl, wherein C 6 -ioaryl is optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from phenyl.
- R 16 and R 17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from Ci-cheteroaryl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, R 16 and R 17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole.
- Ci- 9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R 9 . In some embodiments, R 16 may be pyrazinyl. In some embodiments, R 17 may be thiophenyl.
- R 18 and R 19 are independently selected from H and Ci- 6 alkyl.
- R 18 is H.
- R 19 is H.
- R 19 is Ci- 6 alkyl.
- a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof wherein R 19 is methyl, ethyl, propyl, butyl, or pentyl.
- R 19 is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R 19 is substituted methyl, ethyl, propyl, butyl, or pentyl.
- R 19 is methyl or ethyl.
- a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof wherein R 20 is C 3-6 cycloalkyl or C 2-9 heterocycloalkyl.
- a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof wherein R 20 is C 3-6 cycloalkyl or C 2-9 heterocycloalkyl, wherein C 3-6 cycloalkyl or C 2 - 9 heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- R 20 is C 2-9 heterocycloalkyl.
- R 20 is C 2-9 heterocycloalkyl, wherein C 2-9 heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- R 2 is Ci- 6 alkyl.
- X is Ci- 6 alkyl
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl;
- R 3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci-6alkyl, C 2-6 alkenyl, C 2-6 alkynyl,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2 .
- each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2 .
- each R 9 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, -Ci- 6 alkyl-C 6 -ioaryl, C 6 -ioaryl, Ci-9heteroaryl, - OR 11 , -SR 11 , -N(R 12 )(R 13 ), -C(0)0R 12 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), - 0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )
- each R 12 is independently selected from H and Ci- 6 alkyl
- each R 13 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, C3-6cycloalkyl, C 2 .
- each R 14 is independently selected from H and Ci- 6 alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, C3-6cycloalkyl, C 2 .
- R 16 and R 17 are independently selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and Ci- 9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 and R 19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
- R 20 is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, or Ci- 9 heteroaryl, wherein C 3 -
- 6cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- [00191] is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is methyl, ethyl, or propyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is ethyl.
- Ring A is C 2-9 heteroaryl.
- a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is C 2-9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C 2-9 heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- [00193] is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
- [00194] is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is Ci-6alkyl.
- n is 0, 1, or 2.
- n is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
- n is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci-6alkyl.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci- iheteroaryl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R 16 and R 17 are independently selected from C 6 -ioaryl and Ci- iheteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from C 6 -ioaryl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R 16 and R 17 are independently selected from C 6 -ioaryl, wherein C 6 -ioaryl is optionally substituted with one, two, or three R 9 . In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R 16 and R 17 are independently selected from phenyl.
- R 16 and R 17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from Ci-9heteroaryl.
- R 16 and R 17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole.
- Ci- 9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R 9 . In some embodiments, R 16 may be pyrazinyl. In some embodiments, R 17 may be thiophenyl.
- R 18 and R 19 are independently selected from H and Ci- 6 alkyl.
- R 18 is H.
- R 19 is H.
- R 19 is Ci- 6 alkyl.
- a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof wherein R 19 is methyl, ethyl, propyl, butyl, or pentyl.
- R 19 is substituted methyl, ethyl, propyl, butyl, or pentyl.
- a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof wherein R 20 is C3-6cycloalkyl or C2-9heterocycloalkyl.
- a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof wherein R 20 is C3-6cycloalkyl or C2-9heterocycloalkyl, wherein C3-6cycloalkyl or C2- 9heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- R 20 is C2-9heterocycloalkyl.
- R 20 is C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- [00200] is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is Ci- 6 alkyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH 3 .
- X is Ci- 6 alkyl
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and C 2-9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -Ci ⁇ alkyl-C 6 -ioaryl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci. 6 alkoxy, Ci.
- each R 10 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 11 is independently selected from H, Ci- 6 alkyl, Ci ⁇ haloalkyl, C 2-6 alkenyl, C 2
- each R 14 is independently selected from H and Ci ⁇ alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2.
- R 16 and R 17 are independently selected from C3-6cycloalkyl, C 2. 9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 and R 19 are independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl;
- R 20 is C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is - C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-ealkyl-NFh.
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(H)CH3.
- R 1 is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is Ci- 6 alkyl.
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci-ealkyl-NFh.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci- 6 alkyl-N(H)CH .
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , , , furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2-
- 9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- pyridinyl pyrimidinyl
- pyrazinyl pyridazinyl
- pyridazinyl a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
- In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is Ci-6alkyl.
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Ring B is C2-9heteroaryl.
- R 1 Ring B is C2-9heteroaryl.
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is C2- iheterocycloalkyl.
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is C2- iheterocycloalkyl selected from pyrrolidinyl, piped dinyl, morpholinyl, and piperazinyl.
- n is 0, 1, or 2.
- n is 1. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- n is i and R 4 is unsubstituted Ci- 6 alkyl.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci- iheteroaryl.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci- cheteroaryl, wherein C 6 -ioaryl and Ci-cheteroaryl are optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from C 6 -ioaryl.
- R 16 and R 17 are independently selected from C 6 -ioaryl, wherein C 6 -ioaryl is optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from phenyl.
- R 16 and R 17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from Ci-9heteroaryl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, R 16 and R 17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole.
- Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R 9 . In some embodiments, R 16 may be phenyl optionally substituted with one, two, or three R 9 . In some embodiments, R 17 may be thiophenyl.
- R 18 and R 19 are independently selected from H and Ci- 6 alkyl.
- R 18 is H.
- R 19 is H.
- R 19 is Ci- 6 alkyl.
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein R 19 is methyl, ethyl, propyl, butyl, or pentyl.
- R 19 is substituted methyl, ethyl, propyl, butyl, or pentyl.
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein R 19 is methyl or ethyl.
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein R 20 is C3-6cycloalkyl or C2-9heterocycloalkyl.
- a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof wherein R 20 is C3-6cycloalkyl or C2-9heterocycloalkyl, wherein C3-6cycloalkyl or C2- 9heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- R 20 is C2-9heterocycloalkyl.
- R 20 is C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- [00215] is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is H. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is Ci- 6 alkyl.
- In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CH 3 .
- X is Ci- 6 alkyl
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 9 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -Ci- 6 alkyl-C 6 -ioaryl, C 6 -ioaryl, Ci- 9 heteroaryl, - OR 11 , -SR 11 , -N(R 12 )(R 13 ), -C(0)0R 12 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), - 0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )C(0)R 15 , -
- R 16 and R 17 are independently selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 and R 19 are independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; and R 20 is C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, or Ci- 9 heteroaryl, wherein C 3 -
- 6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; or a pharmaceutically acceptable salt or solvate thereof.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci- 9 heteroaryl.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci- cheteroaryl, wherein C 6 -ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from C 6 -ioaryl.
- R 16 and R 17 are independently selected from C 6 -ioaryl, wherein C 6 -ioaryl is optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from phenyl.
- R 16 and R 17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from Ci-9heteroaryl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, R 16 and R 17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole.
- Ci- 9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R 9 . In some embodiments, R 16 may be phenyl optionally substituted with one, two, or three R 9 . In some embodiments, R 17 may be thiophenyl.
- R 18 and R 19 are independently selected from H and Ci- 6 alkyl.
- R 18 is H.
- R 19 is H.
- R 19 is Ci- 6 alkyl.
- a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof wherein R 19 is methyl, ethyl, propyl, butyl, or pentyl.
- a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof wherein R 19 is substituted methyl, ethyl, propyl, butyl, or pentyl.
- [00220] is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R 20 is C 3-6 cycloalkyl or C 2-9 heterocycloalkyl.
- R 20 is C 3-6 cycloalkyl or C 2-9 heterocycloalkyl, wherein C 3-6 cycloalkyl or C 2 - 9 heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- R 2 is Ci- 6 alkyl.
- X is Ci ⁇ alkyl
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and C 2-5> heteroaryl;
- R 2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 hetero
- R 16 and R 17 are independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 18 and R 19 are independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl;
- R 20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, or Ci-9heteroaryl, wherein C3-
- 6 cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- Ring A is C2-9heteroaryl.
- a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
- [00226] is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is Ci- 6 alkyl.
- n is 0, 1, or 2.
- n is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
- n is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci- iheteroaryl.
- R 16 and R 17 are independently selected from C 6 -ioaryl and Ci- cheteroaryl, wherein C 6 -ioaryl and Ci-cheteroaryl are optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from C 6 -ioaryl.
- R 16 and R 17 are independently selected from C 6 -ioaryl, wherein C 6 -ioaryl is optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from phenyl.
- R 16 and R 17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R 9 .
- R 16 and R 17 are independently selected from Ci-9heteroaryl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, R 16 and R 17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole.
- Ci- 9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R 9 .
- Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R 9 . In some embodiments, R 16 may be phenyl optionally substituted with one, two, or three R 9 . In some embodiments, R 17 may be thiophenyl.
- R 18 and R 19 are independently selected from H and Ci- 6 alkyl.
- R 18 is H.
- R 19 is H.
- R 19 is Ci- 6 alkyl.
- a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 19 is methyl, ethyl, propyl, butyl, or pentyl.
- R 19 is substituted methyl, ethyl, propyl, butyl, or pentyl.
- a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 20 is C3-6cycloalkyl or C2-9heterocycloalkyl.
- a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 20 is C3-6cycloalkyl or C2-9heterocycloalkyl, wherein C3-6cycloalkyl or C2- 9heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- R 20 is C2-9heterocycloalkyl.
- R 20 is C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl are optionally substituted with one, two, or three R 9 .
- R 2 is Ci- 6 alkyl.
- X is -C(0)N(R 19 )- or -N(R 19 )C(0)-;
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and C 2-9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -Ci ⁇ alkyl-C 6 -ioaryl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 alkoxy, Ci- ehaloalkoxy, -OR 11 , -SR 11 , -N(R U ) 2 , -C(0)0R u , -C(0)N(R u ) 2 , -C(0)C(0)N(R u ) 2 , - 0C(0)N(R u ) 2 , -N(R 12 )C(0)N(R u ) 2 , -N(R 12 )C(0)0R u ,
- each R 14 is independently selected from H and Ci ⁇ alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2.
- R 18 is selected from H and Ci ⁇ alkyl
- R 19 is selected from H and Ci ⁇ alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is - C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-ealkyl-NFF.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(H)CH3.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is Ci- 6 alkyl.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci-ealkyl-NFh.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci- 6 alkyl-N(H)CH .
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , , , furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2-
- 9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- pyridinyl pyrimidinyl
- pyrazinyl pyridazinyl
- pyridazinyl a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Ring B is C2-9heteroaryl.
- R 1 Ring B is C2-9heteroaryl.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is C2- iheterocycloalkyl.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein Ring B is C2-9heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.
- n is 0, 1, or 2.
- n is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, 2, or 3.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, or 2.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein q is 3.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 16 and R 17 are each independently selected from halogen, -CN, Ci- 6 alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , - SR 6 , -N(R 6 ) 2 , -C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen and Ci ⁇ alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 and R 17 are each independently selected from halogen and -OR 6 .
- R 6 is methyl.
- R 16 and R 17 are each independently selected from halogen.
- R 16 and R 17 are each independently selected from -F, -Cl, or -Br.
- R 16 is Cl.
- R 16 is Cl, and p is 2.
- R 17 is OMe.
- R 18 and R 19 are independently selected from H and Ci- 6 alkyl.
- a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 and R 19 are independently selected from H, substituted or unsubstituted methyl, ethyl, propyl, or butyl.
- R 18 and R 19 are H.
- R 2 is Ci- 6 alkyl.
- X is -C(0)N(R 19 )- or -N(R 19 )C(0)-;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9he
- each R 12 is independently selected from H and Ci- 6 alkyl
- each R 13 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, C3-6cycloalkyl, C 2 .
- each R 14 is independently selected from H and Ci- 6 alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2.6 alkenyl, C 2 ⁇ alkynyl, C3-6cycloalkyl, C 2 .
- each R 16 and each R 17 are independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , - N(R 6 ) 2 , -C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -C(0)R 8 , -S(0) 2 R 8 , -C(0)R 8 ,
- R 18 is selected from H and Ci- 6 alkyl
- R 19 is selected from H and Ci- 6 alkyl; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- R 16 and R 17 are each independently selected from halogen, -CN, Ci- 6 alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , - SR 6 , -N(R 6 ) 2 , -C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 )
- a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen and Ci- 6 alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 and R 17 are each independently selected from halogen and -OR 6 .
- R 6 is methyl.
- R 16 and R 17 are each independently selected from halogen.
- R 16 and R 17 are each independently selected from -F, -Cl, or -Br.
- R 16 is Cl.
- R 16 is Cl, and p is 2.
- R 17 is OMe.
- R 18 and R 19 are H.
- R 2 is Ci ⁇ alkyl.
- X is -C(0)N(R 19 )- or -N(R 19 )C(0)-;
- Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and C2-9heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci-6alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , -N(R 6 )2, - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0)
- R 5 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 hetero
- R 18 is selected from H and Ci- 6 alkyl
- R 19 is selected from H and Ci- 6 alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- X is -C(0)N(H)-.
- X is -N(H)C(0)-.
- Ring A is C2-9heteroaryl.
- a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- [00260] is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is Ci- 6 alkyl.
- n is 0, 1, or 2.
- n is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
- n is 0.
- a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 16 and R 17 are each independently selected from halogen, -CN, Ci- 6 alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , - SR 6 , -N(R 6 ) 2 , -C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 )
- a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen and Ci ⁇ alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 and R 17 are each independently selected from halogen and -OR 6 .
- R 6 is methyl.
- R 16 and R 17 are each independently selected from halogen.
- R 16 and R 17 are each independently selected from -F, -Cl, or -Br.
- R 16 is Cl.
- R 16 is Cl, and p is 2.
- R 17 is OMe.
- R 18 and R 19 are independently selected from H and Ci- 6 alkyl.
- a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof wherein R 18 and R 19 are independently selected from H, substituted or unsubstituted methyl, ethyl, propyl, or butyl.
- R 18 and R 19 are H.
- R 2 is Ci- 6 alkyl.
- Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, and C2-9heteroaryl;
- Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
- R 2 is selected from H, Ci. 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci-6alkyl-N(R 10 )2; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , -N(R 6 )2, - C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- [00269] is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is -P(0)(OH) 2 .
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is - C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6 alkyl-N(R 10 ) 2 .
- R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci- 6 alkyl-NH 2 .
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(H)CH3.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 .
- R 3 is Ci- 6 alkyl.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- OC(0)R 3 and R 3 is -Ci- 6 alkyl-N(R 10 ) 2 .
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl- OC(0)R 3 and R 3 is -Ci- 6 alkyl-NH 2 .
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl- OC(0)R 3 and R 3 is -Ci-6alkyl-N(H)CH .
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein , , , furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is C2- iheteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2- iheteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is pyridinyl.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is phenyl.
- [00273] is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is Ci- 6 alkyl.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein , , imidazolyl.
- 9heterocycloalkyl In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C2-9heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl. [00276] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, 2, or 3.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, or 2.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein q is 3.
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 16 and R 17 are each independently selected from halogen, -CN, Ci-ealkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , - N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , - S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -OC(0)R 8 , wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen and Ci- 6 alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 and R 17 are each independently selected from halogen and -OR 6 .
- R 6 is methyl.
- R 16 and R 17 are each independently selected from halogen.
- R 16 and R 17 are each independently selected from -F, -Cl, or -Br.
- p is 0
- q is 0
- R 18 is selected from H, substituted or unsubstituted methyl, ethyl, propyl, or butyl.
- R 18 is H.
- R 18 is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R 18 is methyl.
- R 2 is Ci- 6 alkyl.
- R 2 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2 .
- each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2 .
- each R 9 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, -Ci- 6 alkyl-C 6 -ioaryl, C 6 -ioaryl, Ci-9heteroaryl, -
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, -Ci- 6 alkyl-C 6 - loaryl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci ⁇ alkyl, Ci- 6 haloalkyl, Ci- ealkoxy, Ci-ehaloalkoxy, -OR 11 , -SR 11 , -N(R U ) 2 , -C(0)0R u , -C(0)N(R u ) 2 , - C(0)C(0)N(R u ) 2 , -0C(0)N(R n ) 3 ⁇ 4 -N(R 12 )C(0)N(R u ) 2 , -N(R 12 )C(0)0R u ,
- each R 12 is independently selected from H and Ci- 6 alkyl
- each R 13 is selected from Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl
- each R 14 is independently selected from H and Ci- 6 alkyl
- each R 15 is selected from Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl
- each R 16 and each R 17 are independently selected from halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkyny
- a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, 2, or 3.
- a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, or 2.
- a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof wherein q is 3.
- R 16 and R 17 are each independently selected from halogen, -CN, Ci-ealkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , - N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , - S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 ,
- a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen and Ci- 6 alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 and R 17 are each independently selected from halogen and -OR 6 .
- R 6 is methyl.
- R 16 and R 17 are each independently selected from halogen.
- ⁇ is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 16 and R 17 are each independently selected from -F, -Cl, or -Br.
- p is 0
- q is 0
- R 18 is selected from H, substituted or unsubstituted methyl, ethyl, propyl, or butyl.
- R 18 is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R 18 is H.
- R 18 is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 18 is methyl.
- R 2 is Ci- 6 alkyl.
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and C 2-9 heteroaryl;
- R 2 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 hetero
- Ci_ 6alkyl C 2-9 heterocycloalkyl, -Ci- 6 alkyl-C 6 -ioaryl, C 6 -ioaryl, Ci- 9 heteroaryl, - OR 11 , -SR 11 , -N(R 12 )(R 13 ), -C(0)0R 12 , -C(0)N(R 12 )(R 13 ), -C(0)C(0)N(R 12 )(R 13 ), - 0C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)N(R 12 )(R 13 ), -N(R 14 )C(0)0R 15 , -N(R 14 )C(0)R 15 , - N(R 14 )S(0) 2 R 15 , -C(0)R 15 , -S(0) 2 R 15 , -S(0) 2 N(R 12 )(R 13 ), and -0C(0)R 15 , wherein Ci_ 6alkyl,
- each R 12 is independently selected from H and Ci- 6 alkyl
- each R 13 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, C3-6cycloalkyl, C 2.
- each R 14 is independently selected from H and Ci- 6 alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2 ⁇ alkynyl, C3-6cycloalkyl, C 2.
- each R 16 and each R 17 are independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , - N(R 6 ) 2 , -C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -C(0)R 8 , -S(0) 2 R 8 , -C(0)R 8 ,
- each R 18 is independently selected from H and Ci- 6 alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- Ring A is C 2 -9heteroaryl.
- a compound of Formula (Vlllb), or a pharmaceutically acceptable salt or solvate thereof wherein Ring A is C 2 -9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C 2 -9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
- n is 0, 1, or 2.
- n is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
- n is 0.
- a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, 2, or 3.
- a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, or 2.
- a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof wherein q is 3.
- R 16 and R 17 are each independently selected from halogen, -CN, Ci-ealkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , - N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , - S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -0C(0)R 8 , wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9
- a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen and Ci- 6 alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 and R 17 are each independently selected from halogen and -OR 6 .
- R 6 is methyl.
- R 16 and R 17 are each independently selected from halogen.
- R 16 and R 17 are each independently selected from -F, -Cl, or -Br.
- p is 0
- q is 0
- R 18 is H.
- R 2 is Ci- 6 alkyl.
- a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 2 is -CFR is a compound of Formula (IX): Formula (IX); wherein:
- X is Ci-ioalkyl
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C6-ioaryl, and C 2-9 heteroaryl;
- Ring B is selected from C 2-9 heterocycloalkyl and C 2-9 heteroaryl;
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 ,
- R 5 is selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, -Ci ⁇ alkyl-C 6 -ioaryl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, Ci- 6 alkoxy, Ci.
- each R 10 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 11 is independently selected from H, Ci- 6 alkyl, Ci ⁇ haloalkyl, C 2-6 alkenyl, C 2
- each R 14 is independently selected from H and Ci ⁇ alkyl
- each R 15 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2.
- Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R 9 ; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (LX), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is - C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-ealkyl-NFh.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and R 3 is -Ci-6alkyl-N(H)CH3.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is Ci- 6 alkyl.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci-6alkyl-N(R 10 )2.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci-ealkyl-NFh.
- R 1 is -C(0)N(CH 3 )C 2-6 alkyl- 0C(0)R 3 and R 3 is -Ci- 6 alkyl-N(H)CH .
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Ring A is C2-9heteroaryl.
- R 1 Ring A is C2-9heteroaryl.
- Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C2- iheteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is a compound of Formula (LX), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 Ring B is C2-9heteroaryl.
- R 1 is a compound of aceutically acceptable salt or solvate thereof, wherein R 1 is ing B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
- 9heterocycloalkyl In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C2-
- 9heterocycloalkyl selected from pyrrolidinyl, piped dinyl, morpholinyl, and piperazinyl.
- n is 0, 1, or 2.
- n is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
- n is 0.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, 2, or 3.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, or 2.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein q is 3.
- a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 16 and R 17 are each independently selected from halogen, -Ci- 6 alkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , - N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , - S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -OC(0)R 8 , wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- a compound of Formula (LX), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen and Ci- 6 alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 and R 17 are each independently selected from halogen and -OR 6 .
- R 6 is hydrogen or methyl.
- R 16 and R 17 are each independently selected from halogen or -OH.
- R 16 and R 17 are each -OH.
- R 16 is -OH.
- R 16 is -OH, and p is 2.
- R 17 is -OH.
- R 17 is -OH, and q is 1.
- X is Ci-ioalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-c > heteroaryl, wherein Ci- 6 alkyl, C 2 .
- each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and Ci-9heteroaryl, wherein Ci- 6 alkyl, C 2-6 alkenyl, C 2 .
- each R 9 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, -Ci- 6 alkyl-C 6 -ioaryl, C 6 -ioaryl, Ci-9heteroaryl, -
- each R 11 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2 - 6alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl; each R 12 is independently selected from H and Ci- 6 alkyl; each R 13 is selected from Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, and Ci- 9
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
- R 16 and R 17 are each independently selected from halogen, -Ci-ealkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , - N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , - S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -OC(0)R 8 , wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen and Ci- 6 alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 and R 17 are each independently selected from halogen and -OR 6 .
- R 6 is hydrogen or methyl.
- R 16 and R 17 are each independently selected from halogen or -OH.
- R 16 and R 17 are each - OH.
- R 16 is -OH.
- R 16 is -OH, and p is 2.
- R 17 is -OH.
- R 17 is -OH, and q is 1.
- X is Ci-ioalkyl
- Ring A is selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and C 2-9 heteroaryl
- R 3 is selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2
- each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 ,
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 5 is selected from H, Ci- 6 alkyl, and Ci ⁇ haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 hetero
- each R 10 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 11 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 al
- Ring A is C 2-9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is C 2-9 heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- Ring A is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
- n is 0, 1, or 2.
- n is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
- n is 0.
- a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, 2, or 3.
- a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof wherein q is 0, 1, or 2.
- a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof wherein q is 3.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- n is 1 and R 4 is unsubstituted Ci- 6 alkyl.
- R 16 and R 17 are each independently selected from halogen, -Ci-ealkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , - N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , - S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , - S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , - S(0) 2 R 8 , -C(0)R 8 , -
- a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 and R 17 are each independently selected from halogen and Ci- 6 alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 and R 17 are each independently selected from halogen and -OR 6 .
- R 6 is hydrogen or methyl.
- R 16 and R 17 are each independently selected from halogen or -OH.
- R 16 and R 17 are each - OH.
- R 16 is -OH.
- R 16 is -OH, and p is 2.
- R 17 is -OH.
- R 17 is -OH, and q is 1.
- each R 1 is independently selected from -P(0)(OH) 2 , -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3
- each Ring A is independently selected from C3-6cycloalkyl, C 2 -9heterocycloalkyl, C 6 -ioaryl, and C 2 -9heteroaryl
- each Ring B is independently selected from C 2 -9heterocycloalkyl and C 2 -9heteroaryl
- each R 3 is independently selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2
- each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3 - 6cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 )
- R 17 is selected from H, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , -N(R 6 )2, -C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , - C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -0C(0)R 8 , wherein Ci-ealkyl,
- each R 1 is -P(0)(OH) 2.
- each R 1 is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R 1 is -C(0)N(R 5 )C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein each R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 .
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein each R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and each R 3 is Ci- 6 alkyl.
- each R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and each R 3 is -Ci-6alkyl-N(R 10 )2.
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein each R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and each R 3 is -Ci-ealkyl-NFh.
- each R 1 is -C(0)N(H)C 2-6 alkyl-0C(0)R 3 and each R 3 is -Ci- 6 alkyl- N(H)CH3.
- each R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 .
- each R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and each R 3 is Ci- 6 alkyl.
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein each R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and each R 3 is -Ci-6alkyl-N(R 10 )2.
- each R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and each R 3 is -Ci- 6 alkyl- NFF.
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein each R 1 is -C(0)N(CH 3 )C 2-6 alkyl-0C(0)R 3 and each R 3 is -Ci- 6 alkyl-N(H)CH 3.
- each some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each each Ring A is C2-9heteroaryl.
- each Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- each and each Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- each each Ring A is phenyl.
- each R 5 is Ci- 6 alkyl.
- each embodiment is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each each Ring B is C2-9heteroaryl.
- each each Ring B is C2- iheterocycloalkyl.
- each Ring B is C2- iheterocycloalkyl selected from pyrrolidinyl, piped dinyl, morpholinyl, and piperazinyl.
- n is 0, 1, or 2.
- n is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is 1.
- n is 0.
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein p is 2.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 16 is independently selected from halogen, Ci- 6 alkyl, -OR 6 , - SR 6 , -N(R 6 ) 2 , -C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , - N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -OC(0)R 8 , wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 is independently selected from halogen and Ci- 6 alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 is independently selected from halogen and -OR 6 .
- R 6 is hydrogen or methyl.
- R 16 is independently selected from halogen.
- R 17 is selected from H, halogen, Ci- 6 alkyl, C3-6cycloalkyl, C 2 . 9 heterocycl oalkyl , -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , and -OC(0)R 8 .
- R 17 is selected from H, halogen, Ci- 6 alkyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , and -OC(0)R 8 , wherein Ci-ealkyl, C 3 - 6 cycloalkyl, C 2 -9heterocycloalkyl, are optionally substituted with one, two, or three R 9 .
- R 17 is selected from H, halogen, Ci- 6 alkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , and -C(0)R 8 .
- a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is selected from H, halogen, C oalkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , and - C(0)R 8 , wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- R 17 is selected from H, halogen, and Ci- 6 alkyl.
- each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ; each R 7 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 8 is independently selected from Ci ⁇ alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and
- R 17 is selected from H, halogen, -CN, Ci- 6 alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C 6 -ioaryl, Ci-9heteroaryl, -OR 6 , -SR 6 , -N(R 6 )2, -C(0)0R 6 , - C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , - N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -0C(0)R 8 , wherein Ci- 6alkyl,
- a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- R 16 is independently selected from halogen, Ci- 6 alkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , - N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -OC(0)R 8 , wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- R 16 is independently selected from halogen and -OR 6 .
- R 6 is hydrogen or methyl.
- R 16 is independently selected from halogen.
- R 17 is selected from H, halogen, Ci- 6 alkyl, C3- ecycloalkyl, C ⁇ heterocycloalkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , and - OC(0)R 8 .
- R 17 is selected from H, halogen, Ci- 6 alkyl, C3- ecycloalkyl, C 2.9 heterocycloalkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , and - OC(0)R 8 , wherein Ci- 6 alkyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, are optionally substituted with one, two, or three R 9 .
- a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is selected from H, halogen, Ci- 6 alkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , and -C(0)R 8 .
- R 17 is selected from H, halogen, Ci ⁇ alkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , and -C(0)R 8 , wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- R 17 is H.
- each Ring A is independently selected from C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and C 2-9 heteroaryl; each R 3 is independently selected from Ci- 6 alkyl or -Ci- 6 alkyl-N(R 10 ) 2 ; each R 4 is independently selected from halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , - C(0)0R 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -
- each R 5 is independently selected from H, Ci- 6 alkyl, and Ci- 6 haloalkyl; each R 6 is independently selected from H, Ci- 6 alkyl, Ci- 6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl, wherein Ci- 6 alkyl, C 2 - 6alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2-9 heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with
- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, and Ci- 9 heteroaryl are optionally substituted with one, two, or three R 9 ;
- R 17 is selected from H, halogen, -CN, Ci- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 2 - 9heterocycloalkyl, C 6 -ioaryl, Ci- 9 heteroaryl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)0R 6 , - C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , -N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , - N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -0C(0)R 8 , wherein Ci-
- each Ring A is C 2-9 heteroaryl.
- a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof wherein each Ring A is C 2-9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- each Ring A is C 2-9 heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
- n is 0, 1, or 2.
- n is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.
- n is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.
- n is 0.
- a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, 2, or 3.
- a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 0, 1, or 2.
- a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof wherein p is 3.
- each R 4 is independently selected from halogen and unsubstituted Ci- 6 alkyl.
- R 16 is independently selected from halogen, Ci- 6 alkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)OR 6 , -C(0)N(R 6 ) 2 , -0C(0)N(R 6 ) 2 , -N(R 7 )C(0)N(R 6 ) 2 , - N(R 7 )C(0)0R 6 , -N(R 7 )C(0)R 8 , -N(R 7 )S(0) 2 R 8 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , -S(0) 2 N(R 6 ) 2 , and -OC(0)R 8 , wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof wherein R 16 is independently selected from halogen and Ci ⁇ alkyl optionally substituted with one, two, or three R 9 , or -OR 6 .
- R 16 is independently selected from halogen and -OR 6 .
- R 6 is hydrogen or methyl.
- R 16 is independently selected from halogen.
- R 17 is selected from H, halogen, Ci- 6 alkyl, C3- ecycloalkyl, C 2.9 heterocycloalkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , and - OC(0)R 8 .
- R 17 is selected from H, halogen, Ci- 6 alkyl, C3- ecycloalkyl, C 2 -9heterocycloalkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , -C(0)R 8 , -S(0)R 8 , -S(0) 2 R 8 , and - OC(0)R 8 , wherein Ci- 6 alkyl, C3-6cycloalkyl, C 2 -9heterocycloalkyl, are optionally substituted with one, two, or three R 9 .
- a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof wherein R 17 is selected from H, halogen, Ci- 6 alkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , and -C(0)R 8 .
- R 17 is selected from H, halogen, Ci ⁇ alkyl, -OR 6 , -SR 6 , -N(R 6 ) 2 , and -C(0)R 8 , wherein Ci- 6 alkyl is optionally substituted with one, two, or three R 9 .
- R 17 is H.
- the compound disclosed herein is a compound of any one of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof.
- a compound, or a pharmaceutically acceptable salt or solvate thereof having the structure: [00359] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
- [00361] is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from: [00362] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
- the compounds described herein are prepared by the general synthetic routes described below in Schemes la-lOb.
- intermediate 1-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate 1-3.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate 1-3 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound la.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is water/acetone.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate 1-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate 1-5.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is tetrahydrofuran.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate 1-5 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound lb.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is ethyl acetate.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate II-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 2a.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is water/acetone.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- R 2 , R 5 , R 6 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18 , and p are as described herein.
- X is a bond, Ci ⁇ alkyl, C2-6alkenyl, or C2-6alkynyl.
- intermediate II-l is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate II-3.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate II-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 2b.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is ethyl acetate.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate III-l is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate III-2.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is dichloromethane.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate III-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 3a.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is water/acetone.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate III-l is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate III-3.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is tetrahydrofuran.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate III-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 3b.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is ethyl acetate.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate IV-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate IV-2.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate IV-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 4a.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is water/acetone.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate IV-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate IV-3.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is tetrahydrofuran.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate IV-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 4b.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is ethyl acetate.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate V-l is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate V-2.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is dichloromethane.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate V-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 5a.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is water/acetone.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate V-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate V-3.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is tetrahydrofuran.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate V-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 5b.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is ethyl acetate.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate VI-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VI-2.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is dichloromethane.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate VI-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 6a.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is water/acetone.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate VI-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VI-3.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is tetrahydrofuran.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate VI-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 6b.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is ethyl acetate.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate VII-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VII-2.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate VII-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 7a.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is water/acetone.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate VII-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VII-3.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is tetrahydrofuran.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate VII-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 7b.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is ethyl acetate.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate VIII-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VIII-2.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate VIII-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 8a.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is water/acetone.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate VIII-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VIII-3.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is tetrahydrofuran.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate VIII-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 8b.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is ethyl acetate.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate IX-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate IX-2.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate IX-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 9a.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is water/acetone.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate IX-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate IX-3.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is tetrahydrofuran.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate IX-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 9b.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is ethyl acetate.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate X-l is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate X-2.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is dichloromethane.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate X-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 10a.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is water/acetone.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- intermediate X-l is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate X-3.
- the base is an organic base such as triethylamine or diisopropylamine.
- the base is cesium carbonate, sodium carbonate, or potassium carbonate.
- the base is sodium hydride.
- the base is sodium hydroxide.
- the base is potassium hydroxide.
- the appropriate solvent is tetrahydrofuran.
- the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
- intermediate X-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 10b.
- the acid is trifluoroacetic acid.
- the acid is hydrochloric acid.
- the appropriate solvent is ethyl acetate.
- the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
- the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
- Z isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
- mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the applications described herein.
- the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture.
- the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
- dissociable complexes are preferred (e.g ., crystalline diastereomeric salts).
- the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
- the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
- the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.
- the compounds described herein exist in their isotopically-labeled forms.
- the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
- the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
- the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
- Compounds described herein, and the pharmaceutically acceptable salts, esters, solvate, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
- isotopically-labeled compounds for example those into which radioactive isotopes such as 3 ⁇ 4 and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
- the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.
- the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
- the compounds described herein exist as their pharmaceutically acceptable salts.
- the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
- the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
- the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
- these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
- the compounds described herein exist as solvates.
- Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.
- Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol.
- the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
- the compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (IHb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed.
- a pharmaceutical composition comprising at least one compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Ilia), (Illb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers.
- the carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
- One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (la), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (lb), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Ha), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (lib), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (III), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Ilia), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Illb), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IVa), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IVb), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (V), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Va), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Vb), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (VI), or a pharmaceutically acceptable salt thereof.
- One embodiment provides a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Via), or a pharmaceutically acceptable salt thereof.
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Abstract
Described herein are compounds and pharmaceutical compositions containing such compounds which are prodrugs of ALOX-15 inhibitors. Also described herein are methods for using such compounds in the treatment of disease.
Description
PRODRUGS OF ALOX-15 INHIBITORS AND METHODS OF USING THE SAME
CROSS-REFERENCE
[0001] This application claims the benefit of U.S. Provisional Application No. 62/883,446, filed on August 6, 2019, which is herein incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Human ALOX-15 (15-lipoxygenase) protein is highly expressed in circulating blood eosinophils, airway epithelial cells and esophageal squamous epithelial cells. As such, ALOX- 15 inhibitors are a druggable target for treating eosinophilic airway diseases, such as asthma, chronic rhinosinusitis, nasal polyposis, and allergic rhinitis and eosinophilic diseases of the gastro-intestinal tract, such as eosinophilic esophagitis and eosinophilic gastroenteritis.
SUMMARY OF THE INVENTION
[0003] Described herein are prodrugs of ALOX-15 inhibitors. Also disclosed herein are methods for synthesizing such prodrugs and methods for using such prodrugs in the treatment of diseases wherein ALOX-15 inhibition provides therapeutic benefit to the patient having the disease. Further described are pharmaceutical formulations that include a prodrug of an ALOX- 15 inhibitor.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2;
each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- ryl, -OR11, -
)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl;
each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
Formula (II); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8,
wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- ryl, -OR11, -
)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R17 is -C(0)OR6, -C(0)N(R6)2, -C(0)R8, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci- 9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is -C(0)OR6, -C(0)N(R6)2, N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)2R8, or - S(0)2N(R6)2; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or -S(0)2N(R6)2;
R17 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or -S(0)2N(R6)2; and n is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt or solvate thereof.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci.6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, - SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from H, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, - N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
Formula (V); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, - SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, and Ci.9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 and R19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
Formula (VI); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci_
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 and R19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
Formula (VII);
wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci_
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups
independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci.6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is selected from H and Ci^alkyl;
R19 is selected from H and Ci^alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci.6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- -ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, -
13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci-
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, -
0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-cheteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R18 is independently selected from H and Ci^alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
Formula (IX); wherein:
X is Ci-ioalkyl;
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci. ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl;
each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
Formula (X); wherein: each R1 is independently selected from -P(0)(OH)2, -C(0)N(R5)C2-6alkyl-0C(0)R3,
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-
6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, -
C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2^alkenyl, C2.
6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- -ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, -
13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2^alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R16 is independently selected from halogen, -CN, Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, -
C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R17 is selected from H, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, - C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2.6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[0014] In another aspect described herein is a pharmaceutical composition comprising a compound of Formula (I), (la), (lb), (II), (Da), (lib), (III), (Ilia), (mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
[0015] Also described herein is a method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (Mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Da), (lib), (III), (Ilia), (Mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic airway disease is selected from asthma, chronic rhinosinusitis, nasal polyposis, and allergic rhinitis.
[0016] Also described herein is a method of treating an eosinophilic disease of the gastro intestinal tract in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (Mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or
solvate thereof. In some embodiments is a method of treating an eosinophilic disease of the gastro-intestinal tract in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic disease of the gastro-intestinal tract is selected from eosinophilic esophagitis and eosinophilic gastritis.
DETAILED DESCRIPTION OF THE INVENTION [0017] ALOX15 is one of five (ALOX5/12/12B/15/15B) human lipoxygenases and is involved in the metabolism of arachidonic acid and other polyunsaturated fatty acid substrates. 15-HETE is its major arachidonic acid-derived metabolite, which is then further metabolized to eoxins, 5- oxo-15-hydroxy-ETE and other metabolites. ALOX15 metabolites are largely pro-inflammatory and have been shown to induce airway epithelial injury and promote goblet cell hyperplasia/mucus hypersecretion (15-HETE), increase vascular permeability (eoxin C4) and are potent eosinophil chemoattractants (5-oxo-15-hydroxy-ETE). ALOX15 is highly expressed in circulating blood eosinophils, airway epithelial cells and esophageal squamous epithelial cells and is induced in vitro by IL-13, a central mediator of the Th2 response. Accordingly, therapies as described herein designed to inhibit the production of ALOX15 protein delivered locally to the nasal epithelium, via inhalation to the airway, orally or systemically, can be efficacious in treating eosinophilic diseases of the upper and lower airway, including nasal polyposis, chronic rhinosinusitis, allergic rhinitis and asthma; and eosinophilic diseases of the gastro-intestinal tract, including eosinophilic esophagitis and eosinophilic gastroenteritis.
Definitions
[0018] As used herein and in the appended claims, the singular forms "a," "and," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range varies between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including")
is not intended to exclude that which in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of or "consist essentially of" the described features.
[0019] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.
[0020] As used herein, Ci-Cx includes C1-C2, C1-C3 . . . Ci-Cx. Ci-Cx refers to the number of carbon atoms that make up the moiety to which it designates (excluding optional substituents). [0021] "Amino" refers to the -NH2 radical.
[0022] "Cyano" refers to the -CN radical.
[0023] "Nitro" refers to the -NO2 radical.
[0024] "Oxa" refers to the -O- radical.
[0025] "Oxo" refers to the =0 radical.
[0026] "Thioxo" refers to the =S radical.
[0027] "Imino" refers to the =N-H radical.
[0028] "Oximo" refers to the =N-OH radical.
[0029] "Alkyl" or "alkylene" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms ( e.g ., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to ten carbon atoms (e.g., C1-C10 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., Ci-Cs alkyl). In other embodiments, an alkyl comprises one to six carbon atoms (e.g., C1-C6 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cx alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (//-propyl), 1 -methyl ethyl (Ao-propyl), 1 -butyl (//-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (Ao-butyl), 1,1 -dimethyl ethyl (/e/7-butyl), and 1 -pentyl (//-pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
trimethylsilanyl, -ORa, -SRa, -0C(0)Ra, -N(Ra)2, -C(0)Ra, -C(0)0Ra, -C(0)N(Ra)2, - N(Ra)C(0)0Rf, -0C(0)-NRaRf, -N(Ra)C(0)Rf, -N(Ra)S(0)tRf (where t is 1 or 2), -S(0)t0Ra (where t is 1 or 2), -S(0)tRf (where t is 1 or 2), and -S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.
[0030] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.
[0031] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In other embodiments, an alkenyl comprises two to ten carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to six carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (z.e., vinyl), prop-l-enyl (z.e., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, - SRa, -OC(0)-Rf, -N(Ra)2, -C(0)Ra, -C(0)ORa, -C(0)N(Ra)2, -N(Ra)C(0)ORf, -OC(O)- nRaRf, -N(Ra)C(0)Rf, -N(Ra)S(0)tRf (where t is 1 or 2), -S(0)tORa (where t is 1 or 2), -S(0)tRf (where t is 1 or 2), and -S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.
[0032] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to ten carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -ORa, -SRa, -OC(0)Ra, -N(Ra)2, -C(0)Ra, -C(0)ORa, - C(0)N(Ra)2, -N(Ra)C(0)ORf, -OC(0)-NRaRf, -N(Ra)C(0)Rf, -N(Ra)S(0)tRf (where t is 1 or 2), - S(0)tORa (where t is 1 or 2), -S(0)tRf (where t is 1 or 2), and -S(0)tN(Ra)2 (where t is 1 or 2),
where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each Rf is independently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl.
[0033] "Aryl" refers to a radical derived from an aromatic monocyclic or multi cyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from six to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C (0)Ra, -Rb-C(0)0Ra, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C( 0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tORa (where t is 1 or 2), -Rb-S(0)tRa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkyl ene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain.
[0034] "Aryloxy" refers to a radical bonded through an oxygen atom of the formula -O-aryl, where aryl is as defined above.
[0035] "Aralkyl" refers to a radical of the formula -Rc-aryl where Rc is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.
[0036] " Aralkyloxy" refers to a radical bonded through an oxygen atom of the formula -O- aralkyl, where aralkyl is as defined above.
[0037] "Aralkenyl" refers to a radical of the formula -Rd-aryl where Rd is an alkenylene chain as defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.
[0038] "Aralkynyl" refers to a radical of the formula -Re-aryl, where Re is an alkynylene chain as defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.
[0039] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl is attached to the rest of the molecule by a single bond. Cycloalkyls are saturated, (i.e., containing single C-C bonds only) or partially unsaturated (i.e., containing one or more double bonds or triple bonds.) Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certain embodiments, a cycloalkyl comprises three to eight carbon atoms (e.g., C3-C8 cycloalkyl). In other embodiments, a cycloalkyl comprises three to seven carbon atoms (e.g., C3-C7 cycloalkyl). In other embodiments, a cycloalkyl comprises three to six carbon atoms (e.g., C3-C6 cycloalkyl). In other embodiments, a cycloalkyl comprises three to five carbon atoms (e.g., C3-C5 cycloalkyl). In other embodiments, a cycloalkyl comprises three to four carbon atoms (e.g., C3-C4 cycloalkyl). A partially unsaturated cycloalkyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbomenyl, decalinyl,
7, 7-dimethyl -bicyclo[2.2. l]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C (0)Ra, -Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C( 0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tORa (where t is 1 or 2), -Rb-S(0)tRa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkyl ene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain.
[0040] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo substituents.
[0041] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above.
[0042] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical are optionally substituted as defined above for an alkyl group.
[0043] "Haloalkoxy" refers to an alkoxy radical, as defined above, that is substituted by one or more halo radicals, as defined above.
[0044] "Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which include fused, spiro, or bridged ring systems. The heteroatoms in the heterocycloalkyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heterocycloalkyl radical is partially or fully saturated. In some embodiments, the heterocycloalkyl is attached to the rest of the molecule through any atom of the ring(s).
Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocycloalkyl" is meant to include heterocycloalkyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, -Rb-ORa, -Rb-OC(0)-Ra, -Rb-OC(0)-ORa, -Rb-OC(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C (0)Ra, -Rb-C(0)ORa, -Rb-C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)ORa, -Rb-N(Ra)C( 0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tORa (where t is 1 or 2), -Rb-S(0)tRa (where t is 1 or 2) and -Rb-S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenyl ene chain, and Rc is a straight or branched alkylene or alkenylene chain.
[0045] "Heteroaryl" refers to a radical derived from a 5- to 18-membered aromatic ring radical that comprises one to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, heteroaryl alkyl, -Rb-ORa, -Rb-0C(0)-Ra, -Rb-0C(0)-0Ra, -Rb-0C(0)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(0)Ra, -Rb-C(0)0Ra, -Rb- C(0)N(Ra)2, -Rb-0-Rc-C(0)N(Ra)2, -Rb-N(Ra)C(0)0Ra, -Rb-N(Ra)C(0)Ra, -Rb-N(Ra)S(0)tRa (where t is 1 or 2), -Rb-S(0)tORa (where t is 1 or 2), -Rb-S(0)tRa (where t is 1 or 2) and -Rb- S(0)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroaryl alkyl, each Rb is independently a direct bond or a straight or branched alkylene or alkenylene chain, and Rc is a straight or branched alkylene or alkenylene chain.
[0046] "A-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
[0047] "C -heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.
[0048] "Heteroaryloxy" refers to radical bonded through an oxygen atom of the formula -O- heteroaryl, where heteroaryl is as defined above.
[0049] "Heteroarylalkyl" refers to a radical of the formula -Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.
[0050] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula - 0-Rc-heteroaryl, where Rc is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.
[0051] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:
[0052] "Optional" or "optionally" means that a subsequently described event or circumstance may or may not occur and that the description includes instances when the event or circumstance occurs and instances in which it does not. The term “optionally substituted” or “substituted” means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, Ci-C6alkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2- alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di -substituted amino groups (e.g. -NH2, -NHR, -N(R)2), and the protected derivatives thereof. By way of example, an optional substituent may be LSRS, wherein each Ls is independently selected from a bond, -0-, - C(=0)-, -S-, -S(=0)-, -S(=0)2-, -NH-, -NHC(O)-, -C(0)NH-, S(=0)2NH-, -NHS(=0)2, -
0C(0)NH-, -NHC(0)0-, -(Ci-Cealkyl)-, or -(C2-C6alkenyl)-; and each Rs is independently selected from among H, (Ci-C6alkyl), (Cri-Cxcycloalkyl), aryl, heteroaryl, and heterocycloalkyl. [0053] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
[0054] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, / oluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt.
[0055] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted
amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, A/ A'-dibenzyl ethyl enedi ami ne, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N- methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine,
A -ethyl pi peri dine, polyamine resins, and the like. See Berge et al., supra.
[0056] As used herein, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including, but not limited to, therapeutic benefit and/or a prophylactic benefit. By "therapeutic benefit" is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made.
[0057] A “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they are easier to administer than the parent drug. They are, for instance, bioavailable by oral administration whereas the parent is not. The prodrug may be a substrate for a transporter. Further or alternatively, the prodrug also has improved solubility in pharmaceutical compositions over the parent drug. In some embodiments, the design of a prodrug increases the effective water solubility. An example, without limitation, of a prodrug is a compound described herein, which is administered as an phosphonooxymethyl derivative (the “prodrug”), but then is metabolically hydrolyzed to provide the active entity. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically active form of the compound. In certain embodiments, a prodrug is enzymatically metabolized by one or more steps or processes to the biologically, pharmaceutically or therapeutically active form of the compound. In some embodiments, compounds described herein are cleaved by an esterase. In some embodiments, compounds described herein are cleaved by a phosphatase.
[0058] Prodrugs described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphate esters, sulfonamides, amides, phosphoramidates and sulfonate esters. See for example Design of Prodrugs,
Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al. , Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. “Design and Application of Prodrugs” in A Textbook of Drug Design and Development, Krosgaard -Larsen and H. Bundgaard, Ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference.
(IXa), (IXb), (X), (Xa), or (Xb) described herein are prodrugs of ALOX-15 inhibitors. In some embodiments, the compounds of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (Illb), (IV),
(IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, and pharmaceutical compositions comprising these compounds, are useful for the treatment of an eosinophilic airway disease including, but not limited to, asthma, chronic rhinosinusitis, nasal polyposis and allergic rhinitis. In some embodiments, the compounds of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia),
(Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, and pharmaceutical compositions comprising these compounds, are useful for the treatment of an eosinophilic disease of the gastro-intestinal tract including, but not limited to, eosinophilic esophagitis and eosinophilic gastritis.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[0061] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -P(0)(OH)2.
[0062] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(R5)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is Ci^alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci- 6alkyl-N(R10)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci- 6alkyl-NH2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci- 6alkyl-N(H)CH3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is -Ci-ealkyl-NFh. In some
embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH3.
[0063] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is Ring A is C2-9heteroaryl. In some embodiments is a compound of ceutically acceptable salt or solvate thereof, wherein R1 is
Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is C2- cheteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is pyridinyl.
[0064] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is phenyl.
[0065] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci^alkyl.
[0066] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is Ring B is C2-9heteroaryl. In some embodiments is a compound of maceutically acceptable salt or solvate thereof, wherein R1 is
Ring B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
[0067] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-9heterocycloalkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or
solvate thereof, wherein
Ring B is C2-9heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.
[0068] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[0069] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[0070] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[0071] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is
independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci-6alkyl.
[0072] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen, -CN, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR6, -SR6, -N(R6)2, -C(0)0R6, -C(0)N(R6)2, - 0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, - S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, Cs-ecycloalkyl, and C2- 9heterocycloalkyl are optionally substituted with one, two, or three R9 In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and Ci-6alkyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from -F, -Cl, or -Br. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p and q are 0.
[0073] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
[0074] In some embodiments is a compound of Formula (I) having the structure of Formula (la):
Formula (la); wherein:
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; or a pharmaceutically acceptable salt or solvate thereof.
In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (la), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
[0075] In some embodiments is a compound of Formula (I) having the structure of Formula (lb):
wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci^haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci^haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci^alkyl, Ci-6haloalkyl, Ci- ealkoxy, Ci-6haloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, - C(0)C(0)N(Ru)2, -0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, - N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[0076] In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2- 9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and
pyridazinyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
[0077] In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
[0078] In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci^alkyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -Ci-6alkyl-N(R10)2.
In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -Ci-ealkyl-NFh. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -Ci-6alkyl-N(H)CH3. [0079] In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci^alkyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CFF. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is H.
[0080] In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[0081] In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is i and R4 is unsubstituted Ci- 6alkyl.
[0082] In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (lb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
[0083] In some embodiments is a compound of Formula (II):
Formula (II); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, - SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R17 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci. 9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is -C(0)0R6, -C(0)N(R6)2, N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)2R8, or - S(0)2N(R6)2; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[0084] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond, Ci^alkyl, or C2-6alkenyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond or Ci-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is Ci-6alkyl.
[0085] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -P(0)(OH)2.
[0086] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(R5)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is Ci^alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci- 6alkyl-N(R10)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci- 6alkyl-NH2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci- 6alkyl-N(H)CH3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is -Ci-ealkyl-NFh. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH3.
[0087] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Ring A is C2-9heteroaryl. In some embodiments is a compound of aceutically acceptable salt or solvate thereof, wherein R1 is
Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is C2-
9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is pyridinyl.
[0088] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is phenyl.
[0089] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci^alkyl.
[0090] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is Ring B is C2-9heteroaryl. In some embodiments is a compound of maceutically acceptable salt or solvate thereof, wherein R1 is
Ring B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
[0091] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-9heterocycloalkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-9heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.
[0092] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[0093] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[0094] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[0095] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, each R16 is independently selected from halogen, -CN, Ci-6alkyl, C3- ecycloalkyl, C2.9heterocycloalkyl, -OR6, -SR6, -N(R6)2, -C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, - S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl, C3-6cycloalkyl, and C2. iheterocycloalkyl, are optionally substituted with one, two, or three R9 In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R16 is independently selected from halogen and Ci-6alkyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R16is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (II), or a
pharmaceutically acceptable salt or solvate thereof, wherein each R16is independently selected from halogen. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein each R16 are each independently selected from -F, -Cl, or -Br. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[0096] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is -C(0)OR6, -C(0)N(R6)2, -C(0)R8, C6-ioaryl, or Ci- iheteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is -C(0)OR6, -C(0)R8, C6-ioaryl, or Ci-cheteroaryl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is Ci-9heteroaryl, wherein Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci-9heteroaryl is selected from benzothiophenyl, benzofuranyl, indolyl, benzimidazolyl, furopyridinyl, furopyrimidinyl, furopyrazinyl, benzooxazolyl, and benzoisoxazolyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci-9heteroaryl is selected from benzothiophenyl, benzofuranyl, benzooxazolyl, and benzoisoxazolyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci-9heteroaryl is benzothiophenyl or benzofuranyl. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci- 9heteroaryl is benzofuranyl.
[0097] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)OR6, -C(0)N(R6)2, N(R7)C(0)R8, -N(R7)S(0)2R8, - S(0)2R8, or -S(0)2N(R6)2. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -S(0)2R8, -N(R7)S(0)2R8, or N(R7)C(0)R8. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -N(R7)S(0)2R8.
[0098] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some
embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
[0099] In some embodiments is a compound of Formula (II) having the structure of Formula
X is a bond, Ci^alkyl, C2-6alkenyl, or C2-6alkynyl;
R2 is selected from H, Ci-6alkyl, and Ci^haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R17 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9; and R18 is -C(0)0R6, -C(0)N(R6)2, N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)2R8, or - S(0)2N(R6)2; or a pharmaceutically acceptable salt or solvate thereof.
[00100] In some embodiments is a compound of Formula (Ha), or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond, Ci-6alkyl, or C2^alkenyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond or Ci-6alkyl. In some embodiments is a compound of Formula (Ha), or a pharmaceutically acceptable salt or solvate thereof, wherein X is Ci^alkyl.
[00101] In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is -C(0)OR6, -C(0)N(R6)2, -C(0)R8, C6-ioaryl, or Ci-9heteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is -C(0)OR6, -C(0)R8, C6-ioaryl, or Ci- 9heteroaryl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is Ci- 9heteroaryl, wherein Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci-9heteroaryl is benzothiophenyl, benzofuranyl, indolyl, benzimidazolyl, furopyridinyl, furopyrimidinyl, furopyrazinyl, benzooxazolyl, or benzoisoxazolyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci-9heteroaryl is benzothiophenyl, benzofuranyl, benzooxazolyl, or benzoisoxazolyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically
acceptable salt or solvate thereof, wherein Ci-cheteroaryl is benzothiophenyl or benzofuranyl. In some embodiments is a compound of Formula (Ha), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci-9heteroaryl is benzofuranyl.
[00102] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)OR6, -C(0)N(R6)2, N(R7)C(0)R8, -N(R7)S(0)2R8, - S(0)2R8, or -S(0)2N(R6)2. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -S(0)2R8, -N(R7)S(0)2R8, or N(R7)C(0)R8. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -N(R7)S(0)2R8.
[00103] In some embodiments is a compound of Formula (Ha), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFR
[00104] In some embodiments is a compound of Formula (II) having the structure of Formula
Formula (lib); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; X is a bond, Ci^alkyl, C2-6alkenyl, or C2-6alkynyl;
R2 is selected from H, Ci-6alkyl, and Ci^haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - OC(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-
cheterocydoalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R17 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 is -C(0)0R6, -C(0)N(R6)2, N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)2R8, or - S(0)2N(R6)2; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00105] In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
[00106] In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
[00107] In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00108] In some embodiments is a compound of Formula (Hb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond, Ci-6alkyl, or C2^alkenyl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond or Ci-6alkyl. In some embodiments is a compound of Formula (Hb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is Ci^alkyl.
[00109] In some embodiments is a compound of Formula (Hb), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-6alkyl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -Ci- 6alkyl-N(R10)2. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -Ci-6alkyl-NH2. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -Ci.6alkyl-N(H)CH .
[00110] In some embodiments is a compound of Formula (Hb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CFf.
In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is H.
[00111] In some embodiments is a compound of Formula (Hb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00112] In some embodiments is a compound of Formula (Hb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00113] In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is -C(0)OR6, -C(0)N(R6)2, -C(0)R8, C6-ioaryl, or Ci- iheteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is -C(0)OR6, -C(0)R8, C6-ioaryl, or Ci- iheteroaryl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is Ci- 9heteroaryl, wherein Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci-9heteroaryl is benzothiophenyl, benzofuranyl, indolyl, benzimidazolyl, furopyridinyl, furopyrimidinyl, furopyrazinyl, benzooxazolyl, or benzoisoxazolyl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci-9heteroaryl is benzothiophenyl, benzofuranyl, benzooxazolyl, or benzoisoxazolyl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci-9heteroaryl is benzothiophenyl or benzofuranyl. In
some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein Ci-9heteroaryl is benzofuranyl.
[00114] In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)0R6, -C(0)N(R6)2, N(R7)C(0)R8, - N(R7)S(0)2R8, -S(0)2R8, or -S(0)2N(R6)2. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -S(0)2R8, - N(R7)S(0)2R8, or N(R7)C(0)R8. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -N(R7)S(0)2R8.
[00115] In some embodiments is a compound of Formula (Hb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (lib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- ryl, -OR11, -
)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or -S(0)2N(R6)2;
R17 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or -S(0)2N(R6)2; and
n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00117] In some embodiments is a compound of Formula (PI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -P(0)(OH)2.
[00118] In some embodiments is a compound of Formula (PI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(R5)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-ealkyl-NFF. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- OC(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- OC(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- OC(0)R3 and R3 is -Ci-ealkyl-NFh. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- OC(0)R3 and R3 is -Ci-6alkyl-N(H)CH .
[00119] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
, , , furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is C2-
9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is pyridinyl.
[00120] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is phenyl.
[00121] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00122] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 Ring B is C2-9heteroaryl. In some embodiments is a compound of aceutically acceptable salt or solvate thereof, wherein R1 is
ing B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
[00123] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-
9heterocycloalkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-
9heterocycloalkyl selected from pyrrolidinyl, piped dinyl, morpholinyl, and piperazinyl.
[00124] In some embodiments is a compound of Formula (PI), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00125] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00126] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)OR6, -C(0)R8, or -S(0)2R8. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)OR6 or -C(0)R8. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8, wherein R8 is C6-ioaryl or Ci-cheteroaryl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8, wherein R8 is C6-ioaryl or Ci-9heteroaryl, wherein C6-ioaryl or Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8, wherein R8 is phenyl.
[00127] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C2-9heterocycloalkyl, C6-ioaryl, or Ci- 9heteroaryl, wherein C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl. In some embodiments is a compound of Formula (PI), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl, wherein C6-ioaryl and Ci-9heteroaryl
are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl, wherein C6-ioaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein Ce- ioaryl is phenyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three halo or Ci^alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
[00128] In some embodiments is a compound of Formula (PI), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or - S(0)2N(R6)2. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)OR6, -C(0)R8, or -S(0)2R8. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three halo or Ci-6alkyl. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three halo. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
[00129] In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl.
In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
Formula (Ilia); wherein:
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, -
OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci-
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl;
each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or -S(0)2N(R6)2;
R17 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R9;
R18 is -C(0)0R6, -C(0)N(R6)2, N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)2R8, or - S(0)2N(R6)2; or a pharmaceutically acceptable salt or solvate thereof.
[00131] In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)0R6, -C(0)R8, or -S(0)2R8. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)0R6 or -C(0)R8. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8, wherein R8 is C6-ioaryl or Ci-9heteroaryl. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8, wherein R8 is C6-ioaryl or Ci-9heteroaryl, wherein C6-ioaryl or Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8, wherein R8 is phenyl.
[00132] In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C2-9heterocycloalkyl, C6-ioaryl, or Ci- 9heteroaryl, wherein C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl, wherein C6-ioaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein C6-ioaryl is phenyl. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is phenyl, wherein the phenyl is
optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three halo or Ci-6alkyl. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
[00133] In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or - S(0)2N(R6)2. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)0R6, -C(0)R8, or -S(0)2R8. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three halo or Ci-6alkyl. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three halo. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
[00134] In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci^alkyl. In some embodiments is a compound of Formula (Ilia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
[00135] In some embodiments is a compound of Formula (III) having the structure of Formula (Bib):
Formula (Illb); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci^haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or -S(0)2N(R6)2;
R17 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-
6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or -S(0)2N(R6)2; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00136] In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
[00137] In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
[00138] In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00139] In some embodiments is a compound of Formula (nib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00140] In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00141] In some embodiments is a compound of Formula (Rib), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)OR6, -C(0)R8, or -S(0)2R8. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)OR6 or -C(0)R8. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8, wherein R8 is C6-ioaryl or Ci-9heteroaryl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8, wherein R8 is C6-ioaryl or Ci-9heteroaryl, wherein C6-ioaryl or Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, R16 is selected from is -C(0)R8, wherein R8 is phenyl.
[00142] In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C2-9heterocycloalkyl, C6-ioaryl, or Ci- 9heteroaryl, wherein C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl. In some embodiments is a compound of Formula (Rib), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl or Ci-9heteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl, wherein C6-ioaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein C6-ioaryl is phenyl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is phenyl, wherein the phenyl is
optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three halo or Ci-6alkyl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is phenyl, wherein the phenyl is optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
[00143] In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or - S(0)2N(R6)2. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)0R6, -C(0)R8, or -S(0)2R8. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three halo or Ci-6alkyl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three halo. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8, wherein R8 is phenyl optionally substituted with one, two, or three halo, wherein halo is -F, -Cl, or -Br.
[00144] In some embodiments is a compound of Formula (Rib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (Illb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci.6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- -ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, -
13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci-
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, -
0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from H, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, - N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00146] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -P(0)(OH)2.
[00147] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(R5)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-NH2. In some embodiments is a
compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-ealkyl-NFfc. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH .
[00148] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
, , , furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically
acceptable salt or solvate thereof, wherein
Ring A is C2-
9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is pyridinyl.
[00149] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is phenyl.
[00150] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00151] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
Ring B is C2-9heteroaryl. In some embodiments is a compound of
Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Ring B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
[00152] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2- iheterocycloalkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2- iheterocycloalkyl selected from pyrrolidinyl, piped dinyl, morpholinyl, and piperazinyl. [00153] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00154] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00155] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from H, halogen, Ci- 6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, -OR6, -SR6, -N(R6)2, -C(0)0R6, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are unsubstituted. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from H, halogen, Ci-6alkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, -OR6, -SR6, -N(R6)2, -C(0)0R6, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from H, halogen, or Ci^alkyl, wherein Ci-6alkyl is unsubstituted. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from H, halogen, or Ci-6alkyl, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, R16 is H. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, R17 is H. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are H.
[00156] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is selected from Ci^alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, and C2-9heterocycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl or C2-6alkenyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl or C2-6alkenyl, wherein Ci-6alkyl and C2-6alkenyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci^alkyl, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is C2-6alkenyl, wherein C2- 6alkenyl is optionally substituted with one, two, or three R9.
[00157] In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of
Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (IV), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
[00158] In some embodiments is a compound of Formula (IV) having the structure of Formula
Formula (IVa); wherein:
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci^alkyl, Ci-6haloalkyl, Ci- ealkoxy, Ci-ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, - C(0)C(0)N(Ru)2, -0C(0)N(Rn)¾ -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, - N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2.
6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R18 is Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
cheterocydoalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; or a pharmaceutically acceptable salt or solvate thereof.
[00159] In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, or C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl or C2-6alkenyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl or C2-6alkenyl, wherein Ci-6alkyl and C2-6alkenyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is C2-6alkenyl, wherein C2-6alkenyl is optionally substituted with one, two, or three R9.
[00160] In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (IVa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
Formula (IVb); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci^haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci^alkyl, Ci-6haloalkyl, Ci. ealkoxy, Ci-6haloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, - C(0)C(0)N(Ru)2, -0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, - N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl;
each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R18 is Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00162] In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
[00163] In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
[00164] In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00165] In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00166] In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a
compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00167] In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, and C3-6cycloalkyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl or C2-6alkenyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl or C2-6alkenyl, wherein Ci-6alkyl and C2-6alkenyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is C2-6alkenyl, wherein C2-6alkenyl is optionally substituted with one, two, or three R9.
[00168] In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (IVb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
Formula (V); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci.6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- -ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, -
13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci-
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, -
0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-cheteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 and R19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00170] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein X is methyl, ethyl, or propyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein X is ethyl.
[00171] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -P(0)(OH)2.
[00172] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(R5)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2.6alkyl-0C(0)R3 and R3 is Ci^alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci- 6alkyl-N(R10)2. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-
6alkyl-NH2. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci- 6alkyl-N(H)CH3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is -Ci-ealkyl-NFF. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH3.
[00173] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is Ring A is C2-9heteroaryl. In some embodiments is a compound of aceutically acceptable salt or solvate thereof, wherein R1 is
Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (V), or a pharmaceutically
acceptable salt or solvate thereof, wherein
Ring A is C2-
9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is pyridinyl.
[00174] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is phenyl.
[00175] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci^alkyl.
[00176] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Ring B is C2-9heteroaryl. In some embodiments is a compound of
Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Ring B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
[00177] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-9heterocycloalkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-9heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.
[00178] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00179] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00180] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci-9heteroaryl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci-9heteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl, wherein C6-ioaryl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole. In some embodiments, Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci- 9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R9. In some embodiments, R16 may be pyrazinyl. In some embodiments, R17 may be thiophenyl.
[00181] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is H. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is Ci-6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically
acceptable salt or solvate thereof, wherein R19 is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is substituted methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl or ethyl.
[00182] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl, wherein C3-6cycloalkyl or C2- 9heterocycloalkyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl are optionally substituted with one, two, or three R9.
[00183] In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (V), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
Formula (Va); wherein:
X is Ci-6alkyl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, -
OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-cheteroaryl are optionally substituted with one, two, or three
each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2.
6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 and R19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; and R20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-
6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; or a pharmaceutically acceptable salt or solvate thereof.
[00185] In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein X is methyl, ethyl, or propyl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein X is ethyl.
[00186] In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci- 9heteroaryl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci- 9heteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Va), or a pharmaceutically
acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl, wherein C6-ioaryl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-cheteroaryl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole. In some embodiments, Ci- 9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R9. In some embodiments, R16 may be pyrazinyl. In some embodiments, R17 may be thiophenyl.
[00187] In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is H. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is Ci-6alkyl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is substituted methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl or ethyl.
[00188] In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl, wherein C3-6cycloalkyl or C2- 9heterocycloalkyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl are optionally substituted with one, two, or three R9.
[00189] In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl.
In some embodiments is a compound of Formula (Va), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
[00190] In some embodiments is a compound of Formula (V) having the structure of Formula
Formula (Vb); wherein:
X is Ci-6alkyl;
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; R2 is selected from H, Ci-6alkyl, and Ci^haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl,
C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci.9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-ioaryl, and Ci.9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2.
6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 and R19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-
6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00191] In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is methyl, ethyl, or propyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is ethyl.
[00192] In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
[00193] In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
[00194] In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00195] In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00196] In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (Vb), or a
pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00197] In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci- iheteroaryl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci- iheteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl, wherein C6-ioaryl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole. In some embodiments, Ci- 9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R9. In some embodiments, R16 may be pyrazinyl. In some embodiments, R17 may be thiophenyl.
[00198] In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is H. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is Ci-6alkyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is substituted methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl or ethyl.
[00199] In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl, wherein C3-6cycloalkyl or C2- 9heterocycloalkyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl are optionally substituted with one, two, or three R9.
[00200] In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (Vb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
Formula (VI);
wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci_
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups
independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci.6alkoxy, Ci. ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from C3-6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 and R19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00202] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X is methyl, ethyl, or propyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein X is ethyl.
[00203] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -P(0)(OH)2.
[00204] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(R5)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -
C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-ealkyl-NFh. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH3. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-ealkyl-NFh. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH .
[00205] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
, , , furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically
acceptable salt or solvate thereof, wherein
Ring A is C2-
9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is pyridinyl.
[00206] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is phenyl.
[00207] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00208] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
Ring B is C2-9heteroaryl. In some embodiments is a compound of
Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Ring B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
[00209] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2- iheterocycloalkyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2- iheterocycloalkyl selected from pyrrolidinyl, piped dinyl, morpholinyl, and piperazinyl. [00210] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00211] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein n is i and R4 is unsubstituted Ci- 6alkyl.
[00212] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci- iheteroaryl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci- cheteroaryl, wherein C6-ioaryl and Ci-cheteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl, wherein C6-ioaryl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole. In some embodiments, Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R9. In some embodiments, R16 may be phenyl optionally substituted with one, two, or three R9. In some embodiments, R17 may be thiophenyl.
[00213] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is H. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate
thereof, wherein R19 is Ci-6alkyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is substituted methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl or ethyl.
[00214] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl, wherein C3-6cycloalkyl or C2- 9heterocycloalkyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl are optionally substituted with one, two, or three R9.
[00215] In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl.
In some embodiments is a compound of Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
[00216] In some embodiments is a compound of Formula (VI) having the structure of Formula
Formula (Via); wherein:
X is Ci-6alkyl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 and R19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; and R20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-
6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; or a pharmaceutically acceptable salt or solvate thereof.
[00217] In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein X is methyl, ethyl, or propyl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein X is ethyl.
[00218] In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci- 9heteroaryl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci-
cheteroaryl, wherein C6-ioaryl and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl, wherein C6-ioaryl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole. In some embodiments, Ci- 9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R9. In some embodiments, R16 may be phenyl optionally substituted with one, two, or three R9. In some embodiments, R17 may be thiophenyl.
[00219] In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is H. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is Ci-6alkyl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is substituted methyl, ethyl, propyl, butyl, or
pentyl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl or ethyl.
[00220] In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl, wherein C3-6cycloalkyl or C2- 9heterocycloalkyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl are optionally substituted with one, two, or three R9.
[00221] In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (Via), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
[00222] In some embodiments is a compound of Formula (VI) having the structure of Formula
Formula (VIb); wherein:
X is Ci^alkyl;
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-5>heteroaryl; R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2;
each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci^haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl;
each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 and R19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-
6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00223] In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is methyl, ethyl, or propyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is ethyl.
[00224] In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
[00225] In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
[00226] In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00227] In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00228] In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00229] In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci- iheteroaryl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl and Ci- cheteroaryl, wherein C6-ioaryl and Ci-cheteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from C6-ioaryl, wherein C6-ioaryl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from phenyl, wherein phenyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, R16 and R17 are independently selected from Ci-9heteroaryl, wherein Ci-9heteroaryl is optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole. In some embodiments, Ci- 9heteroaryl may be oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, thiophenyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazole, or tetrazole optionally substituted with one, two, or three R9. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl. In some embodiments, Ci-9heteroaryl may be pyrazolyl, furanyl, thiophenyl, pyridinyl, pyrimidinyl,
pyrazinyl, or pyridazinyl optionally substituted with one, two, or three R9. In some embodiments, R16 may be phenyl optionally substituted with one, two, or three R9. In some embodiments, R17 may be thiophenyl.
[00230] In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is H. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is Ci-6alkyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is substituted methyl, ethyl, propyl, butyl, or pentyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is methyl or ethyl.
[00231] In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C3-6cycloalkyl or C2-9heterocycloalkyl, wherein C3-6cycloalkyl or C2- 9heterocycloalkyl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl, wherein C2-9heterocycloalkyl are optionally substituted with one, two, or three R9.
[00232] In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (VIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
Formula (VII);
wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci_
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups
independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is selected from H and Ci^alkyl;
R19 is selected from H and Ci^alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00234] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(0)N(H)-. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(H)C(0)-.
[00235] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -P(0)(OH)2.
[00236] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(R5)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3. In some embodiments is a compound of
Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-ealkyl-NFF. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH3. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-ealkyl-NFh. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH .
[00237] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
, , ,
furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is C2-
9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is pyridinyl.
[00238] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is phenyl.
[00239] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00240] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
Ring B is C2-9heteroaryl. In some embodiments is a compound of
Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Ring B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
[00241] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2- iheterocycloalkyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-9heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl. [00242] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00243] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
- Ill -
[00244] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[00245] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00246] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen, -CN, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, - SR6, -N(R6)2, -C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and Ci^alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and -OR6. In some embodiments, R6 is methyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from -F, -Cl, or -Br. In some embodiments, R16 is Cl. In some embodiments, R16 is Cl, and p is 2. In some embodiments, R17 is OMe.
[00247] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H, substituted or unsubstituted methyl, ethyl, propyl, or butyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are H.
[00248] In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (VII), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
[00249] In some embodiments is a compound of Formula (VII) having the structure of Formula (Vila):
wherein:
X is -C(0)N(R19)- or -N(R19)C(0)-;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)OR12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, -
N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2.
6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2.6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R16 and each R17 are independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, - N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is selected from H and Ci-6alkyl;
R19 is selected from H and Ci-6alkyl; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00250] In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(0)N(H)-. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(H)C(0)-.
[00251] In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt
or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00252] In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[00253] In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen, -CN, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, - SR6, -N(R6)2, -C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and Ci-6alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and -OR6. In some embodiments, R6 is methyl. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from -F, -Cl, or -Br. In some embodiments, R16 is Cl. In some embodiments, R16 is Cl, and p is 2. In some embodiments, R17 is OMe.
[00254] In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H,
substituted or unsubstituted methyl, ethyl, propyl, or butyl. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are H.
[00255] In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci^alkyl. In some embodiments is a compound of Formula (Vila), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3.
Formula (Vllb); wherein:
X is -C(0)N(R19)- or -N(R19)C(0)-;
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci^haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R16 and each R17 are independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, - N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is selected from H and Ci-6alkyl;
R19 is selected from H and Ci-6alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and
q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00257] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(0)N(H)-. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(H)C(0)-.
[00258] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
[00259] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
[00260] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00261] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00262] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00263] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[00264] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00265] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen, -CN, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, - SR6, -N(R6)2, -C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and Ci^alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and -OR6. In some embodiments, R6 is methyl. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from -F, -Cl, or -Br. In some embodiments, R16 is Cl. In some embodiments, R16 is Cl, and p is 2. In some embodiments, R17 is OMe.
[00266] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are independently selected from H, substituted or unsubstituted methyl, ethyl, propyl, or butyl. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 and R19 are H.
[00267] In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (Vllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci.6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8,
wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- ryl, -OR11, -
)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R18 is independently selected from H and Ci^alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00269] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -P(0)(OH)2.
[00270] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(R5)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-NH2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH3. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- OC(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- OC(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- OC(0)R3 and R3 is -Ci-6alkyl-NH2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- OC(0)R3 and R3 is -Ci-6alkyl-N(H)CH .
[00271] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein
, , , furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is C2- iheteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is pyridinyl.
[00272] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is phenyl.
[00273] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00274] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein
, , imidazolyl.
[00275] In some embodiments is a compound of Formula (VUI), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-
9heterocycloalkyl. In some embodiments is a compound of Formula (VIII), or a
pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-9heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl. [00276] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00277] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00278] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[00279] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is
independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00280] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen, -CN, Ci-ealkyl, -OR6, -SR6, -N(R6)2, -C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, - N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, - S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and Ci-6alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and -OR6. In some embodiments, R6 is methyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from -F, -Cl, or -Br. In some embodiments, p is 0 In some embodiments, q is 0
[00281] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is selected from H, substituted or unsubstituted methyl, ethyl, propyl, or butyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is methyl.
[00282] In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci-6alkyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFF.
[00283] In some embodiments is a compound of Formula (VIII) having the structure of Formula (Villa):
Formula (Villa); wherein:
R2 is selected from H, Ci-6alkyl, and Ci^haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, -
OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci-
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci^alkyl, Ci-6haloalkyl, Ci- ealkoxy, Ci-ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, - C(0)C(0)N(Ru)2, -0C(0)N(Rn)¾ -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, - N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2.
6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl;
each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R16 and each R17 are independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, - N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R18 is independently selected from H and Ci-6alkyl; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00284] In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00285] In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[00286] In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen, -CN, Ci-ealkyl, -OR6, -SR6, -N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, - N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, - S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and Ci-6alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and -OR6. In some embodiments, R6 is methyl. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from -F, -Cl, or -Br. In some embodiments, p is 0 In some embodiments, q is 0
[00287] In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is selected from H, substituted or unsubstituted methyl, ethyl, propyl, or butyl. In some embodiments is a compound of Formula (VIII), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is methyl.
[00288] In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci- 6alkyl. In some embodiments is a compound of Formula (Villa), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFR
[00289] In some embodiments is a compound of Formula (VIII) having the structure of Formula (Vlllb):
Formula (Vlllb); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci^haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl,
C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, -
N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci.9heteroaryl are optionally substituted with one, two, or three
N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R16 and each R17 are independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, - N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci.6alkyl, C2-6alkenyl, C2^alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R18 is independently selected from H and Ci-6alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00290] In some embodiments is a compound of Formula (Vffib), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (Vlllb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (Vlllb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and
pyridazinyl. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
[00291] In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
[00292] In some embodiments is a compound of Formula (Vlllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00293] In some embodiments is a compound of Formula (Vlllb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00294] In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00295] In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[00296] In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a
compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00297] In some embodiments is a compound of Formula (Vlllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen, -CN, Ci-ealkyl, -OR6, -SR6, -N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, - N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, - S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and Ci-6alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and -OR6. In some embodiments, R6 is methyl. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from -F, -Cl, or -Br. In some embodiments, p is 0 In some embodiments, q is 0
[00298] In some embodiments is a compound of Formula (Vlllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is selected from H and Ci-6alkyl. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is selected from H, substituted or unsubstituted methyl, ethyl, propyl, or butyl. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is methyl. [00299] In some embodiments is a compound of Formula (Vlllb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is H. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is Ci- 6alkyl. In some embodiments is a compound of Formula (VUIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CFR [00300] In some embodiments is a compound of Formula (IX):
Formula (IX); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci_
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups
independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci. ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00301] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted Ci-ioalkyl. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted propyl, butyl, pentyl, or hexyl. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted butyl. [00302] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -P(0)(OH)2.
[00303] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(R5)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (LX), or a pharmaceutically acceptable salt or solvate
thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is - C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-ealkyl-NFh. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH3. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is Ci-6alkyl. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-ealkyl-NFh. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(CH3)C2-6alkyl- 0C(0)R3 and R3 is -Ci-6alkyl-N(H)CH .
[00304] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
Ring A is C2-9heteroaryl. In some embodiments is a compound of
Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is
Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is C2- iheteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (LX), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is pyridinyl.
[00305] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring A is phenyl.
[00306] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00307] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein
some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R1
Ring B is C2-9heteroaryl. In some embodiments is a compound of aceutically acceptable salt or solvate thereof, wherein R1 is
ing B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
[00308] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-
9heterocycloalkyl. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein
Ring B is C2-
9heterocycloalkyl selected from pyrrolidinyl, piped dinyl, morpholinyl, and piperazinyl.
[00309] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00310] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2.
In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00311] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[00312] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00313] In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen, -Ci-6alkyl, -OR6, -SR6, -N(R6)2, -C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, - N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, - S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (LX), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and Ci-6alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (LX), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and -OR6. In some embodiments, R6 is hydrogen or methyl. In some embodiments is a compound of Formula (IX),
or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen or -OH. In some embodiments is a compound of Formula (IX), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each -OH. In some embodiments, R16 is -OH. In some embodiments, R16 is -OH, and p is 2. In some embodiments, R17 is -OH. In some embodiments, R17 is -OH, and q is 1.
[00314] In some embodiments is a compound of Formula (IX) having the structure of Formula
Formula (IXa); wherein:
X is Ci-ioalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-c>heteroaryl, wherein Ci-6alkyl, C2. 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, -
OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci-
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R16 and each R17 are independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, - N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00315] In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted Ci-ioalkyl. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted propyl, butyl, pentyl, or hexyl. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted butyl. [00316] In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00317] In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[00318] In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen, -Ci-ealkyl, -OR6, -SR6, -N(R6)2, -C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, - N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, - S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and Ci-6alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and -OR6. In some embodiments, R6 is hydrogen or methyl. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen or -OH. In some embodiments is a compound of Formula (IXa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each - OH. In some embodiments, R16 is -OH. In some embodiments, R16 is -OH, and p is 2. In some embodiments, R17 is -OH. In some embodiments, R17 is -OH, and q is 1.
[00319] In some embodiments is a compound of Formula (IX) having the structure of Formula
Formula (IXb); wherein:
X is Ci-ioalkyl;
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci^haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci^alkyl, Ci-6haloalkyl, Ci. ealkoxy, Ci-6haloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, - C(0)C(0)N(Ru)2, -0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, - N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl;
each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R16 and each R17 are independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, - N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00320] In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted Ci-ioalkyl. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted methyl, ethyl, propyl, butyl, pentyl, or hexyl. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted propyl, butyl, pentyl, or hexyl. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein X is substituted butyl. [00321] In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
[00322] In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
[00323] In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
[00324] In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00325] In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00326] In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, 2, or 3. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0, 1, or 2. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 3. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 2. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
[00327] In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00328] In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen, -Ci-ealkyl, -OR6, -SR6, -N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, - N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, - S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and Ci-6alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen and -OR6. In some embodiments, R6 is hydrogen or methyl. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each independently selected from halogen or -OH. In some embodiments is a compound of Formula (IXb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 and R17 are each - OH. In some embodiments, R16 is -OH. In some embodiments, R16 is -OH, and p is 2. In some embodiments, R17 is -OH. In some embodiments, R17 is -OH, and q is 1.
Formula (X); wherein: each R1 is independently selected from -P(0)(OH)2, -C(0)N(R5)C2-6alkyl-0C(0)R3,
each Ring A is independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; each Ring B is independently selected from C2-9heterocycloalkyl and C2-9heteroaryl; each R3 is independently selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2;
each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- ryl, -OR11, -
)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl;
each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R17 is selected from H, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, - C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-ealkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00330] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -P(0)(OH)2.
[00331] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(R5)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(H)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and each R3 is Ci-6alkyl. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and each R3 is -Ci-6alkyl-N(R10)2. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and each R3 is -Ci-ealkyl-NFh. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(H)C2-6alkyl-0C(0)R3 and each R3 is -Ci-6alkyl- N(H)CH3. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and each R3 is Ci-6alkyl. In some
embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and each R3 is -Ci-6alkyl-N(R10)2.
In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and each R3 is -Ci-6alkyl- NFF. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is -C(0)N(CH3)C2-6alkyl-0C(0)R3 and each R3 is -Ci- 6alkyl-N(H)CH3.
[00332] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each
some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each
each Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each
each Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each
and each Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (X), or a pharmaceutically
acceptable salt or solvate thereof, wherein each
each Ring A is pyridinyl.
[00333] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each
each Ring A is phenyl.
[00334] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5 is Ci-6alkyl.
[00335] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each
some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each
each Ring B is C2-9heteroaryl. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each
each Ring B is C2-9heteroaryl selected from pyrazolyl, pyrrol yl, and imidazolyl.
[00336] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each
each Ring B is C2- iheterocycloalkyl. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each
each Ring B is C2- iheterocycloalkyl selected from pyrrolidinyl, piped dinyl, morpholinyl, and piperazinyl.
[00337] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00338] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00339] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein n is
1 and R4 is halogen. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00340] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from halogen, Ci-6alkyl, -OR6, - SR6, -N(R6)2, -C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from halogen and Ci-6alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from halogen and -OR6. In some embodiments, R6 is hydrogen or methyl. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from halogen. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00341] In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci-6alkyl, C3-6cycloalkyl, C 2. 9heterocycl oalkyl , -OR6, -SR6, -N(R6)2, -C(0)R8, -S(0)R8, -S(0)2R8, and -OC(0)R8. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -OR6, -SR6, -N(R6)2, -C(0)R8, -S(0)R8, -S(0)2R8, and -OC(0)R8, wherein Ci-ealkyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci-6alkyl, -OR6, -SR6, -N(R6)2, and -C(0)R8.
In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, C oalkyl, -OR6, -SR6, -N(R6)2, and - C(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, and Ci-6alkyl. In some embodiments is a compound of Formula (X), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is H.
Formula (Xa); wherein: each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl;
each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R16 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R17 is selected from H, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, -C(0)0R6, - C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, - N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci. 9heteroaryl are optionally substituted with one, two, or three R9; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00343] In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00344] In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from halogen, Ci-6alkyl, -OR6, -SR6, -N(R6)2, -C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, - N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from halogen and Ci^alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from
halogen and -OR6. In some embodiments, R6 is hydrogen or methyl. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from halogen. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00345] In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci-6alkyl, C3- ecycloalkyl, C^heterocycloalkyl, -OR6, -SR6, -N(R6)2, -C(0)R8, -S(0)R8, -S(0)2R8, and - OC(0)R8. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci-6alkyl, C3- ecycloalkyl, C2.9heterocycloalkyl, -OR6, -SR6, -N(R6)2, -C(0)R8, -S(0)R8, -S(0)2R8, and - OC(0)R8, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci- 6alkyl, -OR6, -SR6, -N(R6)2, and -C(0)R8. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci^alkyl, -OR6, -SR6, -N(R6)2, and -C(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, and Ci-6alkyl. In some embodiments is a compound of Formula (Xa), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is H.
[00346] In some embodiments is a compound of Formula (X) having the structure of Formula
Formula (Xb);
wherein: each Ring A is independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; each R3 is independently selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R5 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, - OR11, -SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6- loaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three
each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
each R12 is independently selected from H and Ci-6alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- iheterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci-6alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-cheteroaryl; each R16 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and - 0C(0)R8, wherein Ci.6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R17 is selected from H, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, -C(0)0R6, - C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, - N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
[00347] In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein each Ring A is C2-9heteroaryl. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein each Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein each Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein each Ring A is pyridinyl. [00348] In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein each Ring A is phenyl.
[00349] In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R5 is Ci-6alkyl.
[00350] In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
[00351] In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, 2, or 3. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0, 1, or 2. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 3. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 2. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00352] In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci-6alkyl. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 or 2 and each R4 is independently selected from halogen and unsubstituted Ci^alkyl. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is halogen. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1 and R4 is unsubstituted Ci- 6alkyl.
[00353] In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from halogen, Ci-6alkyl, -OR6, -SR6, -N(R6)2, -C(0)OR6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, - N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -OC(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from halogen and Ci^alkyl optionally substituted with one, two, or three R9, or -OR6. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is independently selected from halogen and -OR6. In some embodiments, R6 is hydrogen or methyl. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein
R16 is independently selected from halogen. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
[00354] In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci-6alkyl, C3- ecycloalkyl, C2.9heterocycloalkyl, -OR6, -SR6, -N(R6)2, -C(0)R8, -S(0)R8, -S(0)2R8, and - OC(0)R8. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci-6alkyl, C3- ecycloalkyl, C2-9heterocycloalkyl, -OR6, -SR6, -N(R6)2, -C(0)R8, -S(0)R8, -S(0)2R8, and - OC(0)R8, wherein Ci-6alkyl, C3-6cycloalkyl, C2-9heterocycloalkyl, are optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci- 6alkyl, -OR6, -SR6, -N(R6)2, and -C(0)R8. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, Ci^alkyl, -OR6, -SR6, -N(R6)2, and -C(0)R8, wherein Ci-6alkyl is optionally substituted with one, two, or three R9. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from H, halogen, and Ci-6alkyl. In some embodiments is a compound of Formula (Xb), or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is H.
[00355] Any combination of the groups described above for the various variables is contemplated herein.
[00356] Throughout the specification, groups and substituents thereof can be chosen to provide stable moieties and compounds.
[00357] In some embodiments, the compound disclosed herein is a compound of any one of the compounds described herein, or a pharmaceutically acceptable salt or solvate thereof.
[00358] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, having the structure:
[00359] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
[00360] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
[00361] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
[00362] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
[00363] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
[00364] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
[00365] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
[00366] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
[00367] In some embodiments is a compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:
Preparation of the Compounds
[00368] The compounds used in the reactions described herein are made according to known organic synthesis techniques, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Geel, Belgium), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville, IL), Avocado Research (Lancashire, U.K.), BDH Inc.
(Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Combi -blocks (San Diego, CA), Crescent Chemical Co. (Hauppauge, NY), eMolecules (San Diego, CA), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Matrix Scientific, (Columbia, SC), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Ryan Scientific, Inc. (Mount Pleasant, SC), Spectrum Chemicals (Gardena, CA), Sundia Meditech, (Shanghai, China), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and WuXi (Shanghai, China).
[00369] Suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press,
New York, 1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley -Interscience, New York, 1992. Additional suitable reference books and treatises that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley- VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3 -527-29645 -X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
[00370] Specific and analogous reactants are also identified through the indices of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C., may be contacted for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses ( e.g ., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the compounds described herein is P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.
[00371] In some embodiments, the compounds described herein are prepared by the general synthetic routes described below in Schemes la-lOb.
[00372] In Scheme la, substituents R2, R6, R9, R10, R11, R12, R13, R14, R15, R16, and R17 , and p and q are as described herein.
[00373] In some embodiments, intermediate 1-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate 1-3. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride.
In some embodiments, the base is sodium hydroxide. In some embodiments, the base is
potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00374] In some embodiments, intermediate 1-3 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound la. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments the appropriate solvent is water/acetone. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00375] In Scheme lb, substituents R2, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, and R17, and p and qare as described herein.
[00376] In some embodiments, intermediate 1-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate 1-5. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is
sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the appropriate solvent is tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00377] In some embodiments, intermediate 1-5 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound lb. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the appropriate solvent is ethyl acetate. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00378] In Scheme 2a, substituents R2, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18, and p are as described herein. In Scheme 2a, X is a bond, Ci-6alkyl, C2-6alkenyl, or C2-6alkynyl. [00379] In some embodiments, intermediate II-l is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate II-2. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride.
In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In
some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00380] In some embodiments, intermediate II-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 2a. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments the appropriate solvent is water/acetone. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00381] In Scheme 2b, substituents R2, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18, and p are as described herein. In Scheme 2b, X is a bond, Ci^alkyl, C2-6alkenyl, or C2-6alkynyl. [00382] In some embodiments, intermediate II-l is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate II-3. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the appropriate solvent is
tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00383] In some embodiments, intermediate II-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 2b. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the appropriate solvent is ethyl acetate. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00384] In Scheme 3a, substituents R2, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are as described herein.
[00385] In some embodiments, intermediate III-l is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate III-2. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00386] In some embodiments, intermediate III-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 3a. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments the appropriate solvent is water/acetone. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00388] In some embodiments, intermediate III-l is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate III-3. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the appropriate solvent is tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00389] In some embodiments, intermediate III-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 3b. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the appropriate solvent is ethyl acetate. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00390] In Scheme 4a, substituents R2, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are as described herein.
[00391] In some embodiments, intermediate IV-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate IV-2. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride.
In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00392] In some embodiments, intermediate IV-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 4a. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the
acid is hydrochloric acid. In some embodiments the appropriate solvent is water/acetone. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00393] In Scheme 4b, substituents R2, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18 are as described herein.
[00394] In some embodiments, intermediate IV-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate IV-3. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the appropriate solvent is tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00395] In some embodiments, intermediate IV-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 4b. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the
acid is hydrochloric acid. In some embodiments, the appropriate solvent is ethyl acetate. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00396] In Scheme 5a, substituents R2, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 are as described herein. In Scheme 5a, X is Ci-6alkyl.
[00397] In some embodiments, intermediate V-l is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate V-2. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00398] In some embodiments, intermediate V-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide
compound 5a. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments the appropriate solvent is water/acetone. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00399] In Scheme 5b, substituents R2, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 are as described herein. In Scheme 5b, X is Ci-6alkyl.
[00400] In some embodiments, intermediate V-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate V-3. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the appropriate solvent is
tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00401] In some embodiments, intermediate V-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 5b. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the appropriate solvent is ethyl acetate. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00402] In Scheme 6a, substituents R2, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 are as described herein. In Scheme 6a, X is Ci-6alkyl.
[00403] In some embodiments, intermediate VI-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VI-2. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In
some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00404] In some embodiments, intermediate VI-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 6a. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments the appropriate solvent is water/acetone. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00405] In Scheme 6b, substituents R2, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, and R20 are as described herein. In Scheme 6b, X is Ci-6alkyl.
[00406] In some embodiments, intermediate VI-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VI-3. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is
sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the appropriate solvent is tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00407] In some embodiments, intermediate VI-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 6b. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the appropriate solvent is ethyl acetate. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00408] In Scheme 7a, substituents R2, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18, and p and q are as described herein. In Scheme 7a, X is -C(0)N(R19)- or -N(R19)C(0)-.
[00409] In some embodiments, intermediate VII-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VII-2. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride.
In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00410] In some embodiments, intermediate VII-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide
compound 7a. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments the appropriate solvent is water/acetone. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
[00411] In Scheme 7b, substituents R2, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18, and p and q are as described herein. In Scheme 7a, X is -C(0)N(R19)- or -N(R19)C(0)-.
[00412] In some embodiments, intermediate VII-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VII-3. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the appropriate solvent is tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00413] In some embodiments, intermediate VII-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 7b. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the appropriate solvent is ethyl acetate. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
Scheme 8a
[00415] In some embodiments, intermediate VIII-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VIII-2. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride.
In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00416] In some embodiments, intermediate VIII-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 8a. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments the appropriate solvent is water/acetone. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
Scheme 8b
[00417] In Scheme 8b, substituents R2, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, R17, and R18, and p and q are as described herein.
[00418] In some embodiments, intermediate VIII-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate VIII-3. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the appropriate solvent is tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00419] In some embodiments, intermediate VIII-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 8b. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the appropriate solvent is ethyl acetate. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
Scheme 9a
9a
[00420] In Scheme 9a, substituents R2, R6, R9, R10, R11, R12, R13, R14, R15, R16, and R17, and p and q are as described herein. In Scheme 9a, X is Ci-ioalkyl.
[00421] In some embodiments, intermediate IX-1 is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate IX-2. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride.
In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00422] In some embodiments, intermediate IX-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 9a. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments the appropriate solvent is water/acetone. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
Scheme 9b
[00423] In Scheme 9b, substituents R2, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, and R17, and p and qare as described herein. In Scheme 9b, X is Ci-ioalkyl.
[00424] In some embodiments, intermediate IX-1 is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate IX-3. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the appropriate solvent is tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00425] In some embodiments, intermediate IX-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 9b. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the appropriate solvent is ethyl acetate. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
Scheme 10a
[00426] In Scheme 9a, substituents R2, R6, R9, R10, R11, R12, R13, R14, R15, R16, and R17, and p are as described herein.
[00427] In some embodiments, intermediate X-l is reacted with a phosphonate 1-2 with an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate X-2. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments the appropriate solvent is dichloromethane. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00428] In some embodiments, intermediate X-2 is hydrolyzed with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 10a. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments the appropriate solvent is water/acetone. In some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
Scheme 10b
[00429] In Scheme 10b, substituents R2, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, and R17, and p are as described herein. In Scheme
[00430] In some embodiments, intermediate X-l is coupled with intermediate 1-4 in the presence of an appropriate base and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide intermediate X-3. In some embodiments, the base is an organic base such as triethylamine or diisopropylamine. In some embodiments, the base is cesium carbonate, sodium carbonate, or potassium carbonate. In some embodiments, the base is sodium hydride. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the appropriate solvent is tetrahydrofuran. In some embodiments, the appropriate time and appropriate temperature is about 2 to about 18 hours (overnight) hours at about room temperature.
[00431] In some embodiments, intermediate X-3 is deprotected with an appropriate acid and solvent or solvent mixture at an appropriate time and at an appropriate temperature to provide compound 10b. In some embodiments, the acid is trifluoroacetic acid. In some embodiments, the acid is hydrochloric acid. In some embodiments, the appropriate solvent is ethyl acetate. In
some embodiments, the suitable temperature is about 0°C to room temperature and the appropriate amount of time is about 18 hours (overnight).
Further Forms of Compounds Disclosed Herein
Isomers
[00432] Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion, are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred ( e.g ., crystalline diastereomeric salts). In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.
Labeled compounds
[00433] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds,
which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that are incorporated into compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chloride, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35 S, 18F, and 36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, esters, solvate, hydrates, or derivatives thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as ¾ and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e., 2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, the isotopically labeled compounds, pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative thereof is prepared by any suitable method.
[00434] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
[00435] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
[00436] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
Solvates
[00437] In some embodiments, the compounds described herein exist as solvates. In some embodiments, are methods of treating diseases by administering such solvates. Further described
herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.
[00438] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous/organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
Pharmaceutical Compositions and Methods of Administration
[00439] In certain embodiments, the compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) as described herein is administered as a pure chemical. In some embodiments, the compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (IHb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). [00440] Accordingly, provided herein is a pharmaceutical composition comprising at least one compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Ilia), (Illb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject) of the composition.
[00441] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[00442] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (la), or a pharmaceutically acceptable salt thereof.
[00443] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (lb), or a pharmaceutically acceptable salt thereof.
[00444] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt thereof.
[00445] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Ha), or a pharmaceutically acceptable salt thereof.
[00446] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (lib), or a pharmaceutically acceptable salt thereof.
[00447] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (III), or a pharmaceutically acceptable salt thereof.
[00448] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Ilia), or a pharmaceutically acceptable salt thereof.
[00449] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Illb), or a pharmaceutically acceptable salt thereof.
[00450] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IV), or a pharmaceutically acceptable salt thereof.
[00451] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IVa), or a pharmaceutically acceptable salt thereof.
[00452] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IVb), or a pharmaceutically acceptable salt thereof.
[00453] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (V), or a pharmaceutically acceptable salt thereof.
[00454] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Va), or a pharmaceutically acceptable salt thereof.
[00455] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Vb), or a pharmaceutically acceptable salt thereof.
[00456] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (VI), or a pharmaceutically acceptable salt thereof.
[00457] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Via), or a pharmaceutically acceptable salt thereof.
[00458] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (VIb), or a pharmaceutically acceptable salt thereof.
[00459] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (VII), or a pharmaceutically acceptable salt thereof.
[00460] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Vila), or a pharmaceutically acceptable salt thereof.
[00461] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Vllb), or a pharmaceutically acceptable salt thereof.
[00462] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof.
[00463] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Villa), or a pharmaceutically acceptable salt thereof.
[00464] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Vinb), or a pharmaceutically acceptable salt thereof.
[00465] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IX), or a pharmaceutically acceptable salt thereof.
[00466] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IXa), or a pharmaceutically acceptable salt thereof.
[00467] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (IXb), or a pharmaceutically acceptable salt thereof.
[00468] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (X), or a pharmaceutically acceptable salt thereof.
[00469] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Xa), or a pharmaceutically acceptable salt thereof.
[00470] One embodiment provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula (Xb), or a pharmaceutically acceptable salt thereof.
[00471] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (la), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (lb), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (II), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Ila), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (lib), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting
essentially of a pharmaceutically acceptable excipient and a compound of Formula (III), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Ilia), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Illb), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (IV), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (IVa), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (IVb), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (V), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Va), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Vb), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (VI), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Via), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (VIb), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (VII), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Vila), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Vllb), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (VIII), or a pharmaceutically acceptable salt thereof. Another embodiment provides
a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Villa), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Vlllb), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (IX), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (IXa), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (IXb), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (X), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Xa), or a pharmaceutically acceptable salt thereof. Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable excipient and a compound of Formula (Xb), or a pharmaceutically acceptable salt thereof.
[00472] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure. [00473] In some embodiments, the compounds described herein are administered either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition. Administration of the compounds and compositions described herein can be effected by any method that enables delivery of the compounds to the site of action. These methods include, though are not limited to, delivery via enteral routes (including oral, gastric or duodenal feeding tube, rectal suppository, and rectal enema), parenteral routes
(injection or infusion, including intraarterial, intracardiac, intradermal, intraduodenal, intramedullary, intramuscular, intraosseous, intraperitoneal, intrathecal, intravascular, intravenous, intravitreal, epidural, and subcutaneous), inhalational, transdermal, transmucosal, sublingual, buccal, and topical (including epicutaneous, dermal, enema, eye drops, ear drops, intranasal, vaginal) administration, although the most suitable route may depend upon for example, the condition and disorder of the recipient. By way of example only, compounds described herein can be administered locally to the area in need of treatment, by local infusion during surgery, topical application such as creams or ointments, injection, catheter, or implant. The administration can also be by direct injection at the site of a diseased tissue or organ.
[00474] In some embodiments, pharmaceutical compositions suitable for oral administration are presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. In some embodiments, the active ingredient is presented as a bolus, electuary, or paste.
[00475] Pharmaceutical compositions which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. In some embodiments, the tablets are coated or scored and are formulated so as to provide slow or controlled release of the active ingredient therein.
All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In some embodiments, stabilizers are added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or Dragee coatings for identification or to characterize different combinations of active compound doses.
[00476] In some embodiments, pharmaceutical compositions are formulated for parenteral administration by injection, e.g ., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. , in ampoules or in multi -dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The compositions may be presented in unit-dose or multi dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
[00477] Pharmaceutical compositions for parenteral administration include aqueous and non- aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
[00478] Pharmaceutical compositions may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[00479] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.
[00480] Pharmaceutical compositions may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast,
systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.
[00481] Pharmaceutical compositions suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation.
[00482] In some embodiments, pharmaceutical compositions are formulated for intranasal administration. Potential excipients for intranasal formulations include, for example, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Formulations solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents. See, for example, Ansel, H. C. etal ., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably these compositions and formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions.
[00483] Pharmaceutical compositions for administration by inhalation are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, pharmaceutical preparations may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.
[00484] It should be understood that in addition to the ingredients particularly mentioned above, the compounds and compositions described herein may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
[00485] Generally, an agent, such as a compound of Formula (I), (la), (lb), (II), (Ha), (lib),
(III), (Ilia), (mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (VUIb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), is administered in an amount effective for amelioration of, or prevention of the development of symptoms of, the disease or disorder (i.e., a therapeutically effective amount). Thus, a therapeutically effective amount can be an amount that is capable of at least partially preventing or reversing a disease or disorder.
The dose required to obtain an effective amount may vary depending on the agent, formulation, disease or disorder, and individual to whom the agent is administered.
[00486] Determination of effective amounts may also involve in vitro assays in which varying doses of agent are administered to cells in culture and the concentration of agent effective for ameliorating some or all symptoms is determined in order to calculate the concentration required in vivo. Effective amounts may also be based in in vivo animal studies.
[00487] An agent can be administered prior to, concurrently with, and subsequent to the appearance of symptoms of a disease or disorder. In some embodiments, an agent is administered to a subject with a family history of the disease or disorder, or who has a phenotype that may indicate a predisposition to a disease or disorder, or who has a genotype which predisposes the subject to the disease or disorder.
[00488] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.
Methods
[00489] In one embodiment, the compounds described herein, or a pharmaceutically acceptable salt thereof, are used in the preparation of medicaments for the treatment of diseases or conditions in a mammal that would benefit from administration of an ALOX-15 inhibitor. Methods for treating any of the diseases or conditions described herein in a mammal in need of such treatment, involves administration of pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, active metabolite, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said mammal.
[00490] In some embodiments disclosed herein, are methods of administering an ALOX-15 inhibitor in combination with an additional therapeutic agent.
[00491] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of
the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
[00492] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.
[00493] In some embodiments is a method of treating a disease in a patient that would benefit from treatment with an ALOX-15 inhibitor, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb), or a pharmaceutically acceptable salt or solvate thereof.
[00494] In some embodiments is a method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (Illb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (Illb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (Vlllb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic airway disease is asthma, chronic rhinosinusitis, nasal polyposis or allergic rhinitis. In some embodiments is a method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III),
(Ilia), (mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (VUIb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic airway disease is asthma. In some embodiments is a method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Ilia), (Illb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (VUIb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic airway disease is chronic rhinosinusitis. In some embodiments is a method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Ilia), (Illb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (VUIb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic airway disease is nasal polyposis. In some embodiments is a method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Ilia), (Illb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (VUIb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic airway disease is allergic rhinitis.
[00495] In some embodiments is a method of treating an eosinophilic disease of the gastro intestinal tract in a mammal in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Ilia), (Illb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (VUIb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a method of treating eosinophilic disease of the gastro-intestinal tract in a mammal in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ila), (lib), (III), (Ilia), (Illb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (VUIb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic disease of the gastro-intestinal tract is eosinophilic esophagitis or eosinophilic gastritis. In some embodiments is a method of treating an eosinophilic disease of the gastro-intestinal tract in a mammal in need thereof, comprising administering to the patient a therapeutically effective amount of a
compound of Formula (I), (la), (lb), (II), (Da), (lib), (III), (Ilia), (mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (VUIb), (IX), (IXa), (Kb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic disease of the gastro-intestinal tract is eosinophilic esophagitis. In some embodiments is a method of treating an eosinophilic disease of the gastro-intestinal tract in a mammal in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), (la), (lb), (II), (Ha), (lib), (III), (Ilia), (Mb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (Via), (VIb), (VII), (Vila), (Vllb), (VIII), (Villa), (VUIb), (IX), (IXa), (IXb), (X), (Xa), or (Xb) described herein, or a pharmaceutically acceptable salt or solvate thereof, wherein the eosinophilic disease of the gastro-intestinal tract is eosinophilic gastritis.
[00496] Disclosed compounds are administered to patients (mammals) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted above, a contemplated compound disclosed herein is administered orally, subcutaneously, topically, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral administration includes subcutaneous injections, intravenous or intramuscular injections or infusion techniques.
[00497] Also contemplated herein are combination therapies, for example, co-administering a disclosed compound and an additional active agent, as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents. The beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually weeks, months, or years depending upon the combination selected). Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
[00498] Substantially simultaneous administration is accomplished, for example, by administering to the subject a single formulation or composition, ( e.g ., a tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single formulations (e.g., capsules) for each of the therapeutic agents. Sequential or substantially simultaneous administration of each therapeutic agent is effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues. The therapeutic agents are administered by the same route or by different routes. For example, a first therapeutic agent of the combination selected is administered by intravenous injection while the other therapeutic agents of the combination are administered orally. Alternatively, for example, all therapeutic agents are administered orally or all therapeutic agents are administered by intravenous injection.
[00499] Combination therapy also embraces the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non -drug therapies. Where the combination therapy further comprises a non-drug treatment, the non-drug treatment is conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
[00500] The components of the combination are administered to a patient simultaneously or sequentially. It will be appreciated that the components are present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients are present in separate pharmaceutical carriers, such as conventional oral dosage forms, that are administered either simultaneously or sequentially. Kits/Articles of Manufacture
[00501] For use in the therapeutic applications described herein, kits and articles of manufacture are also described herein. Such kits can include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) including one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed from a variety of materials such as glass or plastic.
[00502] The articles of manufacture provided herein contain packaging materials. Packaging materials for use in packaging pharmaceutical products include, e.g, U.S. Patent Nos.
5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers,
syringes, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment. A wide array of formulations of the compounds and compositions provided herein are contemplated as are a variety of treatments for any disease, disorder, or condition that would benefit by an ALOX-15 inhibitor.
[00503] For example, the container(s) can include one or more compounds described herein, optionally in a composition or in combination with another agent as disclosed herein. The container(s) optionally have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). Such kits optionally comprising a compound with an identifying description or label or instructions relating to its use in the methods described herein.
[00504] A kit will typically include one or more additional containers, each with one or more of various materials (such as reagents, optionally in concentrated form, and/or devices) desirable from a commercial and user standpoint for use of a compound described herein. Non-limiting examples of such materials include, but not limited to, buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.
[00505] A label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g ., as a package insert. A label can be used to indicate that the contents are to be used for a specific therapeutic application. The label can also indicate directions for use of the contents, such as in the methods described herein.
[00506] In certain embodiments, the pharmaceutical compositions can be presented in a pack or dispenser device which can contain one or more unit dosage forms containing a compound provided herein. The pack can for example contain metal or plastic foil, such as a blister pack. The pack or dispenser device can be accompanied by instructions for administration. The pack or dispenser can also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, can be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions containing a compound provided herein formulated in a compatible pharmaceutical carrier can also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
EXAMPLES
Example 1: Phosphatase Treatment of Phosphate Prodrugs
[00507] To determine if there is an effect of addition phosphatase to the phosphate prodrugs described herein, 30 units of alkaline phosphatase (EMD Millipore Phosphatase, Alkaline, Calf Intestine catalog number 524572) is added to a phosphate prodrugs described herein and the UV spectrum (210-600 nm) is measured before and after addition of phosphatase.
[00508] Phosphatase treatment is repeated with 0.1 unit of phosphatase (56 ug) and 0.6 mM of a phosphate prodrug described herein at a volume of 100 uL (100 mM Tris pH 8.8, 5 mM MgCb) and monitored as function of time.
Example 2: Recombinant Human ALOX15 Assay Generation of stock solutions:
[00509] 5 mM of a phosphate prodrug described herein in 100 mM Tris-HCl buffer pH 8.6 and 1 mM MgCh is treated by the addition of 0.1 unit of alkaline phosphatase (Alkaline, Calf Intestine EMD Millipore catalog number 524572). The enzymatic reaction is quenched and precipitate (presumably parent compound) is dissolved by the addition of 2 volume equivalents of DMSO to yield 1.66 mM solution. Three solutions are generated: parent compound, a phosphate prodrug described herein with phosphatase treatment, phosphate prodrug described herein without phosphatase treatment.
Lipoxygenase enzyme assay:
[00510] Lipoxygenase activity is measured in black 384-plates from Corning (#3711) in quadruplicate. To each well in a 384-well plate, the following are added: 15 pL of human lipoxygenase (Genway ALOX15 Active Human Recombinant Protein, GWB-6672E3) diluted in PBS at 3.18 pg/mL or PBS alone and 15 nL of 66% DMSO or compound dissolved in 66% DMSO. This mixture is incubated for 5 min before the addition of 1.5 pL 0.2 mM arachidonic acid. The plate is then incubated at room temperature for 10 min before the reaction is terminated with 2 volumes (30 pL) of 1:1 methanol :DMSO containing 0.125 mM diphenyl-1 - pyrenylphosphine (DPPP). Fluorescence is measured after 30 min (excitation filter 330/30 nm, and emission filter 385/35 nm using a ClarioStar plate reader).
[00511] The relative activity of ALOX15 as a function of parent compound and prodrug is calculated by the following equation:
(I-Iblank)/ (IALOX-Iblank)
Where I is the fluorescent intensity at each concentration, Ibiank is the intensity in the absence of
ALOX15 and IALOX is the intensity observed in the absence of inhibitor. A plot of the relative
ALOX15 activity as a function of inhibitor concentration results in IC50 values.
Example 3: Solubility Assessment of Phosphate Prodrugs as Free Phosphoric Acid [00512] Water is added slowly to 4.7 mg of a phosphate prodrug described herein until 4.7 ml of water is added at which point the phosphate fully dissolved.
[00513] The stock of phosphate is diluted to 0.1 mg/mL and the UV absorbance spectrum is measured from 210 to 600 nm. From a pathlength of nanodrop (1mm), the extinction coefficient at 250 nm is 6,520 M cm 1.
Example 4: Inhibition of 15-lipoxygenase in Human Primary Eosinophils [00514] In this experiment, inhibition of 15 -lipoxygenase is performed in primary peripheral blood eosinophils, to evaluate the effect on arachidonic acid metabolite production. Primary peripheral blood eosinophils from 2 separate donors (StemExpress) are thawed and allowed to recover in growth media for 4 hours at 37°C. Cells are washed with Hank’s Balanced Salt Solution, then aliquoted into 96 well round bottomed plate at 1*105 cells/well, 200 pL/well.
Cells are treated with either 10 mM parent compound, 10 mM phosphate prodrug or 10 pM phosphate prodrug + 0.2 U alkaline phosphatase (AP) pretreated for 15 minutes. Arachidonic acid is added to final concentration of 3 pM and experiment starts. At 1 hour post-treatment the supernatant is collected and 15(S)-HETE was quantified by ELISA (Cayman Chemical) according to manufacturer’s recommended protocol. Comparisons are made between the cells treated with the test compounds and cells treated with vehicle only.
Example 5: Inhibition of 15-lipoxygenase in Human Cells
[00515] In this experiment, inhibition of 15 -lipoxygenase is performed in primary human nasal epithelial cells (pHNEC) and primary peripheral blood eosinophils, to evaluate the effect on arachidonic acid metabolite production.
[00516] Primary human nasal epithelial cells (pHNEC) and primary peripheral blood eosinophils are induced for 24 hours with 20 ng/mL IL13 are treated with 10 pM of a test compound, or vehicle only (DMSO) for 5 minutes prior to the addition of 10 uM arachidonic acid. At 2 hours post-treatment the supernatant is collected and arachidonic acid metabolites of 15 -lipoxygenase including prostaglandin E2, cysteinyl leukotrienes (LTC4, D4, and E4), and 15(S)-HETE are quantified by ELISA (Cayman Chemical) according to manufacturer’s recommended protocol. Comparisons are made between the groups treated with the test compounds and cells are treated with vehicle only.
Example 6: Inhibition of 15-lipoxygenase in a Murine Model for Nasal Polyposis [00517] In this experiment, a murine model of nasal polyposis is used to evaluate the effect of inhibition of 15 -lipoxygenase. The murine model consists of inducing chronic rhinitis with ovalbumin (OVA) treatment, followed by a combination of ovalbumin and Staphylococcus
aureus enterotoxin B (SEB) treatment leading to nasal polyp formation. This model has characteristics of the human disease.
[00518] 2-week-old female BALB/c mice are obtained from Charles River Laboratories. The animals are kept in environmentally controlled rooms under specific pathogen-free conditions (temperature, 20-26°C); humidity, 30-70%) with a 12-hour light-dark cycle for 2 weeks before use. Food and water are available ad libitum. All animals are used in accordance with animal care guidelines.
[00519] Nasal polyposis is induced in age-matched (4-week-old) mice divided into five groups. Group A (n = 5) is a control group in which mice are treated with neither reagent nor surgery.
For groups B-E (n = 5 for each), mice are sensitized with an intraperitoneal injection of 25 ug of OVA plus 2 mg of aluminum hydroxide on days 0 and 7. From Day 14 to Day 20 mice are nasally challenged daily with 6% OVA. From Day 20, 6% OVA + Staphylococcus aureus enterotoxin B (10 ng) is instilled into the nasal cavity of mice three times per week for 8 weeks. [00520] From week 4, animals in groups B-E receive 10 ul of 1 mg/mL of a test compound (groups B-D) or vehicle only (1 part DMSO, 9 parts PBS) (group E) three times a week for 4 weeks. Anesthesia during intranasal administration is achieved with intraperitoneal injection of 0.2 ml nembutal (5 mg/ml).
[00521] At the end of eight weeks of OVA+SEB and inhibitor treatment, mice are euthanized by cervical dislocation following injection of 0.3 ml nembutal. Nasal cavity samples are prepared using a large scalpel to remove the snout with a transverse cut behind the back molars. The external nares are flushed with PBS to wash out any blood within the nasal cavity.
Histologic quantification of the number of nasal polyps and the amount of eosinophil infiltration is performed using hematoxylin and eosin (H&E) staining of the nasal cavity. The number of polyps and amount of eosinophilic infiltration is compared between all groups. Additionally, nasal mucosa is removed using a small curette after bisecting the nasal tissue sagitally along the nasal septum. Cell lysates are prepared using a RIP A buffer, and these lysates are used to measure arachidonic acid metabolites of 15 -lipoxygenase including prostaglandin E2, cysteinyl leukotrienes (LTC4, D4, and E4), and 15(S)-HETE. The metabolites are quantified by ELISA (Cayman Chemical) according to manufacturer’s recommended protocol. Comparisons are made between the control group, groups treated with the test compounds and the group treated with vehicle only.
Example 7: Inhibition of 15-lipoxygenase in a Rabbit Model for Nasal Polyposis [00522] In this experiment, a rabbit model of nasal polyposis is used to evaluate the effect of inhibition of 15 -lipoxygenase. In the rabbit model eosinophilic nasal polyps are induced by
eliciting an allergic reaction in animals with ovalbumin (OVA) and poly-L-arginine treatment. This model has characteristics of the human disease.
[00523] Male New Zealand white rabbits are obtained from Charles River Laboratories. The animals are kept in environmentally controlled rooms under specific pathogen-free conditions (temperature, 20-26°C); humidity, 30-70%) with a 12-hour light-dark cycle for 2 weeks before use. Food and water are available ad libitum. All animals are used in accordance with animal care guidelines.
[00524] Maxillary sinusitis is induced in age-matched (13-week-old) rabbits divided into five groups. Group A (n = 4) is a control group in which rabbits are treated with neither reagent nor surgery. For groups B-E (n = 6 for each), rabbits are sensitized by subcutaneous injection with 1 mL of saline containing 2.5% OVA plus 0.4% alum on days 0 and 7. On day 14, under anesthesia with i.v. injection of 25 mg/kg of pentobarbital sodium (Nembutal, Dainippon Sumitomo Pharma, Osaka, Japan), nasal dorsa are incised to expose maxillary sinus cavities and both sides of the ostia were occluded with plugs of sterile cotton wool and butylcyanoacrylate tissue glue (Histoacryl; B. Braun, Melsungen AG, Germany) under a microscope. After 2 weeks of wound closure, OVA is administered into both sides of the maxillary sinuses (0.5 mL/sinus of 2.5% OVA in saline, three times a week for 2 weeks). Thereafter, the animals in groups B-D receive 5 mg/mL poly-L-arginine in saline three times a week for 4 weeks.
[00525] After induction of maxillary sinusitis with OVA and poly-L-arginine, the animals receive 100 ul of 1 mg/mL of a test compound (groups B-D) or vehicle only (1 part DMSO, 9 parts PBS) (group E) three times a week for 4 weeks. One week after the last administration into the maxillary sinus, the rabbits are sacrificed by i.v. injection of pentobarbital sodium and the anterior nasal region with the attached bone, excluding the ocular bulb, is dissected. The mucosal tissues for gene analysis are collected from the right side of the maxillary sinus and stored in RNAlater RNA stabilization reagent (Ambion, Austin, TX) at 4°C until analysis. The left side of the maxillary sinus is used for histopathological analysis. Anesthesia for administration of the test compounds is achieved with intraperitoneal injection of 0.2 ml nembutal (5 mg/ml).
[00526] Antibodies to OVA are measured using enzyme-linked immunosorbent assay (ELISA). Blood samples are collected from the pinna vein on day 13 to measure OVA-specific IgG levels. ELISA is performed according to the protocol of a previous study. The titers of samples are calculated by comparison with internal standard serum, prepared from the rabbits immunized with 2.5% OVA plus 0.4% alum eight times. The value of this standard is arbitrarily calculated as 10,000 U/ml.
[00527] Histopathological analysis of nasal tissue is carried out on tissue fixed with 10% neutral buffered formalin solution for 1 week, decalcified in 0.5 mol/L of ethylenediaminetetraacetic acid at 37°C, embedded in paraffin, and cut into 2-pm-thick sections. After hematoxylin-eosin staining, histopathological analysis is performed by selecting a representative field of mucosa per sinus where the most prominent change is detected with 200x magnification. The number of eosinophils and the area of mucosa in each field are measured to calculate the density of eosinophils (cells/mm2). The width of the lamina propria (pm) is measured as an indirect indication of mucosal hypertrophy. The degree of polyp formation is graded semi quantitatively according to the following score: 0 = little or no polyp formation detected; 1 = slight (slight prominence of mucosa); 2 = moderate (polyp of a size from one- quarter to one-half of the field); 3 = severe (polyp of a size more than one-half of the field).
Claims
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, - SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
2. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
3. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.
4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1.
Formula (II); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R17 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci- 9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is -C(0)0R6, -C(0)N(R6)2, N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)2R8, or - S(0)2N(R6)2;
n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
7. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein X is a bond.
8. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein X is Ci-6alkyl.
9. The compound of claim 6, or a pharmaceutically acceptable salt or solvate thereof, wherein X is C2-6alkenyl.
10. The compound of any one of claims 6-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -N(R7)S(0)2R8.
11. The compound of any one of claims 6-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8.
12. The compound of any one of claims 6-9, or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)N(R6)2.
13. The compound of any one of claims 6-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is Ci-9heteroaryl is optionally substituted with one, two, or three R13.
14. The compound of any one of claims 6-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is -C(0)OR6.
15. The compound of any one of claims 6-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is -C(0)R8.
16. The compound of any one of claims 6-15, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.
17. The compound of claim 16, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is halogen.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci.6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- -ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, -
13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci-
6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, -
0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-cheteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or -S(0)2N(R6)2;
R17 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is -C(0)0R6, -C(0)N(R6)2, -C(0)R8, -S(0)2R8, or -S(0)2N(R6)2; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
19. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is C6-ioaryl optionally substituted with one, two, or three R9.
20. The compound of claim 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is phenyl optionally substituted with one, two, or three R9.
21. The compound of claim 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is Ci-9heteroaryl optionally substituted with one, two, or three R9.
22. The compound of any one of claims 18-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is -C(0)R8.
23. The compound of any one of claims 18-22, or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is -C(0)R8.
24. The compound of any one of claims 18-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is C6-ioaryl optionally substituted with one, two, or three R9.
25. The compound of any one of claims 18-24, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is phenyl optionally substituted with one, two, or three R9.
26. The compound of any one of claims 18-23, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is Ci-9heteroaryl optionally substituted with one, two, or three R9.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, -
SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci. ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2.6alkenyl, C2.6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from H, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2. 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, - N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
28. The compound of claim 27, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is H.
29. The compound of claim 27 or claim 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is H.
30. The compound of any one of claims 27-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl optionally substituted with one, two, or three R9.
31. The compound of any one of claims 27-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is C2-6alkenyl optionally substituted with one, two, or three R9.
Formula (V); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci.6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-
6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- -ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, -
13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 and R19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4;
or a pharmaceutically acceptable salt or solvate thereof.
Formula (VI); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-5>heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl;
R16 and R17 are independently selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci- 9heteroaryl are optionally substituted with one, two, or three R9;
R18 and R19 are independently selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R20 is C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, or Ci-9heteroaryl, wherein C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; and n is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
34. The compound of claim 32 or claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H.
35. The compound of any one of claims 32-34, or a pharmaceutically acceptable salt or solvate thereof, wherein R19 is H.
36. The compound of any one of claims 32-35, or a pharmaceutically acceptable salt or solvate thereof, wherein R20 is C2-9heterocycloalkyl optionally substituted with one, two, or three R9.
37. The compound of any one of claims 32-36, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is Ci-9heteroaryl optionally substituted with one, two, or three R9.
38. The compound of any one of claims 32-37, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is Ci-9heteroaryl optionally substituted with one, two, or three R9.
Formula (VII); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci.6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- R11, -
Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R18 is selected from H and Ci^alkyl;
R19 is selected from H and Ci^alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
40. The compound of claim 39, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -C(0)N(H)-.
41. The compound of claim 39, or a pharmaceutically acceptable salt or solvate thereof, wherein X is -N(H)C(0)-.
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R2 is selected from H, Ci-6alkyl, and Ci-6haloalkyl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8,
wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- ryl, -OR11, -
)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci^alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R18 is independently selected from H and Ci^alkyl; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
43. The compound of any one of claims 39-42, or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is H.
44. The compound of any one of claims 39-42, or a pharmaceutically acceptable salt or solvate thereof, wherein R18 is Ci-6alkyl.
45. The compound of any one of claims 39-44, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2.
46. The compound of any one of claims 39-45, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is selected from halogen and Ci-6alkyl.
47. The compound of any one of claims 39-44, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
48. The compound of any one of claims 39-47, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1 or 2.
49. The compound of any one of claims 39-48, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from halogen, Ci-6alkyl, and -OR6.
50. The compound of any one of claims 39-47, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
Formula (IX); wherein:
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl;
Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, - SR11, -N(R12)(R13), -C(0)0R12, -C(0)N(R12)(R13), -C(0)C(0)N(R12)(R13), - 0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci_ 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(RU)2, and -0C(0)R13;
each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
52. The compound of claim 51, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2.
53. The compound of claim 51 or claim 52, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is selected from halogen, Ci-6alkyl, and -OR6.
54. The compound of claim 51, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
55. The compound of any one of claims 51-54, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 1 or 2.
56. The compound of any one of claims 51-55, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is selected from halogen, Ci-6alkyl, and -OR6.
57. The compound of any one of claims 51-54, or a pharmaceutically acceptable salt or solvate thereof, wherein q is 0.
Formula (X); wherein: each R1 is independently selected from -P(0)(0H)2, -C(0)N(R5)C2-6alkyl-0C(0)R3,
Ring A is selected from C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and C2-9heteroaryl; Ring B is selected from C2-9heterocycloalkyl and C2-9heteroaryl;
R3 is selected from Ci-6alkyl or -Ci-6alkyl-N(R10)2; each R4 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- 6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, - C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, - N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R5 is selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R6 is independently selected from H, Ci.6alkyl, Ci-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2- 6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R7 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R8 is independently selected from Ci^alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2- 9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl, wherein Ci-6alkyl, C2-6alkenyl, C2- 6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; each R9 is independently selected from halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- -ioaryl, C6-ioaryl, Ci-9heteroaryl, -OR11, - 13), -C(0)C(0)N(R12)(R13), -
0C(0)N(R12)(R13), -N(R14)C(0)N(R12)(R13), -N(R14)C(0)0R15, -N(R14)C(0)R15, - N(R14)S(0)2R15, -C(0)R15, -S(0)2R15, -S(0)2N(R12)(R13), and -0C(0)R15, wherein Ci- 6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, -Ci-6alkyl-C6-ioaryl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three groups independently selected from halogen, oxo, -CN, Ci-6alkyl, Ci-6haloalkyl, Ci-6alkoxy, Ci- ehaloalkoxy, -OR11, -SR11, -N(RU)2, -C(0)0Ru, -C(0)N(Ru)2, -C(0)C(0)N(Ru)2, - 0C(0)N(Ru)2, -N(R12)C(0)N(Ru)2, -N(R12)C(0)0Ru, -N(R12)C(0)R13, -N(R12)S(0)2R13, -C(0)R13, -S(0)2R13, -S(0)2N(Ru)2, and -0C(0)R13; each R10 is independently selected from H, Ci-6alkyl, and Ci-6haloalkyl; each R11 is independently selected from H, Ci-6alkyl, Ci^haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R12 is independently selected from H and Ci^alkyl; each R13 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; each R14 is independently selected from H and Ci^alkyl; each R15 is selected from Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2.
9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl; eac
N(R7)C(0)R8, -N(R7)S(0)2R8, -C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9;
R17 is selected from H, halogen, -CN, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2. 9heterocycloalkyl, C6-ioaryl, Ci-9heteroaryl, -OR6, -SR6, -N(R6)2, -C(0)0R6, -C(0)N(R6)2, -0C(0)N(R6)2, -N(R7)C(0)N(R6)2, -N(R7)C(0)0R6, -N(R7)C(0)R8, -N(R7)S(0)2R8, - C(0)R8, -S(0)R8, -S(0)2R8, -S(0)2N(R6)2, and -0C(0)R8, wherein Ci-6alkyl, C2.6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C2-9heterocycloalkyl, C6-ioaryl, and Ci-9heteroaryl are optionally substituted with one, two, or three R9; n is 0, 1, 2, 3, or 4; and p is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt or solvate thereof.
59. The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1 or 2.
60. The compound of claim 58 or claim 59, or a pharmaceutically acceptable salt or solvate thereof, wherein R16 is selected from halogen, Ci-6alkyl, and -OR6.
61. The compound of claim 58, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.
62. The compound of any one of claims 58-61, or a pharmaceutically acceptable salt or solvate thereof, wherein R17 is H.
64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl.
65. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
66. The compound of any one of claims 1-65, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is C2-9heteroaryl selected from pyridinyl, pyrimidinyl, pyrazinyl, and pyridazinyl.
67. The compound of any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is pyridinyl.
68. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring A is phenyl.
69. The compound of any one of claims 1-68, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is Ci-6alkyl.
71. The compound of claim 70, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C2-9heteroaryl.
72. The compound of claim 71, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C2-9heteroaryl selected from pyrazolyl, pyrrolyl, and imidazolyl.
73. The compound of claim 70, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C2-9heterocycloalkyl.
74. The compound of claim 73, or a pharmaceutically acceptable salt or solvate thereof, wherein Ring B is C2-9heterocycloalkyl selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl.
75. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt or solvate thereof, wherein each R4 is independently selected from halogen and unsubstituted Ci- 6alkyl.
76. The compound of any one of claims 1-75, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0, 1, or 2.
77. The compound of any one of claims 1-74, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.
78. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -C(0)N(R9)C2-6alkyl-0C(0)R7.
79. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is Ci-6alkyl.
80. The compound of any one of claims 1-78, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -Ci-6alkyl-N(R14)2.
81. The compound of any one of claims 1-62, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -P(0)(OH)2.
82. A compound having the structure:
83. A pharmaceutical composition comprising a compound of any one of claims 1-82, or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient.
84. A method of treating an eosinophilic airway disease in a mammal in need thereof, comprising administering to the mammal a compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof.
85. The method of claim 84, wherein the eosinophilic airway disease is selected from asthma, chronic rhinosinusitis, nasal polyposis, and allergic rhinitis.
86. A method of treating an eosinophilic gastrointestinal disease in a mammal in need thereof, comprising administering to the mammal a compound of any one of claims 1-82, or a pharmaceutically acceptable salt or solvate thereof.
87. The method of claim 86, wherein the eosinophilic gastrointestinal disease is selected from eosinophilic esophagitis and eosinophilic gastroenteritis.
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