NLRP3 Modulators

Abstract

Described herein are NLRP3 modulators and methods of utilizing the NLRP3 modulators in the treatment of diseases, disorders, or conditions. Also described herein are pharmaceutical compositions comprising such compounds.

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 63 / 320,157, filed March 15, 2022, and U.S. Provisional Patent Application No. 63 / 356,415, filed June 28, 2022, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, is a critical component of the innate immune response and inflammatory processes, and its abnormal activity is a contributing factor in the pathogenesis of genetic disorders such as cryopyrin-associated periodic syndromes (CAPS), as well as complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis. Current treatments for NLRP3-associated diseases include biologic agents targeting IL-1. Given their safety and potential for improved patient comfort and compliance, small molecule inhibitors of NLRP3 offer an attractive alternative to these biologics. Summary of the Invention

[0003] In one embodiment, a compound of formula (I')

[0004] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, L is -C(R 9a )(R 9b )-, -C(O)-, or -C(=N-OR 16 )- and R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R and R combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 optionally substituted with a group, R6 is

[0005] [ka] and R 6a is hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl can be one, two, or three R 14 optionally substituted with a group, or R 6a and R 15 together form a bridge which is -CH- or -CHCH-, R7 and R8 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11or R7 and R8 combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 optionally substituted with a group, R 9a and R 9b are each independently hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 14 are each independently halogen, -CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 15 are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from two R 15 together form a bridge which is -CH- or -CHCH-, R 16 is hydrogen and C 1-6 alkyl, and n is 0, 1, 2, 3, or 4.

[0006] In another embodiment, a compound of formula (I)

[0007] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, L is -C(R 9a )(R 9b )-, -C(O)-, or -C(=N-OR 16 )- and R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13, -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R and R combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 optionally substituted with a group, R6 is

[0008] [ka] and R 6a is hydrogen and one, two, or three R 14 C optionally substituted with a group 1-6 alkyl, R7 and R8 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R7 and R8 combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 optionally substituted with a group, R 9a and R 9b are each independently hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9optionally substituted with one, two, or three groups selected from heteroaryl; R 14 are each independently halogen, -CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 15 are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10)(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 16 is hydrogen and C 1-6 alkyl, and n is 0, 1, 2, 3, or 4.

[0009] In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0010] [ka] In some embodiments, there is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is one, two, or three R 14 C optionally substituted with a group 1-6 In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is -CH3.

[0011] In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0012] [ka] In some embodiments, the compound is of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0013] In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0014] [ka] is.

[0015] In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, —CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, C 1-6 Alkyl, and C 1-6 In some embodiments, compounds of Formula (I') or (I), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6 In some embodiments, there are compounds of Formula (I') or (I), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are hydrogen. In some embodiments, there are compounds of Formula (I') or (I), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, there are compounds of Formula (I') or (I), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is -CH3 and R8 is hydrogen. In some embodiments, there are compounds of Formula (I') or (I), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are -CH3.

[0016] In some embodiments, there is provided a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5- or 6-membered heteroaryl ring, or the phenyl ring is selected from the group consisting of one, two, or three R 14In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted phenyl ring.

[0017] In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , or -C(O)N(R 10 )(R 11 In some embodiments, there is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, there are compounds of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. In some embodiments, there are compounds of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, there are compounds of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6Alkyl or C 1-6 In some embodiments, there are compounds of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.

[0018] In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, compounds of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b In some embodiments, there is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen, halogen, and C 1-6 In some embodiments, there is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen. In some embodiments, there are compounds of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9b is selected from hydrogen, halogen, and —OH. In some embodiments, there is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9bis —OH. In some embodiments, there is a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(O)—.

[0019] In one embodiment, a compound of formula (II)

[0020] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11)-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R and R combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 optionally substituted with a group, R6 is

[0021] [ka] and R 6a is hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl can be one, two, or three R 14 optionally substituted with a group, or R 6a and R 15 together form a bridge which is -CH- or -CHCH-, R7 and R8 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R7 and R8 combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 optionally substituted with a group, R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 14 are each independently halogen, -CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11Optionally substituted with one, two, or three groups selected from R 15 are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from two R 15 together form a bridge which is -CH- or -CHCH-, and n is 0, 1, 2, 3, or 4.

[0022] In another embodiment, a compound of formula (III)

[0023] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12)S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R and R combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 optionally substituted with a group, R6 is

[0024] [ka] and R 6a is hydrogen and one, two, or three R 14 C optionally substituted with a group 1-6 alkyl, R7 and R8 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R7 and R8 combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 optionally substituted with a group, R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 14 are each independently halogen, -CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 15 are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from n is 0, 1, 2, 3, or 4.

[0025] In some embodiments, there is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0026] [ka] In some embodiments, there is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is one, two, or three R 14 C optionally substituted with a group 1-6 In some embodiments, there is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, there is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is -CH3.

[0027] In some embodiments, there is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0028] [ka] In some embodiments, there is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0029] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0030] [ka] is.

[0031] In some embodiments, there is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, —CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 In some embodiments, there is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, C1-6 Alkyl, and C 1-6 In some embodiments, the compound is of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6 In some embodiments, there are compounds of Formula (II) or (III), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are hydrogen. In some embodiments, there are compounds of Formula (II) or (III), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, there are compounds of Formula (II) or (III), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is -CH3 and R8 is hydrogen. In some embodiments, there are compounds of Formula (II) or (III), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are -CH3.

[0032] In some embodiments, there is provided a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5- or 6-membered heteroaryl ring, or the phenyl ring is selected from the group consisting of one, two, or three R 14 In some embodiments, there is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted phenyl ring.

[0033] In some embodiments, there is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , or -C(O)N(R 10 )(R 11 In some embodiments, there is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, there are compounds of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OH. In some embodiments, there are compounds of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of Formula (II) or (III), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is hydrogen. In some embodiments, there are compounds of Formula (II) or (III), or pharmaceutically acceptable salts or solvates thereof, wherein R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 Alkyl or C 1-6 In some embodiments, there is provided a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10In some embodiments, there is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.

[0034] In some embodiments, there is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 It is alkyl.

[0035] In another aspect, described herein are pharmaceutical compositions comprising a compound of Formula (I'), (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0036] In some embodiments, described herein are methods of treating a metabolic disease in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (F), (F), (F), or (F), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein are methods of treating a metabolic disease in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (F), or (F), or a pharmaceutically acceptable salt or solvate thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout.

[0037] In some embodiments, described herein are methods for treating liver disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein are methods for treating liver disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, and cirrhosis.

[0038] In some embodiments, described herein are methods of treating a pulmonary disease in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (F), (F), (F), or (F), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein are methods of treating a pulmonary disease in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (F), or (F), or a pharmaceutically acceptable salt or solvate thereof, wherein the pulmonary disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis.

[0039] In some embodiments, described herein are methods for treating a central nervous system disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein are methods for treating a central nervous system disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, traumatic brain injury, ischemic stroke and reperfusion, hemorrhagic stroke, epilepsy, and depression.

[0040] In some embodiments, described herein are methods of treating an inflammatory or autoimmune disease in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (F), (F), or (F), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein are methods of treating an inflammatory or autoimmune disease in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (F), or (F), or a pharmaceutically acceptable salt or solvate thereof, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

[0041] In some embodiments, described herein are methods of treating cardiovascular disease in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (F), (F), or (F), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, described herein are methods of treating cardiovascular disease in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (F), or (F), or a pharmaceutically acceptable salt or solvate thereof, wherein the cardiovascular disease is atherosclerosis or stroke.

[0042] Incorporation by Reference All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE INVENTION

[0043] definition In the context of this disclosure, a number of terms will be utilized.

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. In the event of multiple definitions for terms herein, those in this section prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) referenced herein are incorporated by reference. When a URL or other such identifier or address is mentioned, it is understood that such identifiers can change and particular information on the Internet may come and go, but that equivalent information can be found by an Internet search. Reference thereto acknowledges the availability and public dissemination of such information.

[0045] It is understood that the foregoing general description and the following detailed description are exemplary and illustrative only and are not restrictive of the claimed subject matter. In this application, the use of the singular includes the plural unless expressly stated otherwise. It should be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. In this application, the use of "or" means "and / or" unless expressly stated otherwise. Furthermore, the use of the term "including," as well as other forms such as "include," "includes," and "included," is non-exclusive.

[0046] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0047] Definitions of standard chemical terms can be found in references including, but not limited to, Carey and Sundberg "Advanced Organic Chemistry 4th Ed." Vols. A (2000) and B (2001), Plenum PreS, New York. Unless otherwise specified, conventional methods are mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology.

[0048] Unless specific definitions are provided, terminology used in connection with, and laboratory methods and techniques for, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are art-recognized. Standard techniques may be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation, and delivery, and patient treatment. Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reaction and purification techniques may be performed, for example, using kits according to manufacturer's specifications, or as commonly accomplished in the art, or as described herein. The foregoing techniques and procedures may be performed in a generally conventional manner and as described in various general and specific references cited and discussed throughout the specification.

[0049] It is to be understood that the methods and compositions described herein are not limited to the particular methodology, protocols, cell lines, constructs, and reagents described herein, as such may vary. Furthermore, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0050] As used herein, C1-C x is C1-C2, C1-C3...C1-C x Includes C1-C x refers to the number of carbon atoms that make up the moiety it designates (excluding any substituents).

[0051] An "alkyl" group refers to a straight or branched hydrocarbon chain radical, free of unsaturation, consisting solely of carbon and hydrogen atoms. In some embodiments, an "alkyl" group can have 1 to 6 carbon atoms. (Whenever alkyl appears herein, a numerical range, such as "1 to 6," refers to each integer in the range. For example, "1 to 6 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on, up to a maximum of 6 carbon atoms; however, this definition also encompasses occurrences of the term "alkyl" without any numerical range specified.) The alkyl group of the compounds described herein may be designated as "C1-C6 alkyl" or a similar designation. By way of example only, "C1-C6 alkyl" indicates that there are 1 to 6 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, and hexyl. The alkyl group can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monoradical or a diradical (ie, an alkylene group).

[0052] "Alkoxy" refers to the group "-O-alkyl", where alkyl is as defined herein.

[0053] The term "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. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2, and -C(CH3)=CHCH3. In some embodiments, an alkenyl group can have 2 to 6 carbons. Alkenyl groups can be substituted or unsubstituted. Depending on the structure, an alkenyl group can be a monoradical or a diradical (i.e., an alkenylene group).

[0054] The term "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. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -C≡CCH2CH2CH3. In some embodiments, an alkynyl group can have 2 to 6 carbons. Alkynyl groups can be substituted or unsubstituted. Depending on the structure, an alkynyl group can be a monoradical or a diradical (i.e., an alkynylene group).

[0055] "Amino" refers to the group -NH2.

[0056] The term "alkylamine" or "alkylamino" refers to an -N(alkyl) x H y "Dialkylamino" refers to the group -N(alkyl)2, where alkyl is as defined herein, and x and y are selected from the group x=1, y=1, and x=2, y=0. When x=2, the alkyl groups, together with the nitrogen to which they are attached, can optionally form a cyclic ring system. "Dialkylamino" refers to the group -N(alkyl)2, where alkyl is as defined herein.

[0057] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons (n ​​is an integer). Aromatic rings can be formed from 5, 6, 7, 8, 9, or more than 9 atoms. Aromatics can be optionally substituted. The term "aromatic" includes both aryl (e.g., phenyl, naphthalenyl) and heteroaryl (e.g., pyridinyl, quinolinyl) groups.

[0058] As used herein, the term "aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl ring can be formed by 5, 6, 7, 8, 9, or more than 9 carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthalenyl. Depending on the structure, the aryl group can be a monoradical or a diradical (i.e., an arylene group).

[0059] "Carboxy" refers to -COH. In some embodiments, the carboxy moiety can be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties as a carboxylic acid group. A compound containing a carboxylic acid moiety can have the carboxylic acid moiety replaced with a carboxylic acid bioisostere and have similar physical and / or biological properties compared to the compound containing the carboxylic acid. For example, in one embodiment, the carboxylic acid bioisostere will ionize at physiological pH to about the same extent as a carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to:

[0060] [ka] Includes:

[0061] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic radical, in which each of the atoms forming the ring (i.e., skeletal atoms) is a carbon atom. A cycloalkyl can be saturated or partially unsaturated. A cycloalkyl can be fused with an aromatic ring (in which case the cycloalkyl is attached through a non-aromatic ring carbon atom). In some embodiments, cycloalkyl groups include groups having 3 to 10 ring atoms.

[0062] The terms "heteroaryl" or, alternatively, "heteroaromatic" refer to an aryl group that contains one or more ring heteroatoms selected from nitrogen, oxygen, and sulfur. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom.

[0063] A "heterocycloalkyl" or "heteroalicyclic" group refers to a cycloalkyl group in which at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. The radical may be fused with an aryl or heteroaryl. The term heteroalicyclic also includes all cyclic forms of carbohydrates, including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, a heterocycloalkyl has 2 to 10 carbons in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it is noted that the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatom) that comprise the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring).

[0064] The term "halo" or alternatively "halogen" means fluoro, chloro, bromo, and iodo.

[0065] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. The halogens can be the same or different. Non-limiting examples of haloalkyls include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, and the like.

[0066] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups, respectively, that are substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl include -CF, -CHF, -CHF, -CHCF, -CFCF, -CFCF, -CF(CH), and the like. Non-limiting examples of fluoroalkoxy groups include -OCF, -OCHF, -OCHF, -OCHCF, -OCFCF, -OCFCF, -OCF(CH), and the like.

[0067] The term "heteroalkyl" refers to an alkyl radical in which one or more skeletal atoms are selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof. The heteroatoms may be placed at any interior position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH2-NH-OCH3, -CHO-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. Additionally, up to two heteroatoms may be consecutive, such as, by way of example, -CH2-NH-OCH3 and -CHO-Si(CH3)3. In addition to the number of heteroatoms, a "heteroalkyl" may have from 1 to 6 carbon atoms.

[0068] The term "bond" or "single bond" refers to a chemical bond between two atoms or two moieties when the atoms connected by the bond are considered to be part of a larger substructure.

[0069] The term "moiety" refers to a specific segment or functional group of a molecule. Chemical moieties tend to be recognized as chemical entities embedded in or attached to a molecule.

[0070] As used herein, the substituent "R" appearing alone and without a number designation refers to a substituent selected from among alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0071] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes examples when the event or circumstance occurs and examples when it does not occur.

[0072] The term "optionally substituted" or "substituted" means that the referenced group can be substituted with one or more additional groups independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, arylsulfone, -CN, alkyne, C-C alkylalkyne, halo, acyl, acyloxy, -COH, -CO-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino groups (e.g., -NH, -NHR, -N(R)), and protected derivatives thereof. As an example, an optional substituent is L s R s where L s are each independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—, —S(═O)2-, —NH—, —NHC(O)—, —C(O)NH-, S(═O)2NH-, —NHS(═O)2, —OC(O)NH-, —NHC(O)O—, —(C1-C6 alkyl)-, or —(C2-C6 alkenyl)-; and R sare each independently selected from H, (C-C alkyl), (C-C cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C-C heteroalkyl. Protecting groups that can form the protective derivatives of the above substituents can be found in sources such as Greene and Wuts, supra.

[0073] As used herein, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0074] The term "therapeutically effective amount," as used herein, refers to an amount of an NLRP3 inhibitor that, when administered to a mammal in need thereof, is effective to at least partially ameliorate or at least partially prevent a disease or disorder described herein.

[0075] As used herein, the term "expression" includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0076] The term "modulate" encompasses either a decrease or an increase in activity or expression, depending on the target molecule.

[0077] The term "activator" is used herein to refer to any molecular species that, when administered locally, results in receptor activation, regardless of whether the molecular species itself binds to the indicated receptor or whether a metabolite of the molecular species binds to the receptor. Thus, an activator can be a ligand of the receptor, or it can be an activator that is metabolized to a ligand of the receptor, i.e., a metabolite that is formed in the tissue and is the actual ligand.

[0078] The term "patient" or "mammal" refers to a human, non-human primate, canine, feline, bovine, ovine, porcine, murine, or other veterinary or laboratory mammal. Those skilled in the art recognize that a treatment that reduces the severity of a condition in one species of mammal is predictive of the effectiveness of the treatment in another species of mammal.

[0079] "Pharmaceutically acceptable salts" include both acid addition salts and base addition salts. A pharmaceutically acceptable salt of any one of the compounds described herein is intended to encompass 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.

[0080] "Pharmaceutically acceptable acid addition salts" refer to salts which retain the biological effectiveness and properties of the free base, 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, etc. Also included are salts formed with organic acids such as aliphatic monocarboxylic and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic acids, and aromatic sulfonic acids, and which 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, p-toluenesulfonic acid, salicylic acid, etc. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Similarly, salts of amino acids such as arginate, gluconate, and galacturonate are contemplated (see, e.g., Berge SM 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 form with a sufficient amount of the desired acid to produce the salt.

[0081] "Pharmaceutically acceptable base addition salts" refer to salts that retain the biological effectiveness and properties of the free acid and are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or 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 amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al., supra.

[0082] As used herein, "treatment" or "treating" or "alleviating" or "ameliorating" are used interchangeably herein. These terms refer to an approach to obtain a beneficial or desired result, including, but not limited to, a therapeutic benefit and / or a preventative benefit. A "therapeutic benefit" refers to the eradication or amelioration of the underlying disease being treated. Similarly, a therapeutic benefit is achieved by the eradication or amelioration of one or more physiological symptoms associated with an underlying disease, such that an improvement is observed in a patient even though the patient still suffers from the underlying disease. For a preventative benefit, the composition is administered to a patient at risk of developing a particular disease or who reports one or more physiological symptoms of a disease, even if the patient has not been diagnosed with the disease.

[0083] NLRP3 modulators NLRP3 is an intracellular signaling molecule that senses many pathogen-, environmental-, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like protein (ASC), which contains a caspase activation and recruitment domain. ASC then polymerizes to form large aggregates known as ASC specks.

[0084] Polymerized ASC associates with the cysteine ​​protease caspase-1 to form a complex called the inflammasome. This activates active caspase-1, which cleaves the precursor forms of the proinflammatory cytokines IL-1β and IL-18 (pro-IL-ιβ and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 further mediates a form of inflammatory cell death known as pyroptosis. ASC speck aggregates can also recruit and activate caspase-8, which processes pro-IL-ιβ and pro-IL-18 and induces apoptotic cell death.

[0085] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted from cells. Active caspase-1 further cleaves gasdermin-D to induce pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-1 mediates the release of alarmin molecules such as IL-33 and high-mobility group box 1 protein (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and enabling the release of IL-1a. In human cells, caspase-1 can also regulate the processing and secretion of IL-37. Many other caspase-1 substrates, such as components of the cytoskeleton and glycolytic pathways, may contribute to caspase-1-dependent inflammation.

[0086] NLRP3-dependent ASC specks are released into the extracellular environment, where they can activate caspase-1, induce the processing of caspase-1 substrates, and propagate inflammation. Active cytokines derived from NLRP3 inflammasome activation are key drivers of inflammation and interact with other cytokine pathways to shape immune responses to infection and injury. For example, IL-ιβ signaling induces the secretion of the proinflammatory cytokines IL-6 and TNF. IL-1β and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4+ Th17 cells and γδ T cells in the absence of T cell receptor engagement. IL-18 and IL-12 further synergize to induce IFN-γ production from memory T cells and NK cells, driving Th1 responses.

[0087] The inherited CAPS disorders, Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal-onset multisystem inflammatory disease (NOMID), are caused by gain-of-function mutations in NLRP3, thus defining it as a critical component of the inflammatory process. NLRP3 is also involved in the pathogenesis of many complex diseases, including metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0088] The role of NLRP3 in diseases of the central nervous system is becoming clear, and lung diseases have also been shown to be affected by NLRP3. Furthermore, NLRP3 plays a role in the development of liver disease, kidney disease, and aging. While many of these associations were defined using NLRP3 KO mice, insights into the specific activation of NLRP3 in these diseases have also been gained. In type 2 diabetes (T2D), deposition of islet amyloid polypeptide in the pancreas activates NLRP3 and IL-ιβ signaling, leading to cell death and inflammation.

[0089] Current treatments for NLRP3-related diseases include biologic agents that target IL-1. These include the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. These approaches have proven successful in treating CAPS, and these biologic agents are being used in clinical trials for other IL-1β-related diseases. Small molecule inhibitors of NLRP3 offer an attractive alternative to these biologics, given their safety (minimal risk of infection and ease of discontinuation compared to biologics) and potential for improved patient comfort and compliance.

[0090] The compounds of formula (I'), (I), (Ia), (Ib), (II), or (III) described herein are NLRP3 modulators. The compounds of formula (I'), (I), (Ia), (Ib), (II), or (III) described herein and compositions comprising these compounds are useful for treating NLRP3-related diseases, including but not limited to, type 2 diabetes, atherosclerosis, obesity, and gout.

[0091] In some embodiments, the compound of formula (I')

[0092] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, L is -C(R 9a )(R 9b )-, -C(O)-, or -C(=N-OR 16 )- and R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13, -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R and R combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 optionally substituted with a group, R6 is

[0093] [ka] and R 6a is hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl can be one, two, or three R 14 optionally substituted with a group, or R 6a and R 15 together form a bridge which is -CH- or -CHCH-, R7 and R8 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R7 and R8 combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 optionally substituted with a group, R 9a and R 9b are each independently hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 14 are each independently halogen, -CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 15 are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from two R 15 together form a bridge which is -CH- or -CHCH-, R 16 is hydrogen and C 1-6 alkyl, and n is 0, 1, 2, 3, or 4.

[0094] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )- and R 9a is hydrogen, halogen, and C 1-6 In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from -C(R 9a )(R 9b )- and R 9b is selected from hydrogen, halogen, and —OH. In some embodiments, there are compounds of Formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(R 9a )(R 9b )- and R 9bis selected from hydrogen, halogen, and -OH. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where L is -CH2-. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where L is -CH(OH)-. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where L is -CH(CH3)-. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where L is -C(OH)(CH3)-.

[0095] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

[0096] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )-. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )- and R 16 is C 1-6 It is alkyl.

[0097] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0098] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0099] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0100] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0101] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0102] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0103] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0104] [ka] is.

[0105] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is one, two, or three R 14 C optionally substituted with a group 1-6In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is —CH. In some embodiments, there is a compound of formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is —CH 2 CH 3 . In some embodiments, there is a compound of formula (I′), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is hydrogen. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0106] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0107] [ka] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0108] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0109] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from

[0110] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0111] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0112] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0113] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0114] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0115] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0116] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0117] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0118] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0119] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0120] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0121] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0122] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0123] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0124] [ka] In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0125] [ka] is.

[0126] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, —CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, and C1-6 In some embodiments, there is provided a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are selected from alkyl. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are C 1-6 In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are -CH3. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0127] In some embodiments, there is provided a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5- or 6-membered heteroaryl ring, or the phenyl ring is selected from the group consisting of one, two, or three R 14 In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form one, two, or three R 14In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form one, two, or three R 14 In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5- or 6-membered heteroaryl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5- or 6-membered heteroaryl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered cycloalkyl ring.

[0128] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11), -C(O)OR 10 , or -C(O)N(R 10 )(R 11 In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR 10 In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, where R1 is -OH. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, where R1 is hydrogen. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, where R1 is halogen. In some embodiments, there are compounds of formula (I'), or pharmaceutically acceptable salts or solvates thereof, where R1 is C 1-6 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CF3.

[0129] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0130] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl, or C 1-6 In some embodiments, there is provided a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH3. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where R3 is -CF3. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where R3 is hydrogen. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where R3 is halogen. In some embodiments, there are compounds of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, where R3 is -OR 10 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OH. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(R 10 )(R 11 )

[0131] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CH3. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CF3. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OR 10 In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0132] In some embodiments, there is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CF3. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OR 10 In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OH. In some embodiments, there are compounds of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -N(R 10 )(R 11 )

[0133] In some embodiments, the compounds of formula (I)

[0134] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, L is -C(R 9a )(R 9b )-, -C(O)-, or -C(=N-OR 16 )- and R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R and R combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 optionally substituted with a group, R6 is

[0135] [ka] and R 6a is hydrogen and one, two, or three R 14 C optionally substituted with a group 1-6 alkyl, R7 and R8 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R7 and R8 combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 optionally substituted with a group, R 9a and R 9b are each independently hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9optionally substituted with one, two, or three groups selected from heteroaryl; R 14 are each independently halogen, -CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 15 are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10)(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 16 is hydrogen and C 1-6 alkyl, and n is 0, 1, 2, 3, or 4.

[0136] In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(R 9a )(R 9b In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein L is —C(R 9a )(R 9b )- and R 9a is hydrogen, halogen, and C 1-6 In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein L is selected from -C(R 9a )(R 9b )- and R 9bis selected from hydrogen, halogen, and —OH. In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein L is —C(R 9a )(R 9b )- and R 9b is selected from hydrogen, halogen, and -OH. In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein L is -CH2-. In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein L is -CH(OH)-. In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein L is -CH(CH3)-. In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein L is -C(OH)(CH3)-.

[0137] In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

[0138] In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(═N—OR 16 )-. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein L is -C(=N-OH)-. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein L is -C(=N-OR 16 )- and R 16 is C 1-6 It is alkyl.

[0139] In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0140] [ka] In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is one, two, or three R 14 C optionally substituted with a group 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, there are compounds of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is —CH. In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is —CH 2 CH 3 . In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is hydrogen. In some embodiments, there are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0141] In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0142] [ka] In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0143] Compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, —CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, C 1-6 Alkyl, and C 1-6 In some embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are selected from alkyl. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are selected from C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are -CH3. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0144] In some embodiments, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5- or 6-membered heteroaryl ring, or the phenyl ring is selected from the group consisting of one, two, or three R 14 In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R and R are combined to form one, two, or three R groups. 14 In some embodiments, there are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form one, two, or three R 14 In some embodiments, there are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted 5- or 6-membered heteroaryl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted 5- or 6-membered heteroaryl ring. In some embodiments, there are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form one, two, or three R groups. 14In some embodiments, there are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R and R combine to form an unsubstituted 4-, 5-, or 6-membered cycloalkyl ring.

[0145] In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , or -C(O)N(R 10 )(R 11 In some embodiments, there is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR. 10In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OH. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is hydrogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is halogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CH. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is —CF.

[0146] In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is hydrogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is halogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is -CH3. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is C 1-6In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is -CF3. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is -OR 10 In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0147] In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 Alkyl, or C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CH. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CF. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is hydrogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is halogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OR. 10In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OH. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -N(R 10 )(R 11 )

[0148] In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is hydrogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is halogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CH. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CF. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OR. 10 In some embodiments, there is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0149] In some embodiments, there are compounds of Formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10, or -N(R 10 )(R 11 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is hydrogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is -CH3. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is halogen. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CF. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OR. 10 In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is -OH. In some embodiments, there are compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is -N(R 10 )(R 11 )

[0150] In some embodiments, compounds of formula (Ia)

[0151] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, L is -C(R 9a )(R 9b)-, -C(O)-, or -C(=N-OR 16 )- and R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R and R combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 optionally substituted with a group, R6 is

[0152] [ka] and R 6a is hydrogen and one, two, or three R 14 C optionally substituted with a group 1-6 alkyl, R7 and R8 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11or R7 and R8 combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 optionally substituted with a group, R 9a and R 9b are each independently hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 14 are each independently halogen, -CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 15 are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 16 is hydrogen and C 1-6 alkyl, and n is 0, 1, 2, 3, or 4.

[0153] In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(R 9a )(R 9b In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(R 9a )(R 9b )- and R 9a is hydrogen, halogen, and C 1-6 In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from -C(R 9a )(R 9b )- and R 9b is selected from hydrogen, halogen, and —OH. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(R 9a )(R 9b )- and R 9b is selected from hydrogen, halogen, and -OH. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH2-. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(OH)-. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(CH3)-. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(OH)(CH3)-.

[0154] In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(O)—.

[0155] In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(═N—OR 16 )-. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )- and R 16 is C 1-6 It is alkyl.

[0156] In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0157] [ka] In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is one, two, or three R 14 C optionally substituted with a group 1-6 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is —CH. In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is —CH 2 CH 3 . In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6ais hydrogen. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0158] In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, —CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, C 1-6 Alkyl, and C 1-6 In some embodiments, there is provided a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6 In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are selected from alkyl. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are hydrogen. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are C1-6 In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are -CH3. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0159] In some embodiments, there is provided a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5- or 6-membered heteroaryl ring, or the phenyl ring is selected from the group consisting of one, two, or three R 14 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form one, two, or three R 14 In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form one, two, or three R 14In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5- or 6-membered heteroaryl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5- or 6-membered heteroaryl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted 4-, 5-, or 6-membered cycloalkyl ring.

[0160] In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , or -C(O)N(R 10 )(R 11 In some embodiments, there is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR 10 In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OH. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R is hydrogen. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R is halogen. In some embodiments, there are compounds of formula (Ia), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —CF.

[0161] In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0162] In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 Alkyl, or C 1-6 In some embodiments, there is provided a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is halogen. In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR. 10 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OH. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R 10 )(R 11 )

[0163] In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CH3. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR. 10 In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0164] In some embodiments, there is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there are compounds of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR. 10In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OH. In some embodiments, there are compounds of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -N(R 10 )(R 11 )

[0165] In some embodiments, the compounds of formula (Ib)

[0166] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, L is -C(R 9a )(R 9b )-, -C(O)-, or -C(=N-OR 16 )- and R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13, -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R and R combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 optionally substituted with a group, R6 is

[0167] [ka] and R7 and R8 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R7 and R8 combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 optionally substituted with a group, R 9a and R 9b are each independently hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, and C 1-6 alkoxy; R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 14 are each independently halogen, -CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 15 are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13, and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 16 is hydrogen and C 1-6 alkyl, and n is 0, 1, 2, 3, or 4.

[0168] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(R 9a )(R 9b In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(R 9a )(R 9b )- and R 9a is hydrogen, halogen, and C 1-6 In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from -C(R 9a )(R 9b )- and R 9b is selected from hydrogen, halogen, and —OH. In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(R 9a )(R 9b )- and R 9bis selected from hydrogen, halogen, and -OH. In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where L is -CH2-. In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where L is -CH(OH)-. In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where L is -CH(CH3)-. In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where L is -C(OH)(CH3)-.

[0169] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(O)—.

[0170] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is —C(═N—OR 16 )-. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )- and R 16 is C 1-6 It is alkyl.

[0171] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0172] [ka] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0173] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, —CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, C 1-6 Alkyl, and C 1-6 In some embodiments, there is provided a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6 In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are selected from alkyl. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are selected from C 1-6In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are -CH3. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0174] In some embodiments, there is provided a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5- or 6-membered heteroaryl ring, or the phenyl ring is selected from the group consisting of one, two, or three R 14 In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R are combined to form one, two, or three R groups. 14 In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form one, two, or three R 14In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5- or 6-membered heteroaryl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5- or 6-membered heteroaryl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted 4-, 5-, or 6-membered cycloalkyl ring.

[0175] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , or -C(O)N(R 10 )(R 11 In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR 10 In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OH. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R is hydrogen. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R is halogen. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —CF.

[0176] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0177] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 Alkyl, or C 1-6 In some embodiments, there is provided a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6In some embodiments, there are compounds of Formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CF. In some embodiments, there are compounds of Formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R is hydrogen. In some embodiments, there are compounds of Formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R is halogen. In some embodiments, there are compounds of Formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OR. 10 In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OH. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -N(R 10 )(R 11 )

[0178] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is hydrogen. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is halogen. In some embodiments, there are compounds of formula (Ib), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is C 1-6 In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR. 10 In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0179] In some embodiments, there is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR. 10In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OH. In some embodiments, there are compounds of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -N(R 10 )(R 11 )

[0180] In some embodiments, the compounds of formula (II)

[0181] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R and R combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 optionally substituted with a group, R6 is

[0182] [ka] and R 6a is hydrogen, C 1-6 Alkyl, and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl can be one, two, or three R 14 optionally substituted with a group, or R 6a and R 15 together form a bridge which is -CH- or -CHCH-, R7 and R8 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R7 and R8 combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 optionally substituted with a group, R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 14 are each independently halogen, -CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11Optionally substituted with one, two, or three groups selected from R 15 are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from two R 15 together form a bridge which is -CH- or -CHCH-, and n is 0, 1, 2, 3, or 4.

[0183] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0184] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0185] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0186] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0187] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0188] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0189] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0190] [ka] is.

[0191] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is one, two, or three R 14 C optionally substituted with a group 1-6 In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is —CH. In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is —CH 2 CH 3 . In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is hydrogen. In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0192] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0193] [ka] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0194] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0195] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from

[0196] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0197] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0198] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0199] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0200] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0201] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0202] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0203] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0204] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0205] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0206] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0207] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0208] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0209] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0210] [ka] In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0211] [ka] is.

[0212] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, —CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, C 1-6 Alkyl, and C 1-6 In some embodiments, there is provided a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6 In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are selected from alkyl. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are selected from C 1-6In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are -CH3. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0213] In some embodiments, there is provided a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5- or 6-membered heteroaryl ring, or the phenyl ring is selected from the group consisting of one, two, or three R 14 In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R are combined to form one, two, or three R groups. 14 In some embodiments, there are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form one, two, or three R 14In some embodiments, there are compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5- or 6-membered heteroaryl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5- or 6-membered heteroaryl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted 4-, 5-, or 6-membered cycloalkyl ring.

[0214] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , or -C(O)N(R 10 )(R 11 In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR 10 In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OH. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is hydrogen. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is halogen. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CH. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —CF.

[0215] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is hydrogen. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is halogen. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is C 1-6In some embodiments, there are compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, there are compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, there are compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, there are compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0216] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 Alkyl, or C 1-6 In some embodiments, there is provided a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH. In some embodiments, there are compounds of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CF. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is hydrogen. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is halogen. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OR. 10 In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OH. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -N(R 10 )(R 11 )

[0217] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is hydrogen. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is halogen. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is C 1-6 In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CH. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CF. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OR. 10 In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0218] In some embodiments, there is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is hydrogen. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is -CH3. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is halogen. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CF. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OR. 10In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is -OH. In some embodiments, there are compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is -N(R 10 )(R 11 )

[0219] In some embodiments, the compounds of formula (III)

[0220] [ka] or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R and R combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 or R and R taken in combination form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three R 14 optionally substituted with a group, R6 is

[0221] [ka] and R 6a is hydrogen and one, two, or three R 14 C optionally substituted with a group 1-6 alkyl, R7 and R8 are each independently hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 or R7 and R8 combined to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5-, or 6-membered heteroaryl ring, or a phenyl ring, wherein the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5-, or 6-membered heteroaryl ring, or the phenyl ring is optionally substituted with one, two, or three groups selected from R 14 optionally substituted with a group, R 10 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 11 are each independently hydrogen, C 1-6 Alkyl, and C1-6 haloalkyl; R 12 are each independently hydrogen, C 1-6 Alkyl, and C 1-6 haloalkyl; R 13 are each independently, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 optionally substituted with one, two, or three groups selected from heteroaryl; R 14 are each independently halogen, -CN, or C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from R 15 are each independently halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 , -SR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , -OC(O)N(R 10 )(R 11 ), -N(R 12 )C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)OR 13 , -N(R 12 )S(O)2R 13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O)2R 13 , -S(O)2N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH2C(O)N(R 10 )(R 11 ), -CHN(R 12 )C(O)R 13 , -CH2S(O)2R 13 , and -CH2S(O)2N(R 10 )(R 11 ), where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10, and -N(R 10 )(R 11 Optionally substituted with one, two, or three groups selected from n is 0, 1, 2, 3, or 4.

[0222] In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0223] [ka] In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is one, two, or three R 14 C optionally substituted with a group 1-6 In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is —CH. In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is —CH 2 CH 3 . In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is hydrogen. In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0224] In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0225] [ka] In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0226] In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, —CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, and C 1-9 Heteroaryl is substituted with halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , and -N(R 10 )(R 11 In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently hydrogen, halogen, C 1-6 Alkyl, and C 1-6 In some embodiments, there is provided a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are selected from alkyl. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R7 and R8 are selected from C 1-6 In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3. In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0227] In some embodiments, there is provided a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-, 5-, or 6-membered cycloalkyl ring, a 4-, 5-, or 6-membered heterocycloalkyl ring, a 5- or 6-membered heteroaryl ring, or a phenyl ring, and the 4-, 5-, or 6-membered cycloalkyl ring, the 4-, 5-, or 6-membered heterocycloalkyl ring, the 5- or 6-membered heteroaryl ring, or the phenyl ring is selected from the group consisting of one, two, or three R 14 In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R are combined to form one, two, or three R groups. 14 In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted phenyl ring. In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form one, two, or three R 14In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5- or 6-membered heteroaryl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5- or 6-membered heteroaryl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring, optionally substituted with one, two, or three R groups. In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 4-, 5-, or 6-membered heterocycloalkyl ring ..., optionally substituted with one, two, or three R groups. 14 In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R and R combine to form an unsubstituted 4-, 5-, or 6-membered cycloalkyl ring.

[0228] In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , -N(R 10 )(R 11 ), -C(O)OR 10 , or -C(O)N(R 10 )(R 11 In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR 10 In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OH. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is hydrogen. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is halogen. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH. In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —CF.

[0229] In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is hydrogen. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is halogen. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R2 is C 1-6In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH2.

[0230] In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 Alkyl, or C 1-6 In some embodiments, there is provided a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6 In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CH. In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is C 1-6In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CF. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is hydrogen. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is halogen. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OR. 10 In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —OH. In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is —N(R 10 )(R 11 )

[0231] In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or -OR 10 In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is hydrogen. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is halogen. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R4 is C 1-6 In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CH. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is C 1-6In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -CF. In some embodiments, there are compounds of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R is -OR. 10 In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0232] In some embodiments, there is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 , or -N(R 10 )(R 11 In some embodiments, there is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is hydrogen. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is -CH3. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is halogen. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is C 1-6 In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is -CF. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R is -OR. 10In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is -OH. In some embodiments, there are compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof, wherein R5 is -N(R 10 )(R 11 )

[0233] In some embodiments,

[0234] [ka]

[0235] [ka] Provided herein is a compound selected from:

[0236] In some embodiments,

[0237] [ka] Provided herein is a compound which is: or a pharmaceutically acceptable salt or solvate thereof.

[0238] In some embodiments,

[0239] [ka]

[0240] [ka] Provided herein is a compound selected from:

[0241] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof can be selected by one skilled in the art to provide stable moieties and compounds.

[0242] In some embodiments, a therapeutic agent (e.g., a compound of Formula (I'), (I), (Ia), (Ib), (II), or (III)) is present in the pharmaceutical composition as a pharmaceutically acceptable salt. In some embodiments, the compound is suitable for any of the methods or compositions described herein.

[0243] Further forms of the compounds disclosed herein Isomers 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 provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, as well as their corresponding mixtures. In some circumstances, the compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein. In some circumstances, the compounds described herein possess one or more chiral centers, with each center existing in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, as well as their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers derived 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 separation of a racemic mixture. In some embodiments, the compounds described herein are prepared as 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, diastereomers have distinctive physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, diastereomers are separated by chiral chromatography, or preferably, separation / resolution techniques based on differences in solubility.In some embodiments, the optically pure enantiomer is recovered, along with the resolving agent, by any practical means that does not result in racemization.

[0244] labeled compound In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods for treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods for treating disease 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 the compounds listed herein except for the fact that one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes incorporated into the compounds described herein are respectively: 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F, and 36 The present invention also encompasses isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as Cl. Compounds described herein, and pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof, that contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of the present invention. Certain isotopically labeled compounds, e.g., 3 H and 14 Compounds into which radioactive isotopes such as C are incorporated are useful in drug and / or substrate tissue distribution assays. 3 H) and carbon 14-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.2 Substitution with heavy isotopes, such as H, offers certain therapeutic advantages due to increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically-labeled compounds, pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof are prepared by any suitable method.

[0245] In some embodiments, the compounds described herein are labeled by other means, including but not limited to, a chromophore or fluorescent moiety, a bioluminescent label, or a chemiluminescent label.

[0246] Pharmaceutically acceptable salts In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods for treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0247] In some embodiments, the compounds described herein possess acidic or basic groups and thus form pharmaceutically acceptable salts by reacting with any of a number of inorganic or organic bases, and inorganic and organic acids. In some embodiments, these salts are prepared during the final isolation and purification of the compounds described herein, or in situ by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0248] solvate In some embodiments, the compounds described herein exist as solvates. In some embodiments, there are methods of treating diseases by administering such solvates. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0249] Solvates contain stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the crystallization process using pharmaceutically acceptable solvents such as water or ethanol. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are preferably prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein are preferably prepared by recrystallization from aqueous / organic solvent mixtures using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or MeOH. Furthermore, the compounds provided herein exist in both solvated and unsolvated forms. Generally, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0250] Compound synthesis In some embodiments, synthesis of the compounds described herein is achieved using means described in the chemical literature, using methods described herein, or by a combination thereof. In addition, solvents, temperatures, and other reaction conditions given herein may be varied.

[0251] In other embodiments, the starting materials and reagents used in the synthesis of the compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and AcrosOrganics.

[0252] In further embodiments, the compounds described herein, and other related compounds having various substituents, can be synthesized using techniques and materials described herein and other methods known in the art, such as those described in Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Ed., (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Ed., Vols. A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Ed., (Wiley The compounds may be synthesized using art-recognized techniques and materials, such as those described in (1999). General methods for the preparation of compounds as disclosed herein may be derived from reactions, which may be modified using appropriate reagents and conditions to introduce the various moieties found in the formulae as provided herein. The following synthetic methods may be used as a guide.

[0253] Use of Protecting Groups In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups (if desired in the final product), to prevent their undesired participation in the reaction. Protecting groups are used to block some or all of the reactive moieties and prevent such groups from participating in chemical reactions until the protecting group is removed. Preferably, each protecting group is removable by a different means. Protecting groups that are cleaved under distinct reaction conditions fulfill the requirement of differential removal.

[0254] Protecting groups can be removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and t-butyldimethylsilyl may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with an acid-labile, hydrogenolysis-removable Cbz group and a base-labile Fmoc group. Carboxylic acid and hydroxy reactive moieties can be blocked with base-labile groups such as t-butyl carbamate, or with base-labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with carbamates that are both acid- and base-stable but removable by hydrolysis.

[0255] Carboxylic acid and hydroxy reactive moieties can also be protected with hydrolytically removable protecting groups such as benzyl groups, while amine groups capable of hydrogen bonding with acids can be blocked with base-labile groups such as Fmoc. Carboxylic acid reactive moieties can be protected by conversion to simple ester compounds as described herein, including conversion to alkyl esters, or can be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups can be blocked with fluoride-labile silyl carbamates.

[0256] Allyl blocking groups are useful in the presence of acid- and base-protecting groups because the former are stable and can be subsequently removed by metal or π-acid catalysts. For example, allyl-blocked carboxylic acids can be deprotected by Pd in ​​the presence of acid-labile t-butyl carbamate or base-labile acetate amine protecting groups. 0 It can be deprotected by a catalytic reaction. However, another form of protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, its functional group is blocked and cannot react. Once released from the resin, the functional group is available for reaction.

[0257] Typically, the blocking / protecting group is

[0258] [ka] You can choose from:

[0259] Detailed descriptions of other protecting groups and techniques applicable to the creation and removal of protecting groups are found in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for their disclosure.

[0260] Treatment and prevention methods In some embodiments, methods are provided for treating a metabolic disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (Fa), (Fb), (Fc), or (Fc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating a metabolic disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (Fa), (Fc), (Fc), or a pharmaceutically acceptable salt or solvate thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments, methods are provided for treating type 2 diabetes in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (Fa), (Fc), (Fc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating atherosclerosis in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating obesity in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating gout in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0261] In some embodiments, a method of treating liver disease in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (Fa), (Fb), (Fc), (Fd), (Fg ...

[0262] In some embodiments, provided is a method of treating a pulmonary disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fb), (Fc), (Fg ...

[0263] In some embodiments, a method of treating a central nervous system disease in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (Fa), (Fb), (Fc), (Fc), or (Fc), or a pharmaceutically acceptable salt or solvate thereof, wherein the central nervous system disease is selected from Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, traumatic brain injury, ischemic stroke and reperfusion, hemorrhagic stroke, epilepsy, and depression. In some embodiments, a method of treating Alzheimer's disease in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fc), (Fc), (Fc), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods of treating multiple sclerosis in a patient in need thereof are provided, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fb), (Fc), or (FcI), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods of treating amyotrophic lateral sclerosis in a patient in need thereof are provided, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fc), (Fb), (Fc), or (FcI), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods of treating multiple sclerosis in a patient in need thereof are provided, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fb), (Fc), or (FcI), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided are methods of treating Parkinson's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof.In some embodiments, methods are provided for treating Huntington's disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fb), (Fc), or (FcI), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating traumatic brain injury in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fc), (Fb), (FcI), or (FcI), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating ischemic stroke and reperfusion in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fc), (FcI), or (FcI), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating stroke in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (F), (Fa), (Fb), (Fc), (Fd), (Fg ...

[0264] In some embodiments, provided are methods of treating a neurodegenerative disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fb), (Fc), (Fg), (Fg), (Fg), (Fh), (Fg ...

[0265] In some embodiments, methods are provided for treating an inflammatory or autoimmune disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fb), (Fc), (Fg ... In some embodiments, methods are provided for treating an inflammatory or autoimmune disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fb), (Fc), or (FcI), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is multiple sclerosis. In some embodiments, methods are provided for treating an inflammatory or autoimmune disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fc), (FcI), or (FcI), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is psoriasis. In some embodiments, methods are provided for treating an inflammatory or autoimmune disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fc), (FcI), or (FcI), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is lupus. In some embodiments, there is provided a method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the disease is inflammatory bowel disease.In some embodiments, methods are provided for treating an inflammatory or autoimmune disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (F), (F), (Fa), (Fb), (Fc), (Fg), (Fg), (Fg), (Fg), (Fc ...

[0266] In some embodiments, methods are provided for treating cardiovascular disease in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, methods are provided for treating cardiovascular disease in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the cardiovascular disease is atherosclerosis or stroke. In some embodiments, methods are provided for treating atherosclerosis in a patient in need thereof, the methods comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, provided are methods of treating stroke in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0267] Pharmaceutical Compositions and Methods of Administration The NLRP3 inhibitors described herein are administered to subjects in a biologically compatible form suitable for administration to treat or prevent diseases, disorders, or conditions. The administration of the NLRP3 inhibitors described herein can be in any pharmacological form, including a therapeutically effective amount of the NLRP3 inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[0268] In certain embodiments, the compounds described herein are administered as pure chemicals. In other embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice, for example, as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)).

[0269] Thus, provided herein are pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., subject) of the composition.

[0270] In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of Formula (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided comprising a pharmaceutically acceptable carrier and a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof.

[0271] Another embodiment provides a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, is provided. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, is provided. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, is provided. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, is provided. In some embodiments, a pharmaceutical composition is provided that consists essentially of a pharmaceutically acceptable carrier and a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided that consists essentially of a pharmaceutically acceptable carrier and a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof.

[0272] In certain embodiments, the compounds described herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as, for example, contaminating intermediates or by-products produced in one or more of the steps of the synthetic method.

[0273] These formulations include those suitable for oral, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal, or intravenous) or aerosol administration.

[0274] Typical pharmaceutical compositions are used in the form of pharmaceutical preparations, for example, solid, semi-solid, or liquid forms, which contain one or more of the disclosed compounds as an active ingredient in a mixture with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral use. In some embodiments, the active ingredient is typically compounded with a non-toxic, pharmaceutically acceptable carrier, for example, as a tablet, pellet, capsule, suppository, solution, emulsion, suspension, or any other form suitable for use. The active subject compound is included in the pharmaceutical composition in an amount sufficient to exert the desired effect on the disease process or condition.

[0275] In some embodiments, the NLRP3 inhibitors described herein are administered to a subject in a biologically compatible form suitable for topical administration to treat or prevent a skin disease, disorder, or condition. "Biologically compatible form suitable for topical administration" refers to a form of the NLRP3 inhibitor administered such that the therapeutic effects of the inhibitor outweigh any toxic effects. Administration of the NLRP3 inhibitors described herein can be in any pharmacological form containing a therapeutically effective amount of the NLRP3 inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[0276] The topical administration of NLRP3 inhibitors can be presented in the form of aerosol, semi-solid pharmaceutical composition, powder, or solution.The term "semi-solid composition" refers to ointments, creams, salves, jellies, or other pharmaceutical compositions with substantially similar consistency suitable for application to the skin.Examples of semi-solid compositions are shown in Chapter 17 of The Theory and Practice of Industrial Pharmacy, Lachman, Lieberman, and Kanig, published by Lea and Febiger (1970), and Chapter 67 of Remington's Pharmaceutical Sciences, 15th Edition (1975) published by Mack Publishing Company.

[0277] Skin or skin patches are another method for transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches can be provided with absorption enhancers, such as DMSO, to increase absorption of the compound. Patches can also include those that control the rate of drug delivery to the skin. Patches can offer a variety of administration systems, including reservoir systems or monolithic systems. Reservoir designs, for example, may have four layers: an adhesive layer that directly contacts the skin, a control membrane that controls the diffusion of drug molecules, a reservoir of drug molecules, and a water-resistant backing. Such designs deliver a uniform amount of drug over a specified time period, so the delivery rate must be less than the saturation limit of different types of skin. For example, monolithic designs typically have only three layers: an adhesive layer, a polymer matrix containing the compound, and a water-resistant backing. This design delivers a saturating amount of drug to the skin, allowing delivery to be controlled by the skin. If the amount of drug in the patch decreases below the saturation level, the delivery rate will decrease.

[0278] In one embodiment, the topical composition may take the form of a hydrogel, for example based on polyacrylic acid or polyacrylamide, as an ointment, for example with polyethylene glycol (PEG) as a carrier, such as the standard ointment DAB8 (50% PEG 300, 50% PEG 1500), or as an emulsion, in particular a microemulsion based on water-in-oil or oil-in-water, optionally with the addition of liposomes. Suitable permeation enhancers (entraining agents) include sulfoxide derivatives such as dimethyl sulfoxide (DMSO) or decyl methyl sulfoxide (decyl-MSO), and transcutol (diethylene glycol monoethyl ether) or cyclodextrins, as well as pyrrolidones such as 2-pyrrolidone, N-methyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, or biodegradable N-(2-hydroxyethyl)-2-pyrrolidone and its fatty acid esters, urea derivatives such as dodecylurea, 1,3-didodecylurea, and 1,3-diphenylurea, and terpenes such as D-limonene, menthone, α-terpinol, carbol, limonene oxide, or 1,8-cineole.

[0279] Ointments, pastes, creams, and gels can contain excipients such as starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, and talc, or mixtures thereof. Powders and sprays can contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays by any of the known means routinely used in the production of aerosol pharmaceuticals. Generally, such methods involve pressurizing or providing a means for pressurizing a container of the solution, usually with an inert carrier gas, and passing the pressurized gas through a small orifice. Sprays can further contain conventional propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0280] The carrier may also contain other pharmaceutically acceptable excipients to modify or maintain the pH, osmolality, viscosity, clarity, color, sterility, stability, dissolution rate, or odor of the formulation. The anti-skin aging composition may also further include antioxidants, sunscreens, natural retinoids (e.g., retinol), and other additives commonly found in skin treatment compositions.

[0281] In some embodiments for preparing solid compositions such as tablets, the primary active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of the disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When such a preformulation composition is referred to as homogeneous, it means that the active ingredient is evenly dispersed throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0282] In solid dosage forms for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions may be formulated with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or the following: (1) fillers or extenders, such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) sugars, e.g., carboxymethylcellulose, hypromellose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or (3) a binder such as acacia, (4) a humectant such as glycerin, (5) a disintegrant such as crospovidone, croscarmellose sodium, sodium starch glycolate, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (6) a solution retardant such as paraffin, (7) an absorption promoter such as quaternary ammonium compounds, (8) a humectant such as docusate sodium, cetyl alcohol, and glycerol stearate, (9) an absorbent such as kaolin and bentonite clay, (10) a lubricant such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof, and (11) a coloring agent. In the case of capsules, tablets, and pills, the composition may, in some embodiments, include a buffering agent. In some embodiments, solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0283] In some embodiments, tablets are made by compression or molding, optionally with one or more accessory ingredients. In some embodiments, compressed tablets are prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surface active agents, or dispersing agents. In some embodiments, molded tablets are made by molding, in a suitable machine, a mixture of the subject composition moistened with an inert liquid diluent. In some embodiments, tablets and other solid dosage forms, such as dragees, capsules, pills, and granules, are scored or prepared with coatings and shells, such as enteric coatings and other coatings.

[0284] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, in some embodiments, the liquid dosage form contains an inert diluent, such as water or other solvent, solubilizing and emulsifying agents, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0285] In some embodiments, the suspension comprises, in addition to the subject composition, a suspending agent such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0286] In some embodiments, powders and sprays contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. In some embodiments, sprays further comprise conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0287] The compositions and compounds disclosed herein are optionally administered by aerosol. This is accomplished by preparing aqueous aerosols, liposomal preparations, or solid particles containing the compounds. In some embodiments, non-aqueous (e.g., fluorocarbon propellant) suspensions are used. In some embodiments, sonic nebulizers are used to minimize exposure of the drug to shear, which can degrade the compounds contained in the compositions. Aqueous aerosols are typically made by formulating an aqueous solution or suspension of the subject compositions with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular subject composition, but typically include non-ionic surfactants (Tween, Pluronic®, or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are generally prepared from isotonic solutions.

[0288] Pharmaceutical compositions suitable for parenteral administration include the subject composition in combination with one or more pharmaceutically acceptable sterile, isotonic, aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders to be reconstituted into sterile injectable solutions or dispersions immediately prior to use, and in some embodiments contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0289] Examples of suitable water-soluble and non-water-soluble carriers used in pharmaceutical compositions include water, ethanol, polyols (glycerin, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate and cyclodextrin. The appropriate fluidity is maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0290] The dosage of a composition comprising at least one compound described herein will vary depending on the condition of the patient (e.g., human), i.e., the stage of the disease, general health, age, and other factors.

[0291] The pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). The appropriate dose and the appropriate duration and frequency of administration are determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, an appropriate dose and treatment regimen provides a sufficient amount of the composition to provide therapeutic and / or prophylactic benefits (e.g., improved clinical results, such as frequent complete or partial remissions, or longer disease-free periods and / or overall survival, or reduced severity of symptoms). The optimal dose is generally determined using experimental models and / or clinical trials. In some embodiments, the optimal dose depends on the patient's body type, weight, or blood volume.

[0292] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four or more times per day.

[0293] The administration of the dose may be repeated depending on the pharmacokinetic parameters of the dosage formulation and the route of administration used.

[0294] It is particularly advantageous to formulate compositions in dosage unit forms for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as unitary dosages for the mammalian subject to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for dosage unit forms are determined and directly depend on (a) the inherent characteristics of the NLRP3 inhibitor and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the technology of compounding such active compounds for the individual's therapeutic sensitivity. Specific dosages can be easily calculated by those skilled in the art, for example, according to the patient's approximate body weight or body surface area, or the volume of body space occupied. Doses are further calculated depending on the specific route of administration selected. Further refinement of the calculations required to determine the appropriate dosage for treatment can be routinely performed by those skilled in the art. Such calculations can be performed without undue experimentation by those skilled in the art, taking into account the activity of the NLRP3 inhibitors disclosed herein in the target cell assay preparation. The exact dosage is determined in conjunction with standard dose-response studies. It will be understood that the amount of the composition actually administered will be determined by the practitioner taking into account the relevant circumstances, including the disease being treated, the choice of composition to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the chosen route of administration.

[0295] The toxicity and therapeutic efficacy of such NLRP3 inhibitors are discussed, for example, in LD 50 (a dose lethal to 50% of the population) and ED 50The determination of the LD (the dose therapeutically effective in 50% of the population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is defined as the LD 50 / ED 50 The therapeutic index can be expressed as a ratio of NLRP3 to NLRP3. NLRP3 inhibitors that exhibit a high therapeutic index are preferred. NLRP3 inhibitors that exhibit toxic side effects may be used, but care must be taken to design a delivery system that targets the inhibitor to the site of affected tissue to minimize potential damage to non-infected cells and thereby reduce side effects.

[0296] Data obtained from cell culture assays and animal studies can be used to formulate dosage ranges for use in humans. Such doses of NLRP3 inhibitors can be administered at doses that are consistent with little or no toxicity. 50 Preferably, the blood concentration range includes the IC . The dosage may vary within this range depending on the dosage form used and the route of administration utilized. For NLRP3 inhibitors used in the methods described herein, the therapeutically effective dose can be initially predicted from cell culture assays. The IC determined in cell culture is 50 Dosages can be formulated in animal models to achieve a range of blood plasma concentrations, including (i.e., the concentration of the NLRP3 inhibitor that achieves half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful doses in humans. Plasma levels can be measured, for example, by high performance liquid chromatography. [Example]

[0297] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. All citations in these examples and throughout this specification are incorporated herein by reference for all legal purposes provided thereby. The starting materials and reagents used in the synthesis of the compounds described herein can be synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0298] Standard abbreviations and acronyms are used herein as defined in J. Org. Chem. 2007 72(1):23A-24A. Other abbreviations and acronyms used herein are as follows:

[0299] [Table 1]

[0300] Example 1: Synthesis of 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1)

[0301] [ka]

[0302] Step 1: To a solution of 3,6-dichloro-4,5-dimethylpyridazine (3.54 g, 20 mmol) in THF (150 mL) was added pyridin-3-yl-acetonitrile (2.5 g, 21 mmol). The solution was degassed, backfilled with N2, and cooled to 0 °C. NaHMDS (2N in THF, 21 mL, 42 mmol) was added. The reaction mixture was allowed to warm to room temperature over 2 h. The reaction mixture was stirred vigorously under open air for 5 h. The reaction was quenched with saturated NaHCO3 and diluted with EtOAc. The organic phase was separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was triturated with hexane / EtOAc to give (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (3 g).

[0303] Step 2: (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (300 mg, 1.0 equiv.), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (350 mg, 1.3 equiv.), PdCl(dppf) (80 mg, 10%), and NaCO (290 mg, 2.0 equiv.) were combined in dioxane (20 mL) and water (5 mL) under N. The resulting mixture was heated at 100° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine, and concentrated in vacuo. The residue was purified by silica gel chromatography to give (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (205 mg).

[0304] Step 3: (6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (200 mg, 1.0 equiv.) was dissolved in MeOH (10 mL) and THF (10 mL), and the solution was cooled to 0 °C. NaBH (11 mg, 0.5 equiv.) was added at 0 °C. The resulting mixture was stirred for 15 min at 0 °C. The reaction was quenched with saturated NaHCO. The mixture was extracted with EtOAc, and the EtOAc solution was concentrated in vacuo to provide 2-(6-(hydroxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol) (201 mg), which was used without further purification.

[0305] Step 4: To a solution of 2-(6-(hydroxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (200 mg, 1.0 equiv.) in MeOH (100 mL) and water (1 mL) was added PtO (98 mg, 0.8 equiv.). The mixture was degassed by bubbling N gas for 20 minutes and then hydrogenated under H (balloon) at room temperature for 15 hours. The catalyst was removed by filtration and the solvent was concentrated in vacuo to give 2-(6-(hydroxy(piperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (185 mg), which was used without purification.

[0306] Step 5: 2-(6-(hydroxy(piperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (185 mg, 1.0 equiv.) was dissolved in 1,2-dichloroethane (20 mL), and HCHO (48 mg, 37% in water, 1.2 equiv.) and 2 drops of AcOH were added. The mixture was stirred for 30 minutes at room temperature, and NaBH(AcO) (165 mg, 1.5 equiv.) was added. The resulting mixture was stirred for 30 minutes at room temperature, quenched with saturated NaHCO, and stirred for 10 minutes at room temperature. The mixture was extracted with DCM (4 x 25 mL), and the combined DCM extracts were concentrated in vacuo. The residue was purified by silica gel chromatography to give 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1) (48 mg) as a white solid. ESI-MS (EI + , m / z):396.1.

[0307] Stereoisomers 1A (a mixture of two compounds) and 1B (a mixture of two compounds) were separated from compound 1 by C18 preparative HPLC. Peak 1 was stereoisomer 1A, and peak 2 was stereoisomer 1B. Stereoisomer 1A ESI-MS (EI + , m / z):396.2. Stereoisomer 1B ESI-MS (EI + , m / z):396.2.

[0308] Example 2: Synthesis of (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone (Compound 2)

[0309] [ka]

[0310] Step 1: (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (300 mg, 1.0 equiv.), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (360 mg, 1.3 equiv.), PdCl(dppf) (82 mg, 10%), and NaCO (300 mg, 2.0 equiv.) were combined in dioxane (20 mL) and water (5 mL) under N. The resulting mixture was heated at 100° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine, and concentrated in vacuo. The residue was purified on a silica gel column to give (6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (262 mg).

[0311] Step 2: (6-(2-Methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (260 mg, 1.0 equiv) was dissolved in MeOH (20 mL) and THF (20 mL). To the solution was added NaBH (13 mg, 0.5 equiv) at 0 °C. The resulting mixture was stirred for 30 minutes at 0 °C and quenched with saturated NaHCO. The mixture was extracted with EtOAc, and the EtOAc solution was concentrated in vacuo to give (6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanol (259 mg), which was used without further purification.

[0312] Step 3: To a solution of (6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanol (250 mg, 1.0 equiv.) in MeOH (100 mL) and water (1 mL) was added PtO (117 mg, 0.8 equiv.) and (Boc)O (168 mg, 1.2 equiv.). The mixture was degassed by bubbling N gas for 20 minutes and then hydrogenated under H (balloon) at room temperature for 1.5 hours. The H balloon was then removed and the mixture was stirred overnight at room temperature. The catalyst was removed by filtration and the solvent was concentrated in vacuo. The residue was purified on a silica gel column to give tert-butyl 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)methyl)piperidine-1-carboxylate (264 mg).

[0313] Step 4: To a solution of tert-butyl 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)methyl)piperidine-1-carboxylate (260 mg, 1.0 equiv.) in dry DCM (25 mL) was added DMP (268 mg, 1.2 equiv.) at 0° C. and stirred for 1 h at 0° C. Additional DMP (30 mg) was added and the reaction was stirred for 30 min at room temperature and then quenched with saturated NaHCO. The mixture was concentrated and the residue was purified on a silica gel column to give tert-butyl 3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazine-3-carbonyl)piperidine-1-carboxylate (198 mg).

[0314] Step 5: To a solution of tert-butyl 3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazine-3-carbonyl)piperidine-1-carboxylate (190 mg, 1.0 equiv.) in dry DCM (20 mL) under N was added BBr (5 equiv.) at 0° C. The mixture was stirred for 1 h at 0° C. and then for 6 h at room temperature. The reaction was quenched with water at 0° C. and stirred for 30 min at room temperature. Saturated NaHCO was added to adjust the pH to approximately 10. The mixture was extracted with DCM (3×50 mL). The combined extracts were concentrated in vacuo to give (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(piperidin-3-yl)methanone (97 mg).

[0315] Step 6: Under the reaction conditions described in Example 1, Step 5, (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(piperidin-3-yl)methanone (56 mg) was used to obtain (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone (28 mg) (Compound 2). ESI-MS (EI + , m / z):394.2.

[0316] Example 3: Synthesis of 2-(6-(1-hydroxy-1-(1-methylpiperidin-3-yl)ethyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 3)

[0317] [ka]

[0318] A solution of compound 2 (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone (15 mg) in dry THF was treated with MeMgBr (2N, 76 μl, 4.0 equiv.) at 0° C. The mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NH4Cl and extracted with DCM (3×20 mL). The combined extracts were concentrated in vacuo, and the residue was purified by HPLC to give 2-(6-(1-hydroxy-1-(1-methylpiperidin-3-yl)ethyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (8 mg) (compound 3). ESI-MS (EI + , m / z):410.2.

[0319] Example 4: Synthesis of 2-(6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 4)

[0320] [ka]

[0321] Step 1: (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (1.0 g, 1.0 equiv.) was dissolved in MeOH (20 mL) and THF (20 mL) and cooled to 0 °C. NaBH (80 mg, 0.5 equiv.) was added at 0 °C. The resulting mixture was stirred for 15 minutes at 0 °C. The reaction was quenched with saturated NaHCO. The mixture was extracted with EtOAc, and the EtOAc solution was concentrated in vacuo to give (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanol (0.95 g), which was used without further purification.

[0322] Step 2: To a solution of (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanol (300 mg, 1.0 equiv.) in dry DCM (10 mL) was added DAST (388 mg, 2.0 equiv.) at 0° C. The mixture was stirred overnight at room temperature. Additional DAST (100 mg) was added, and the reaction was stirred for an additional 5 h at room temperature. The reaction was quenched with saturated NaHCO at 0° C., and the aqueous phase was extracted with DCM (2×20 mL). The combined extracts were concentrated in vacuo, and the residue was purified on a silica gel column to give 3-chloro-6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazine (174 mg).

[0323] Step 3: 3-Chloro-6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazine (150 mg, 1.0 equiv.), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (160 mg, 1.3 equiv.), PdCl(dppf) (40 mg, 10%), and NaCO (130 mg, 2.0 equiv.) were combined in dioxane (10 mL) and water (3 mL) under N. The resulting mixture was heated at 100° C. for 8 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water, brine, and concentrated in vacuo. The residue was purified on a silica gel column to give ZMG-3134, 2-(6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol) (143 mg).

[0324] Step 4: To a solution of tert-butyl 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)methyl)piperidine-1-carboxylate (260 mg, 1.0 equiv.) in dry DCM (25 mL) was added DMP (268 mg, 1.2 equiv.) at 0° C. and stirred for 1 h at 0° C. Additional DMP (30 mg) was added and the reaction was stirred for 30 min at room temperature before being quenched with saturated NaHCO. The mixture was concentrated and the residue was purified on a silica gel column to give tert-butyl 3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazine-3-carbonyl)piperidine-1-carboxylate (compound 4) (198 mg). ESI-MS (EI + ,m / z):378.3.

[0325] Example 5: Synthesis of 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 5)

[0326] [ka]

[0327] Step 1: To a solution of compound 4 (120 mg) in MeOH (40 mL) was added PtO (40 mg), degassed under vacuum, and then hydrogenated under balloon H for 15 h. The catalyst was removed through a Celite pad, and the reaction mixture was concentrated in vacuo to give 2-(4,5-dimethyl-6-(piperidin-3-ylmethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (92 mg).

[0328] Step 2: Under the reaction conditions described in Example 1, Step 5, 2-(4,5-dimethyl-6-(piperidin-3-ylmethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol) (92 mg) gave 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (21 mg) (Compound 5). ESI-MS (EI + ,m / z):380.3.

[0329] Example 6: Synthesis of 2-(6-(methoxy(1-methylpiperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 6)

[0330] [ka]

[0331] Step 1: To a solution of 2-(6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (100 mg) in dry THF (2 mL) was added 2 M NaOMe in MeOH (2 mL). The resulting mixture was heated in a sealed tube at 90° C. overnight. The mixture was cooled, diluted with water (40 mL), and extracted with ethyl acetate (3×40 mL). The combined extracts were concentrated in vacuo. The residue was purified on a silica gel column to give 2-(6-(methoxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (81 mg).

[0332] Step 2: To a solution of 2-(6-(methoxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (60 mg), PtO2 (25 mg) was added, degassed under vacuum, and hydrogenated under balloon H2 for 15 hours to give 2-(6-(methoxy(piperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (42 mg).

[0333] Step 3: Under the reaction conditions described in Example 1, Step 5, 2-(6-(methoxy(piperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol) (42 mg) was converted to 2-(6-(methoxy(1-methylpiperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (5 mg) (compound 6). ESI-MS (EI + , m / z):410.2.

[0334] Example 7: Synthesis of 3-fluoro-5-methyl-2-(6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (Compound 7)

[0335] [ka]

[0336] Step 1: tert-Butyl 3-methylenepiperidine-1-carboxylate (500 mg, 1.0 equiv.) was added 9-BBN (0.5 M, 5.1 mL, 1.0 equiv.) at 0° C. under N. The mixture was stirred in a sealed tube at room temperature for 10 minutes and then at 70° C. for 1 hour. The mixture was cooled and the solvent removed in vacuo to give tert-butyl 3-((9-borabicyclo[3.3.1]nonan-9-yl)methyl)piperidine-1-carboxylate, which was used without further purification.

[0337] Step 2: tert-Butyl 3-((9-borabicyclo[3.3.1]nonan-9-yl)methyl)piperidine-1-carboxylate (200 mg, 1.0 equiv.), 3,6-dibromopyridazine (300 mg, 2.0 equiv.), PdCl(dppf) (40 mg, 0.1 equiv.), and NaCO (135 mg, 2.0 equiv.) were combined in dioxane (15 mL) and water (5 mL). The mixture was heated at 100° C. for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo, and the residue was purified on a silica gel column to give tert-butyl 3-((6-bromopyridazin-3-yl)methyl)piperidine-1-carboxylate (162 mg).

[0338] Step 3: tert-Butyl 3-((6-bromopyridazin-3-yl)methyl)piperidine-1-carboxylate (50 mg, 1.0 equiv.), (2-fluoro-6-hydroxy-4-methylphenyl)boronic acid (31 mg, 1.3 equiv.), PdCl(dppf) (9 mg, 0.1 equiv.), and NaCO (30 mg, 2.0 equiv.) were combined in dioxane (5 mL) and water (2 mL). The mixture was heated at 100° C. for 8 hours. The crude mixture was purified on a silica gel column to give tert-butyl 3-((6-(2-fluoro-6-hydroxy-4-methylphenyl)pyridazin-3-yl)methyl)piperidine-1-carboxylate (41 mg).

[0339] Step 4: tert-Butyl 3-((6-(2-fluoro-6-hydroxy-4-methylphenyl)pyridazin-3-yl)methyl)piperidine-1-carboxylate (41 mg) was treated with 4N HCl in dioxane (1 mL). The mixture was stirred at room temperature for 15 minutes and concentrated in vacuo to give 3-fluoro-5-methyl-2-(6-(piperidin-3-ylmethyl)pyridazin-3-yl)phenol HCl salt (35 mg).

[0340] Step 5: Under the reaction conditions described in Example 1, Step 5, 3-fluoro-5-methyl-2-(6-(piperidin-3-ylmethyl)pyridazin-3-yl)phenol (35 mg) gave 3-fluoro-5-methyl-2-(6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (12 mg) (compound 7). ESI-MS (EI + ,m / z):316.3.

[0341] Example 8: Synthesis of 3-fluoro-2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-5-methylphenol (Compound 8)

[0342] [ka]

[0343] Step 1: tert-Butyl 3-((6-bromopyridazin-3-yl)methyl)piperidine-1-carboxylate (100 mg, 1.0 equiv.), SeO (4.0 equiv.) in CHCN (2 mL) was heated in a microwave reactor at 135 °C for 8 h. The mixture was cooled to room temperature, quenched with concentrated NHCl, and extracted with DCM. The solvent was removed in vacuo, and the residue was purified on a silica gel column to give tert-butyl 3-(6-hydroxypyridazine-3-carbonyl)piperidine-1-carboxylate (48 mg).

[0344] Step 2: tert-Butyl 3-(6-hydroxypyridazine-3-carbonyl)piperidine-1-carboxylate (40 mg, 1.0 equiv.) and DMAP (40 mg) were dissolved in DCM (2 mL) and pyridine (1 mL) at 0 °C. TfO (2.0 equiv.) in DCM (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 15 hours. The reaction was quenched with water and extracted with DCM. The solvent was removed in vacuo, and the residue was purified on a silica gel column to give tert-butyl 3-(6-(((trifluoromethyl)sulfonyl)oxy)pyridazine-3-carbonyl)piperidine-1-carboxylate) (26 mg).

[0345] Step 3: tert-Butyl 3-(6-(((trifluoromethyl)sulfonyl)oxy)pyridazine-3-carbonyl)piperidine-1-carboxylate (26 mg, 1.0 equiv.), (2-fluoro-6-hydroxy-4-methylphenyl)boronic acid (1.5 equiv.), PdCl(dppf) (0.1 equiv.), and NaCO (2.0 equiv.) were combined in toluene (3 mL) and water (1 mL). The mixture was heated at 85° C. for 8 hours. The mixture was cooled to room temperature and purified on a silica gel column to give tert-butyl 3-(6-(2-fluoro-6-hydroxy-4-methylphenyl)pyridazine-3-carbonyl)piperidine-1-carboxylate (15 mg).

[0346] Step 4: tert-Butyl 3-(6-(2-fluoro-6-hydroxy-4-methylphenyl)pyridazine-3-carbonyl)piperidine-1-carboxylate (15 mg) in DCM (1 mL) was treated with TFA (1 mL) at room temperature for 20 minutes. The solvent was removed in vacuo to give 3-fluoro-2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-5-methylphenol TFA salt (18 mg).

[0347] Step 5: Under the reaction conditions described in Example 1, Step 5, 3-fluoro-2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-5-methylphenol TFA salt (18 mg) gave 3-fluoro-2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-5-methylphenol (compound 8) (9 mg). ESI-MS (EI + ,m / z):332.3.

[0348] Example 9: Synthesis of 2-(4-(hydroxy(1-methylpiperidin-3-yl)methyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (Compound 9)

[0349] [ka]

[0350] Step 1: tert-Butyl 3-((9-borabicyclo[3.3.1]nonan-9-yl)methyl)piperidine-1-carboxylate (200 mg, 1.0 equiv.), 1,4-dichlorophthalazine (250 mg, 2.0 equiv.), PdCl(dppf) (40 mg, 0.1 equiv.), and NaCO (135 mg, 2.0 equiv.) were combined in dioxane (15 mL) and water (5 mL). The mixture was heated at 100° C. for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The solvent was removed in vacuo, and the residue was purified on a silica gel column to give tert-butyl 3-((4-chlorophthalazin-1-yl)methyl)piperidine-1-carboxylate (85 mg).

[0351] Step 2: tert-Butyl 3-((4-chlorophthalazin-1-yl)methyl)piperidine-1-carboxylate (80 mg, 1.0 equiv.), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (68 mg, 1.5 equiv.), PdCl(dppf) (15 mg, 0.1 equiv.), and NaCO (48 mg, 2.0 equiv.) were combined in dioxane (5 mL) and water (2 mL). The mixture was heated at 100° C. for 8 hours. The mixture was cooled to room temperature and purified on a silica gel column to give tert-butyl 3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)methyl)piperidine-1-carboxylate (38 mg).

[0352] Step 3: tert-Butyl 3-((4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)methyl)piperidine-1-carboxylate (38 mg) in DCM (1 mL) was treated with TFA (1 mL) at room temperature for 15 minutes. The mixture was concentrated in vacuo to give 2-(4-(piperidin-3-ylmethyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol TFA salt (42 mg).

[0353] Step 4: Under the reaction conditions described in Example 1, Step 5, 2-(4-(piperidin-3-ylmethyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol TFA salt (42 mg) gave 2-(4-(hydroxy(1-methylpiperidin-3-yl)methyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol) (18 mg) (compound 9). ESI-MS (EI + , m / z):402.2.

[0354] Example 10: Synthesis of 2-(6-(hydroxy(pyridin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 10)

[0355] [ka]

[0356] Step 1: To a degassed solution of 3,6-dichloro-4-methylpyridazine (8.2 g, 50 mmol) and 3-pyridylacetonitrile (6.1 g, 52 mmol) in dry DMA (60 mL) was added NaH (4.2 g, 105 mmol, 60%) portionwise at 0° C. under N. The reaction mixture was stirred at 0° C. for 1 h. m-CPBA (12 g, 72%) was added portionwise to the solution over 10 min at 0° C. The reaction mixture was diluted with EtOAc (200 mL) and stirred at 0° C. for an additional 10 min. Saturated NaHCO (100 mL) was added at 0° C., and the mixture was stirred for 10 min. The mixture was diluted with water (200 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3 × 100 mL), saturated NaHCO (100 mL), brine (100 mL), and dried over NaSO. The solvent was concentrated in vacuo. The solid was sonicated in 50 mL of EtOAc, filtered, washed with 1:1 EtOAc / hexane (20 mL), and then slurried in 50 mL of 1:1 EtOAc / hexane for 30 minutes at 50 °C. The mixture was cooled to room temperature, and the solid was removed by filtration to give (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanone (A-10) (4.2 g). The combined mother liquor was concentrated in vacuo and purified on a silica gel column to give (6-chloro-4-methylpyridazin-3-yl)(pyridin-3-yl)methanone (B-10) (1.3 g).

[0357] Step 2: (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanone (A-10) (1.0 g, 1.0 equiv.) was dissolved in MeOH (20 mL) and THF (20 mL) and cooled to 0 °C. NaBH (81 mg, 0.5 equiv.) was added at 0 °C. The resulting mixture was stirred for 15 minutes at 0 °C. The reaction was quenched with saturated NaHCO and then extracted with ethyl acetate. The solvent was removed in vacuo to give (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (1.0 g), which was used without further purification.

[0358] Step 3: (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (1.0 g, 1.0 equiv.), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (1.14 g, 1.3 equiv.), PdCl(dppf) (0.28 g, 0.1 equiv.), and NaCO (0.9 g, 2.0 equiv.) were combined in dioxane (20 mL) and water (5 mL). The resulting mixture was heated at 100 °C for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine, and concentrated in vacuo. The residue was purified on a silica gel column to give 2-(6-(hydroxy(pyridin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (compound 10) (0.75 g). ESI-MS (EI + ,m / z):362.2.

[0359] Example 11: Synthesis of 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 11)

[0360] [ka]

[0361] Step 1: To a solution of 2-(6-(hydroxy(pyridin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (compound 10) (0.7 g, 1.0 equiv.) in MeOH (150 mL) and water (1 mL) was added PtO (0.35 g, 0.8 equiv.) and (Boc)O (0.47 g, 1.1 equiv.). The mixture was degassed by bubbling N gas for 20 minutes and then hydrogenated under H (balloon) at room temperature for 1.5 hours. The H balloon was then removed, and the mixture was stirred overnight at room temperature. The catalyst was removed by filtration, and the solvent was concentrated in vacuo. The residue was purified on a silica gel column to give tert-butyl 3-(hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate (0.35 g).

[0362] Step 2: To a solution of tert-butyl 3-(hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate (300 mg) in DCM (5 mL) was added TFA (8 mL). The mixture was stirred for 25 minutes at room temperature. The mixture was concentrated in vacuo. The residue was suspended in saturated NaHCO and then extracted with DCM (5 x 20 mL). The combined extracts were concentrated in vacuo to give 2-(6-(hydroxy(piperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol) (180 mg) as the free base, which was used without further purification.

[0363] Step 3: To a solution of 2-(6-(hydroxy(piperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (180 mg, 1.0 equiv.) in 1,2-dichloroethane (15 mL), HCHO (48 mg, 37% in water, 1.2 equiv.) and 2 drops of AcOH were added. The mixture was stirred at room temperature for 30 minutes, and NaBH(AcO)3 (165 mg, 1.5 equiv.) was added. The resulting mixture was stirred at room temperature for 30 minutes, quenched with saturated NaHCO3, and stirred at room temperature for 10 minutes. The mixture was extracted with DCM (4 x 25 mL). The combined extracts were concentrated in vacuo. The residue was purified on a silica gel column to give 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 11) (118 mg) as a white solid. ESI-MS (EI + , m / z):382.2.

[0364] Example 12: Synthesis of 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)-5-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 12)

[0365] [ka]

[0366] Compound 12 was prepared by the procedure described in Example 11, starting from B-10 in Example 10. ESI-MS (EI + ,m / z):382.3.

[0367] Example 13: Synthesis of (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(pyridin-3-yl)methanone (Compound 13)

[0368] [ka]

[0369] (6-Chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanone (30 mg, 1.0 equiv.), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (A-10) (35 mg, 1.3 equiv.), PdCl(dppf) (8 mg, 0.1 equiv.), and NaCO (28 mg, 2.0 equiv.) were combined in dioxane (5 mL) and water (2 mL). The resulting mixture was heated at 100 °C for 8 hours. The reaction mixture was diluted with ethyl acetate (30 mL), washed with water, brine, and concentrated in vacuo. The residue was purified on a silica gel column to give (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(pyridin-3-yl)methanone (compound 13) (26 mg). ESI-MS (EI + ,m / z):360.0.

[0370] Example 14: Synthesis of (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone (Compound 14)

[0371] [ka]

[0372] Step 1: (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (1.2 g, 1.0 equiv.), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (1.45 g, 1.3 equiv.), PdCl(dppf) (325 mg, 0.1 equiv.), and NaCO (1.2 g, 2.0 equiv.) were combined in dioxane (30 mL) and water (5 mL). The resulting mixture was heated at 100° C. for 12 hours. The reaction mixture was diluted with ethyl acetate (120 mL), washed with water, brine, and concentrated in vacuo. The residue was purified on a silica gel column to give (6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (1.18 g).

[0373] Step 2: To a solution of (6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (1.1 g, 1.0 equiv.) in MeOH (250 mL) and water (2 mL) was added PtO (530 mg, 0.8 equiv.) and (Boc)O (720 mg, 1.1 equiv.). The mixture was degassed by bubbling N gas for 20 minutes and then hydrogenated under H (balloon) at room temperature for 1.5 hours. The H balloon was then removed and the mixture was stirred overnight at room temperature. The catalyst was removed by filtration and the solvent was concentrated in vacuo. The residue was purified on a silica gel column to give tert-butyl 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate (1.05 g).

[0374] Step 3: To a solution of tert-butyl 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate (1 g, 1.0 equiv.) in dry DCM (30 mL) was added DMP (1.1 g, 1.2 equiv.) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then quenched with saturated NaHCO. The solvate was removed in vacuo and the residue was purified on a silica gel column to give tert-butyl 3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carbonyl)piperidine-1-carboxylate (890 mg).

[0375] Step 4: To a solution of tert-butyl 3-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carbonyl)piperidine-1-carboxylate (890 mg, 1.0 equiv.) in dry DCM (30 mL) was added BBr (5 equiv.) at 0° C. under N. The mixture was stirred for 1 h at 0° C. and then for 6 h at room temperature. The reaction was quenched with water at 0° C. and stirred for 30 min at room temperature, then adjusted to pH 10 by adding saturated NaHCO and extracted with DCM (3×50 mL). To the DCM solution was added (Boc)O (425 mg, 1.0 equiv.) and the mixture was stirred for 1 h at room temperature. The crude mixture was purified on a silica gel column to give tert-butyl 3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carbonyl)piperidine-1-carboxylate (810 mg).

[0376] Step 5: tert-Butyl 3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carbonyl)piperidine-1-carboxylate (50 mg) in DCM (2 mL) was treated with TFA (1 mL). The mixture was stirred at room temperature for 30 minutes and concentrated in vacuo to give (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(piperidin-3-yl)methanone TFA salt (62 mg).

[0377] Step 6: Under the reaction conditions described in Example 1, Step 5, (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(piperidin-3-yl)methanone TFA salt (62 mg) gave (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone (28 mg) (Compound 14). ESI-MS (EI + ,m / z):380.0.

[0378] Example 15: Synthesis of 2-(6-(1-hydroxy-1-(1-methylpiperidin-3-yl)ethyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 15)

[0379] [ka]

[0380] A solution of (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone (compound 14) (22 mg, 1.0 equiv.) in dry THF (2 mL) was treated with MeMgBr (2N, 0.12 mL, 4.0 equiv.) at 0° C. The mixture was stirred at room temperature for 1 hour, then quenched with saturated NH4Cl and extracted with DCM (4 × 20 mL). The combined extracts were concentrated, and the residue was purified by HPLC to give 2-(6-(1-hydroxy-1-(1-methylpiperidin-3-yl)ethyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (9 mg) (compound 15). ESI-MS (EI + , m / z):396.2.

[0381] Example 16: Synthesis of (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone oxime (Compound 16)

[0382] [ka]

[0383] To a solution of ZMG-3193 (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone (compound 14) (20 mg, 1.0 equiv.) in absolute EtOH (2 mL) was added NHOH (1.2 equiv.) and 2 drops of AcOH. The resulting mixture was heated at 50° C. for 5 hours and concentrated to dryness. The residue was purified on a silica gel column to give (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone oxime (7 mg) (compound 16). ESI-MS (EI + , m / z):395.1.

[0384] Example 17: Synthesis of 2-(6-((S)-hydroxy((R)-1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 17A), 2-(6-((R)-hydroxy((R)-1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 17B), 2-(6-((R)-hydroxy((S)-1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 17C), and 2-(6-((S)-hydroxy((S)-1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 17D)

[0385] [ka]

[0386] The product of Example 14, Step 4, 3-(6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-carbonyl)piperidine-1-carboxylate (250 mg) was subjected to SFC chiral separation to give compound 17-1 (94 mg) and compound 17-2 (97 mg).

[0387] Compound 17-1 (90 mg) under the reaction conditions described in Example 1, Step 3, gave the intermediate alcohol (90 mg), which was separated by chiral column to give Compound 17-1A (36 mg) and Compound 17-1B (32 mg). Compound 17-1A (36 mg) was deprotected using the method described in Example 7, Step 4. The resulting amine intermediate HCl salt was subjected to reductive amination using the method described in Example 1, Step 5, to give Compound 17A (16.4 mg). ESI-MS (EI + , m / z): 382.1. The absolute stereochemistry of compound 17A was confirmed by single crystal x-ray crystallography. Using the same chemistry, compound 17B (13 mg) was obtained from compound 17-1B. ESI-MS (EI + , m / z):382.2.

[0388] In a similar manner, compound 17-2 (95 mg) was reduced and subjected to SFC chiral separation to give compound 17-2A (38 mg) and compound 17-2B (35 mg). Compound 17-2A (38 mg) and compound 17-2B (35 mg) were deprotected and reductively aminated to give compound 17C (16 mg) and compound 17D (13 mg), respectively. Compound 17C: ESI-MS (EI + ,m / z):382.2.Compound 17D:ESI-MS(EI + , m / z):382.2.

[0389] Example 18: Synthesis of 2-(6-((S)-hydroxy((R)-1-methylpiperidin-3-yl)methyl-d)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 18)

[0390] [ka]

[0391] Under the reaction conditions described in Example 1, Step 3, and by replacing d4-MeOD and NaBD4 from peak 17-1 (120 mg) in d4-MeOD (2 mL) and adding NaBD4 (0.5 equivalents) at 0 °C, an intermediate alcohol (119 mg) was obtained, which was separated by chiral column to give peak 18-1A (65 mg) and peak 18-1B (40 mg). Treatment of intermediate peak 18-1B (40 mg) with 4 N HCl gave the amine intermediate, which underwent reductive amination with HCHO (1.2 equivalents) in the presence of NaBH(AcO)3 (1.5 equivalents) to give 2-(6-((S)-hydroxy((R)-1-methylpiperidin-3-yl)methyl-d)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (28 mg) (compound 18). ESI-MS (EI + ,m / z):383.2.

[0392] Example 19: Synthesis of 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (Compound 19)

[0393] [ka]

[0394] Step 1: To a degassed solution of 3,6-dichloropyridazine (3 g, 20 mmol), pyridin-3-yl-acetonitrile (2.5 g, 21 mmol) in DMF (30 mL) was added NaH (1.68 g, 42 mmol, 60%) portionwise at 0 °C under N. The mixture was stirred for 1 h at 0 °C. mCPBA (4.8 g, 20 mmol, 72%) was added portionwise, and the mixture was diluted with EtOAc (200 mL). The mixture was washed with water, aqueous NaHCO, and brine, dried over NaSO, filtered, and concentrated. The residue was triturated with hexane / EtOAc to give (6-chloropyridazin-3-yl)(pyridin-3-yl)methanone (2.3 g).

[0395] Step 2: Under the reaction conditions described in Example 10, Step 2, (6-chloropyridazin-3-yl)(pyridin-3-yl)methanone (1.0 g) gave (6-chloropyridazin-3-yl)(pyridin-3-yl)methanol (1.0 g).

[0396] Step 3: (6-chloropyridazin-3-yl)(pyridin-3-yl)methanol (600 mg, 1.0 equiv.), (2-hydroxy-4,6-dimethylphenyl)boronic acid (585 mg, 1.3 equiv.), PdCl(dppf) (160 mg, 10%), and NaCO (600 mg, 2.0 equiv.) were combined in dioxane (30 mL) and water (5 mL). The resulting mixture was heated at 100 °C for 8 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water, brine, and concentrated in vacuo. The residue was purified on a silica gel column to give 2-(6-(hydroxy(pyridin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (625 mg).

[0397] Step 4: Under the reaction conditions described in Example 1, Step 4, 2-(6-(hydroxy(pyridin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol) (100 mg) gave 2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol) (120 mg), which was used without further purification.

[0398] Step 5: Under the reaction conditions described in Example 1, Step 5, 2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol) (120 mg, 1.0 equivalent) gave 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (35 mg) (compound 19). ESI-MS (EI + ,m / z):328.1.

[0399] Example 20: Synthesis of 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Compound 20)

[0400] [ka]

[0401] Step 1: 3-Methyl-5-(trifluoromethyl)aniline (2.63 g, 15 mmol) was added to a solution of concentrated HSO (30 mL) in water (150 mL) and the mixture was cooled to 0 °C. NaNO (1.1 g, 16 mmol) in water (10 mL) was added dropwise to the mixture and the reaction was stirred for 1 h at 0 °C. Concentrated HSO (30 mL) was added and the mixture was heated to 90 °C for 5 h. The mixture was cooled to room temperature and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography to give 3-methyl-5-(trifluoromethyl)phenol (2.2 g).

[0402] Step 2: To a solution of 3-methyl-5-(trifluoromethyl)phenol (2.1 g, 12 mmol) in toluene (60 mL) was added NaH (0.96 g, 24 mmol, 60%) at 0 °C. The suspension was stirred for 30 min at 0 °C. Iodine (12 mmol) was added slowly in portions, and the mixture was stirred at 0 °C for 3 h. The mixture was diluted with water (50 mL) and acidified to pH 5 with 2 N HCl. The organic phase was separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by flash chromatography to give 2-iodo-3-methyl-5-(trifluoromethyl)phenol (2.7 g).

[0403] Step 3: (Chloromethoxy)methane (0.8 g, 10 mmol) was added dropwise to a suspension of 2-iodo-3-methyl-5-(trifluoromethyl)phenol (2.4 g, 8 mmol) and CsCO (3.26 g, 10 mmol) in DMF (10 mL) at 0 °C. The reaction mixture was warmed to room temperature over 2 h and diluted with EtOAc (50 mL). The mixture was washed with water and brine, dried over NaSO, filtered, and concentrated. The residue was purified by flash chromatography to give 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (2.3 g).

[0404] Step 4: A mixture of 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl)benzene (1.02 g, 3 mmol), bis(pinacolato)diborane (0.9 g, 3.6 mmol), Pd(OAc) (67 mg, 0.3 mmol), and KOAc (0.6 g, 6 mmol) in anhydrous DMF (10 mL) was stirred for 10 h at 100 °C. The mixture was diluted with EtOAc, washed with water (3 times), brine, and dried over Na SO . The solvent was evaporated, and the residue was purified by flash chromatography to give 2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (605 mg).

[0405] Step 5: (6-chloropyridazin-3-yl)(pyridin-3-yl)methanol (120 mg, 1.0 equiv.), 2-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 equiv.), PdCl(dppf) (0.1 equiv.), and NaCO (2.0 equiv.) were combined in dioxane (10 mL) and water (2 mL). The resulting mixture was heated at 100° C. for 12 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water, brine, and concentrated in vacuo. The residue was purified on a silica gel column to give (6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)(pyridin-3-yl)methanol (115 mg).

[0406] Step 6: To a solution of (6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)(pyridin-3-yl)methanol (110 mg, 1.0 equiv.) in MeOH (100 mL) and water (1 mL) was added PtO (0.8 equiv.) and (Boc)O (1.1 equiv.). The mixture was degassed by bubbling N gas for 20 minutes and then hydrogenated under H (balloon) at room temperature for 1.5 hours. The H balloon was then removed and the mixture was stirred overnight at room temperature. The catalyst was removed by filtration and the solvent was concentrated in vacuo. The residue was purified on a silica gel column to give tert-butyl 3-(hydroxy(6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidine-1-carboxylate (92 mg).

[0407] Step 7: To a solution of tert-butyl 3-(hydroxy(6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidine-1-carboxylate (90 mg, 1.0 equiv.) in dry DCM was added DMP (1.2 equiv.) at 0° C. The reaction mixture was stirred for 1 h at 0° C. and then quenched with saturated NaHCO. The solvent was concentrated in vacuo and the residue was purified on a silica gel column to give tert-butyl 3-(6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-3-carbonyl)piperidine-1-carboxylate (62 mg).

[0408] Step 8: To a solution of tert-butyl 3-(6-(2-(methoxymethoxy)-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-3-carbonyl)piperidine-1-carboxylate (58 mg, 1.0 equiv.) in dry DCM (1 mL) at 0° C. under N was added TFA (1 mL). The mixture was stirred for 1 h at 0° C. and then overnight at room temperature. The reaction was concentrated in vacuo. The residue was suspended in water and adjusted to pH 10 by adding saturated NaHCO, then extracted with DCM (3×50 mL). The combined organic layers were concentrated and the residue was purified on a silica gel column to give (6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)(piperidin-3-yl)methanone (28 mg).

[0409] Step 9: Under the reaction conditions described in Example 1, Step 5, 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Compound 20) (11 mg) was obtained from (6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazin-3-yl)(piperidin-3-yl)methanone (18 mg). ESI-MS (EI + ,m / z):382.3.

[0410] Example 21: Synthesis of 3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidin-3-ol (Compound 21)

[0411] [ka]

[0412] Step 1: A solution of 3-chloro-6-methylpyridazine (1.0 g, 7.81 mmol), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (2.05 g, 9.37 mmol), Pd(dppf)Cl (570 mg, 0.78 mmol), and NaCO (1.65 g, 15.62 mmol) in dioxane (32 mL) and HO (8 mL) was stirred at 90 °C under a N atmosphere. The mixture was quenched with brine (100 mL) and then extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-(2-methoxy-4-(trifluoromethyl)phenyl)-6-methylpyridazine (1.91 g, 91%).

[0413] Step 2: To a solution of 3-(2-methoxy-4-(trifluoromethyl)phenyl)-6-methylpyridazine (1.0 g, 3.73 mmol) in anhydrous THF (25 mL) was added n-BuLi (2.2 mL, 5.59 mmol) dropwise at −50° C. The reaction mixture was stirred at −50° C. for 30 minutes, and then tert-butyl 3-oxopiperidine-1-carboxylate (1.48 g, 7.46 mmol) in anhydrous THF (15 mL) was added dropwise at −50° C. The mixture was gradually warmed to room temperature. After 1 hour, the mixture was quenched with NH4Cl(aq) (100 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain tert-butyl 3-hydroxy-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidine-1-carboxylate (1.32 g, 76%).

[0414] Step 3: A solution of tert-butyl 3-hydroxy-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidine-1-carboxylate (200 mg, 0.43 mmol) in anhydrous DCM (25 mL) was cooled to −78° C. BBr (1.2 mL, 1.28 mmol) was added dropwise. The mixture was gradually warmed to room temperature and then stirred at room temperature for 6 h. The mixture was quenched with NaHCO (aq) (100 mL) and then extracted with DCM (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidin-3-ol (Compound 21) (13 mg, 9%). ESI-MS(EI + , m / z):354.2.

[0415] Example 22: Synthesis of 2-(4-(1-(piperidin-3-yl)ethyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (Compound 22)

[0416] [ka]

[0417] Step 1: LiHMDS (1.0 M in THF) (21.8 mL, 21.8 mmol) was added to THF (50 mL) at −78° C. under nitrogen. A solution of 1-(tetrahydro-2H-pyran-4-yl)ethanone (4.5 g, 19.8 mmol) in THF (10 mL) was added, and the mixture was stirred at −78° C. under nitrogen for 1.5 hours. A solution of N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (7.78 g, 21.8 mmol) in THF (10 mL) was added over 20 minutes. The mixture was allowed to warm slowly to room temperature and stirred overnight. The reaction was quenched with NaHCO3, and the crude product was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain tert-butyl 3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-1-carboxylate (6.17 g, 87%).

[0418] Step 2: To a solution of tert-butyl 3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-1-carboxylate (6.17 g, 17.2 mmol) in toluene (50 mL) was added bis(pinacoroto)diboron (6.32 g, 25.8 mmol), followed by triphenylphosphine (451.1 mg, 1.72 mmol), potassium phenoxide (3.4 g, 25.8 mmol), and dichlorobis(triphenylphosphine)palladium(II) (1.21 g, 1.72 mmol). The resulting mixture was stirred for 3 hours at 55° C. The resulting mixture was cooled to room temperature and stirred overnight. The resulting mixture was diluted with saturated aqueous NaHCO3 and EtOAc. The layers were separated, and the organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography to obtain tert-butyl 3-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (1.81 g, 31%).

[0419] Step 3: To a solution of tert-butyl 3-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (1.1 g, 3.3 mmol) in 1,4-dioxane (32 mL) and HO (8 mL) was added 2-(4-chlorophthalazin-1-yl)-5-(trifluoromethyl)phenol (1.0 g, 3.0 mmol), Pd(PPh) (346.5 mg, 0.3 mmol), and KCO (829.2 mg, 6.0 mmol). The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 3 hours. The reaction mixture was extracted with EtOAc. The organic solution was washed with brine, dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 3-(1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)vinyl)piperidine-1-carboxylate (392 mg, 26%).

[0420] Step 4: To a solution of tert-butyl 3-(1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)vinyl)piperidine-1-carboxylate (145 mg, 0.29 mmol) in EtOAc (5 mL) was added Pd / C (100 mg). The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction mixture was filtered and washed with MeOH. The residue was concentrated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl 3-(1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)ethyl)piperidine-1-carboxylate (72.4 mg, 48%).

[0421] Step 5: A solution of tert-butyl 3-(1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)ethyl)piperidine-1-carboxylate (72.4 mg, 0.14 mmol) in DCM (8 mL) was cooled to 0° C. TFA (1 ml) was added dropwise slowly, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC to give 2-(4-(1-(piperidin-3-yl)ethyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (compound 22) (9.5 mg, 14%). ESI-MS (EI + , m / z):402.3.

[0422] Example 23: Synthesis of 3-(hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)-1-methylpiperidin-4-one (Compound 23)

[0423] [ka]

[0424] Step 1: To a solution of methyl 6-chloropyridazine-3-carboxylate (30.0 g, 174 mmol) in toluene (450 mL) and HO (50 mL), (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (42.0 g, 191 mmol), Pd(dppf)Cl (10.0 g, 17.4 mmol), and KPO (73.9 g, 348 mmol) were added. The resulting mixture was stirred at 100 °C for 2 h. The reaction solution was diluted with water, extracted with EtOAc, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give methyl 6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazine-3-carboxylate (31.0 g, 57%) as a yellow solid.

[0425] Step 2: To a solution of methyl 6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazine-3-carboxylate (25.0 g, 80.1 mmol) in THF (400 mL) and MeOH (80 mL) was added LiBH (60 mL, 2 M in THF, 1.5 equiv.) slowly at 0 °C. The resulting mixture was stirred at room temperature under N for 1 h. The reaction solution was quenched with water, extracted with EtOAc, dried over NaSO, filtered, and concentrated in vacuo to give (6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methanol (20.0 g, 88%) as a white solid.

[0426] Step 3: To a solution of (6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methanol (19.0 mg, 66.9 mmol) in DCM (500 mL) was added Dess-Martin periodinane (42.4 g, 100 mmol) slowly at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction solution was quenched with water, extracted with DCM, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazine-3-carbaldehyde (7.0 g, 37%) as a yellow solid.

[0427] Step 4: To a solution of 6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazine-3-carbaldehyde (500 mg, 1.7 mmol) in 1-methylpiperidin-4-one (960 mg, 8.5 mmol) was added (S)-proline (20 mg, 0.17 mmol). The resulting mixture was stirred at room temperature under N for 16 hours. The reaction solution was diluted with DCM and concentrated in vacuo. The residue was purified by silica gel column chromatography to give 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)-1-methylpiperidin-4-one (450 mg, 67%) as a white solid.

[0428] Step 5: To a solution of 3-(hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)-1-methylpiperidin-4-one (30 mg, 0.08 mmol) in DCM (0.5 mL) was added BBr (0.5 mL) dropwise at 0° C. under N. The resulting mixture was stirred for 2 hours at 40° C. The reaction solution was diluted with MeOH and concentrated in vacuo. The residue was purified by preparative HPLC to give 3-(hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)-1-methylpiperidin-4-one (compound 23) (7.5 mg, 26%, anti:syn=2:1) ​​as a brown solid. ESI-MS (EI+ ,m / z):382.15.

[0429] Example 24: Synthesis of (R)-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)((R)-1-methylpiperidin-3-yl)methanol (Compound 24)

[0430] [ka]

[0431] Step 1: 3-Methylfuran (1.0 g, 1.0 equiv.), NBS (2.3 g, 1.05 equiv.), and AIBN (0.16 g, 0.08 equiv.) were combined in anhydrous dioxane (25 mL) degassed under N in a sealed tube and heated at 50° C. for 2 h to give a solution of 2-bromo-3-methylfuran in dioxane, which was used directly in the next step.

[0432] Step 2: To a solution of 2-bromo-3-methylfuran was added (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (3.0 g, 1.12 equiv.), CsCO (10 g, 2.5 equiv.), Pd(PPh) (0.7 g, 0.05 equiv.), and degassed DI water (25 mL). The resulting mixture was heated at 1...

Claims

1. Formula (I) 【Chemistry 1】 A compound thereof, or a pharmaceutically acceptable salt or solvate thereof, During the ceremony, L is -C(R 9a)(R 9b)-, -C(O)-, or -C(=N- OR 16)-, R1, R2, R3, R4, and R5 are each independently hydrogen, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, C1-9 heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13 , -C(O)R 13 , -S(O)R 13 , -OC(O)R 13 , -C(O)N(R 10 )(R 11 ), -C(O)C(O)N(R 10 )(R 11 ), -N(R 12 )C(O)R 13 , -S(O) 2R 13 , -S(O) 2 N(R 10 )(R 11 )-, S(=O)(=NH)N(R 10 )(R 11 ), -CH 2 C(O)N(R 10 )(R 11 ), -CH 2 N(R 12 )C(O)R 13 , -CH 2 S(O) 2 R 13 , and -CH 2 S(O) 2 N(R 10) (R11) is selected, where C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -OR10, and -N (R10) (R11), or R1 and R2 These are combined to form a 4-membered, 5-membered, or 6-membered cycloalkyl ring, a 4-membered, 5-membered, or 6-membered heterocycloalkyl ring, a 5-membered, or 6-membered heteroaryl ring, or a phenyl ring, which may be optionally substituted with one, two, or three R14 groups, or R2 and R3 groups.When combined, they form a 4-membered, 5-membered, or 6-membered cycloalkyl ring, a 4-membered, 5-membered, or 6-membered heterocycloalkyl ring, a 5-membered, or 6-membered heteroaryl ring, or a phenyl ring, and thealkyl ring, a 5-membered, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-membered, 5-membered, or 6-membered cycloalkyl ring, a 4-membered, 5-membered, or 6-membered heteroalkyl ring, a 5-membered, or 6-membered heteroaryl ring, or a phenyl ring, are optionally substituted with one, two, or three R14 groups, or R3 and R4 when combined, they form a 4-membered, 5-membered, or 6-membered cycloalkyl ring, a 4-membered, 5-membered, or 6-membered heteroalkyl ring, a 5 R14 groups are optionally substituted, or R4 and R5 are combined to form a 4-membered, 5-membered, or 6-membered cycloalkyl ring, a 4-membered, 5-membered, or 6-membered heterocycloalkyl ring, a 5-membered, or 6-membered heteroaryl ring, or a phenyl ring, and the 4-membered, 5-membered, or 6-membered cycloalkyl ring, a 4-membered, 5-membered, or 6-membered heterocycloalkyl ring, a 5-membered, or 6-membered heteroaryl ring, or a phenyl ring, which are optionally substituted with one, two, or three R14 groups. R 6 is, 【Chemistry 2】 And, R 6a is selected from C 1-6 alkyl groups optionally substituted with hydrogen and one, two, or three R 14 groups. R7 and R8 are each independently selected from hydrogen, halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl, where C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, -OR10, and -N(R10)(R11). R9a and R9b are independently selected from hydrogen, halogen, -OH, C1-6 alkyl, C1-6 haloalkyl, and C1-6 alkoxy, Each R10 is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl, where C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl. R11 is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. R12 is independently selected from hydrogen, C1-6 alkyl, and C1-6 haloalkyl. Each of R13 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl, where C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl. Each of the R14 groups is independently a halogen, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, C1-9 heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, ​​-S(O)R13 Selected from -OC(O)R13, ​​-C(O)N(R10)(R11), -C(O)C(O)N(R10)(R11), -N(R12)C(O)R13, ​​-S(O)2R13, -S(O)2N(R10)(R11)-, S(=O)(=NH)N(R10)(R11), -CH2C(O)N(R10)(R11), -CH2N(R12)C(O)R13, ​​-CH2S(O)2R13, and -CH2S(O)2N(R10)(R11), where C1-6 Alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogens, -CN, C1-6 alkyl, C1-6 haloalkyl, -OR 10, and -N(R 10)(R 11). Each of the R15 groups is independently a halogen, oxo, -CN, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, C1-9 heteroaryl, -OR10, -SR10, -N(R10)(R11), -C(O)OR10, -OC(O)N(R10)(R11), -N(R12)C(O)N(R10)(R11), -N(R12)C(O)OR13, -N(R12)S(O)2R13, -C(O)R13, ​​-S(O)R 13, -OC(O)R 13, -C(O)N(R 10)(R 11), -C(O)C(O)N(R 10)(R 11), -N(R 12)C(O)R 13, -S(O) 2R 13, -S(O) 2N(R 10)(R 11)-, S(=O)(=NH)N(R 10)(R 11), -CH 2C(O)N(R 10)(R 11), -CH 2N(R 12)C(O)R 13, -CH 2S(O) 2R 13, and -CH 2S(O) 2N(R 10)(R 11) are selected, where C 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C2-9 heterocycloalkyl, C6-10 aryl, and C1-9 heteroaryl are optionally substituted with one, two, or three groups selected from halogens, -CN, C1-6 alkyl, C1-6 haloalkyl, -OR10, and -N(R10)(R11). R16 is selected from hydrogen and C1-6 alkyl, and, A compound, or a pharmaceutically acceptable salt or solvate thereof, where n is 0, 1, 2, 3, or 4.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is a C 1-6 alkyl group optionally substituted with one, two, or three R 14 groups.

3. The compound according to claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is an unsubstituted C1-6 alkyl group.

4. The compound according to claim 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is -CH3.

5. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

6. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C1-6 alkyl.

7. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, or -OH.

8. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH.

9. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, R4 is hydrogen, and R5 is hydrogen.

10. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is a C1-6 alkyl or a C1-6 haloalkyl.

11. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a)(R 9b)-.

12. The compound according to claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is selected from hydrogen, halogen, and C1-6 alkyl, and R 9b is selected from hydrogen, halogen, and -OH.

13. The compound according to claim 12, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is hydrogen and R 9b is -OH. 【Request Item 14】 【Chemistry 3-1】 【Chemistry 3-2】 A compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, selected from the above. 【Request Item 15】 【Chemistry 4】 The compound according to claim 14, or a pharmaceutically acceptable salt or solvate thereof. 【Request Item 16】 【Chemistry 5】 The compound according to claim 14, or a pharmaceutically acceptable salt or solvate thereof.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

18. Use of the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a drug for treating metabolic diseases, liver diseases, lung diseases, central nervous system diseases, cardiovascular diseases, inflammatory diseases or autoimmune diseases in patients requiring treatment.

19. The metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout; the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, and cirrhosis; the lung disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis; and the central nervous system disease is Alzheimer's disease. The use according to claim 18, wherein the cardiovascular disease is selected from rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, traumatic brain injury, ischemic stroke and reperfusion, hemorrhagic stroke, epilepsy, and depression, the cardiovascular disease being atherosclerosis or stroke, and the inflammatory disease or autoimmune disease being selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

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