NLRP3 modulators

Abstract

Described herein are NLRP3 modulators and methods of treating diseases, disorders, or conditions using the NLRP3 modulators. Also described herein are pharmaceutical compositions containing such compounds.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 320,157, filed March 15, 2022, and U.S. Provisional Application No. 63 / 356,415, filed June 28, 2022, each of which is incorporated herein by reference in its entirety. Background Art

[0003] The NOD-like receptor (NLR) family pyrin domain-containing protein 3 (NLRP3) inflammasome is a key component of the innate immune response and inflammatory processes. Its aberrant activity is pathogenic in inherited diseases such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease, and atherosclerosis. Current treatments for NLRP3-related diseases include biologics targeting IL-1. Small molecule inhibitors of NLRP3 offer an attractive alternative to these biologics given their potential to improve safety, patient comfort, and adherence. Summary of the Invention

[0004] In one aspect, provided herein is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof:

[0005]

[0006] in:

[0007] L is -C(R 9a )(R 9b )-, -C(O)- or -C(=N-OR 16 )-;

[0008] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 by one, two or three R 14or R and R are 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 by one, two or three R 14 or R and R are 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 by one, two or three R 14 or R4 and R5 are 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 by one, two or three R 14 group substitution;

[0009] R6 is

[0010] R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three R 14 Group substitution; or R 6a and R 15 together form a bridge, said bridge being -CH2- or -CH2CH2-;

[0011] R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group consisting of: R7 and R8; or R7 and R8 are 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 by one, two or three R 14 group substitution;

[0012] R 9a and R 9b are independently selected from hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy;

[0013] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0014] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0015] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0016] Each R 13 Independently selected from 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, 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0017] Each R 14 independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0018] Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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)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 )、-CH2C(O)N(R 10 )(R 11 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group substituted; or two R 15 together form a bridge, said bridge being -CH2- or -CH2CH2-;

[0019] R 16 Selected from hydrogen and C 1-6 alkyl; and

[0020] n is 0, 1, 2, 3 or 4.

[0021] In another aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0022]

[0023] in:

[0024] L is -C(R 9a )(R 9b)-, -C(O)- or -C(=N-OR 16 )-;

[0025] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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, C2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 by one, two or three R 14 or R and R are 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 by one, two or three R 14 or R and R are 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 by one, two or three R 14 or R4 and R5 are 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 by one, two or three R 14 group substitution;

[0026] R6 is

[0027] R 6a Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 group substitution;

[0028] R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group consisting of: R7 and R8; or R7 and R8 are 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 by one, two or three R 14 group substitution;

[0029] R 9a and R 9b are independently selected from hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy;

[0030] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0031] Each R 11 are independently selected from hydrogen, C1-6 Alkyl and C 1-6 alkyl halide;

[0032] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0033] Each R 13 Independently selected from 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0034] Each R 14 independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0035] Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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(R10 )(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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0036] R 16 Selected from hydrogen and C 1-6 alkyl; and

[0037] n is 0, 1, 2, 3 or 4.

[0038] In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3.

[0039] In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0040] In some embodiments is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0041] In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11In some embodiments, the compound is of formula (I') or (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 C 1-6 In some embodiments, the compound of formula (I') or (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, the compound is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen. In some embodiments, the compound is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, the compound is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen. In some embodiments, the compound is a compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3.

[0042] In some embodiments are compounds of Formula (I') or (I), or pharmaceutically acceptable salts or solvates 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, 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 replaced by one, two, or three R 14 In some embodiments 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.

[0043] In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. In some embodiments, the compound 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, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, the compound 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, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 In some embodiments, the compound 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 is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.

[0044] In some embodiments, the 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, the 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, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b In some embodiments, the compound is of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a Selected from hydrogen, halogen and C 1-6 In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R9a In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9b In some embodiments, the compound of formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 9b is -OH. In some embodiments is a compound of Formula (I') or (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

[0045] In one aspect, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0046]

[0047] in:

[0048] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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(R10 )(R 11 )-、S(=O)(=NH)N(R 10 )(R 11 )、-CH2C(O)N(R 10 )(R 11 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 by one, two or three R 14 or R and R are 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 by one, two or three R 14 or R and R are 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 by one, two or three R 14 or R4 and R5 are 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 by one, two or three R 14 group substitution;

[0049] R6 is

[0050] R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three R 14 Group substitution; or R 6a and R 15 together form a bridge, said bridge being -CH2- or -CH2CH2-;

[0051] R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group consisting of: R7 and R8; or R7 and R8 are 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 by one, two or three R 14 group substitution;

[0052] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated 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, C2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0053] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0054] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0055] Each R 13 Independently selected from 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0056] Each R 14 independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9Heterocycloalkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0057] Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group substituted; or two R 15 together form a bridge, said bridge being -CH2- or -CH2CH2-; and

[0058] n is 0, 1, 2, 3 or 4.

[0059] In another aspect, provided herein is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof:

[0060]

[0061] in:

[0062] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 by one, two or three R 14 or R and R are 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 by one, two or three R 14 or R and R are 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 by one, two or three R 14 or R4 and R5 are 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 by one, two or three R 14 group substitution;

[0063] R6 is

[0064] R 6a Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 group substitution;

[0065] R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group consisting of: R7 and R8; or R7 and R8 are 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 by one, two or three R 14 group substitution;

[0066] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, C1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0067] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0068] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0069] Each R 13 Independently selected from 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0070] Each R 14 independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0071] Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11) group; and

[0072] n is 0, 1, 2, 3 or 4.

[0073] In some embodiments, the compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 In some embodiments, the compound is of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, the compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3.

[0074] In some embodiments, the compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0075] In some embodiments is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0076] In some embodiments, the compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 In some embodiments, the compound is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, C 1-6 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, the compound is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen. In some embodiments, the compound is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, the compound is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen. In some embodiments, the compound is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3.

[0077] In some embodiments are compounds of formula (II) or (III), or pharmaceutically acceptable salts or solvates 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, 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 replaced by one, two, or three R 14 In some embodiments, the compound is of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted phenyl ring.

[0078] In some embodiments, the compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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, the compound is of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C1-6 Alkyl, C 1-6 In some embodiments, the compound is a compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. In some embodiments, the compound is a compound of formula (II) or (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, the compound of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, the compound of formula (II) or (III), 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, the compound is of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 In some embodiments, the compound of formula (II) or (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 is a compound of Formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.

[0079] In some embodiments, the 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, the compound is of formula (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 alkyl.

[0080] In another aspect, described herein is a pharmaceutical composition comprising a compound of Formula (I'), (I), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0081] In some embodiments described herein is a method of treating a metabolic disease in a patient in need thereof, 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 is a method of treating a metabolic disease in a patient in need thereof, 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 metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity and gout.

[0082] In some embodiments described herein is a method of treating a liver disease in a patient in need thereof, 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 is a method of treating a liver disease in a patient in need thereof, 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.

[0083] In some embodiments, described herein is a method of treating a lung disease in a patient in need thereof, 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 is a method of treating a lung disease in a patient in need thereof, 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 lung disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis.

[0084] In some embodiments, described herein is a method of treating a central nervous system disease in a patient in need thereof, 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 is a method of treating a central nervous system disease in a patient in need thereof, 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.

[0085] In some embodiments described herein is 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), (II) or (III), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments described herein is 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), (II) or (III), 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.

[0086] In some embodiments, described herein is a method of treating a cardiovascular disease in a patient in need thereof, 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 is a method of treating a cardiovascular disease in a patient in need thereof, 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 cardiovascular disease is atherosclerosis or stroke.

[0087] Incorporation by reference

[0088] 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

[0089] definition

[0090] In the context of this disclosure, several terms will be used.

[0091] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as the commonly understood terms to which the claimed subject matter belongs. Where a term herein has multiple definitions, this section shall prevail. All patents, patent applications, publications and disclosed nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned herein are incorporated herein by reference. When referring to a URL or other such identifier or address, it should be understood that such identifiers may change, and that particular information on the internet may vary, but equivalent information can be found by searching the internet. Reference to this demonstrates the availability and public dissemination of such information.

[0092] It should be understood that the above general description and the following detailed description are exemplary and explanatory only and are not limitations on any subject matter claimed. In this application, unless otherwise expressly stated, the use of the singular includes the plural. It must be noted that the singular forms "a", "an" and "the" as used in the specification and the appended claims include plural references unless the context clearly dictates otherwise. In this application, the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "including" and other forms, such as "include", "includes" is non-restrictive.

[0093] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0094] Definitions of standard chemical terms can be found in reference works including, but not limited to, Carey and Sundberg "Advanced Organic Chemistry 4th Edition," Volumes A (2000) and B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used.

[0095] Unless clearly defined, the nomenclature used in combination with analytical chemistry, synthetic organic chemistry, and medicine and pharmaceutical chemistry as described herein and laboratory procedures and techniques therein are generally recognized in the art. Standard techniques can be used for chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery and the treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis and tissue culture and conversion (e.g., electroporation, lipofection). For example, the test kit of manufacturer's specifications or as generally completed in this area or as described herein, reaction and purification techniques can be performed. The aforementioned techniques and procedures can usually be performed by conventional methods and as described in the various general and more specific references cited and discussed throughout this specification.

[0096] It should be understood that the methods and compositions described herein are not limited to the specific methods, protocols, cell lines, constructs and reagents described herein and can therefore vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only and is not intended to limit the scope of the methods, compounds, and compositions described herein.

[0097] As used herein, C1-C x Including C1-C2, C1-C3...C1-C x C1-C x refers to the number of carbon atoms (excluding optional substituents) that make up the designated moiety.

[0098] An "alkyl" group refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, without unsaturation. In some embodiments, an "alkyl" group can have 1 to 6 carbon atoms (whenever it appears herein, a numerical range such as "1 to 6" refers to each integer within the given range; for example, "1 to 6 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. up to 6 carbon atoms (including 6 carbon atoms), but this definition also encompasses the occurrence of the term "alkyl" without specifying a numerical range). The alkyl groups of the compounds described herein can be designated as "C1-C6 alkyl" or similar names. 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 methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and hexyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, an alkyl group can be a monovalent group or a divalent group (i.e., an alkylene group).

[0099] "Alkoxy" refers to an "-O-alkyl" group where alkyl is as defined herein.

[0100] The term "alkenyl" refers to a straight or branched hydrocarbon chain 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 may have 2 to 6 carbons. An alkenyl group may be substituted or unsubstituted. Depending on the structure, an alkenyl group may be a monovalent group or a divalent group (i.e., an alkenylene group).

[0101] The term "alkynyl" refers to a straight or branched hydrocarbon chain 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 may have 2 to 6 carbon atoms. An alkynyl group may be substituted or unsubstituted. Depending on the structure, an alkynyl group may be a monovalent group or a divalent group (i.e., an alkynylene group).

[0102] "Amino" refers to a -NH2 group.

[0103] The term "alkylamine" or "alkylamino" refers to an -N(alkyl) x H y A group wherein alkyl is as defined herein and x and y are selected from x=1, y=1 and x=2, y=0. When x=2, the alkyl groups, together with the nitrogen to which they are attached, may optionally form a cyclic ring system. A "dialkylamino" group refers to an -N(alkyl)2 group wherein alkyl is as defined herein.

[0104] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. An aromatic ring can be formed by five, six, seven, eight, nine, or more than nine atoms. Aromatic compounds can be optionally substituted. The term "aromatic" includes aryl (e.g., phenyl, naphthyl) and heteroaryl (e.g., pyridyl, quinolinyl).

[0105] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. The aryl ring can be formed by five, six, seven, eight, nine, or more than nine carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Depending on the structure, the aryl group can be a monovalent group or a divalent group (i.e., an arylene group).

[0106] "Carboxyl" refers to -CO2H. In some embodiments, the carboxyl moiety can be replaced by 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. Carboxylic acid bioisosteres have similar biological properties as carboxylic acid groups. Compounds having a carboxylic acid moiety can have a carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties as compared to compounds containing carboxylic acids. For example, in one embodiment, a carboxylic acid bioisostere ionizes at physiological pH to approximately the same extent as a carboxylic acid group. Examples of bioisosteres of carboxylic acids include, but are not limited to wait.

[0107] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group in which each atom (i.e., backbone atom) forming the ring is a carbon atom. The cycloalkyl group may be saturated or partially unsaturated. The cycloalkyl group may be fused to an aromatic ring (in which case the cycloalkyl group is bonded to the non-aromatic ring carbon atom). In some embodiments, the cycloalkyl group includes groups having 3 to 10 ring atoms.

[0108] The term "heteroaryl" or "heteroaromatic" refers to an aromatic group that includes 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.

[0109] A "heterocycloalkyl" group or a "heteroalicyclic" group refers to a cycloalkyl group in which at least one of the backbone ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur. The group may be fused to an aryl or heteroaryl group. The term heteroalicyclic also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise indicated, heterocycloalkyl groups have 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is different from the total number of atoms (including heteroatoms) that constitute the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring).

[0110] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0111] 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 haloalkyl groups include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, etc.

[0112] 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 groups include -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, and the like. Non-limiting examples of fluoroalkoxy groups include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, and the like.

[0113] The term "heteroalkyl" refers to an alkyl group in which one or more backbone chain atoms are selected from atoms other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or a combination thereof). The heteroatom can be located at any internal 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-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3. In addition, up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Excluding the number of heteroatoms, a "heteroalkyl" group may have 1 to 6 carbon atoms.

[0114] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are considered part of a larger substructure.

[0115] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is generally a recognized chemical entity embedded in or appended to a molecule.

[0116] As used herein, a substituent "R" occurring alone without a numerical designation refers to a substituent selected from the group consisting of alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0117] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0118] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups individually and independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, -CN, alkyne, C1-C6 alkylalkyne, halogen, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino (including mono- and disubstituted amino groups (e.g., -NH2, -NHR, -N(R)2)) and protected derivatives thereof. For example, an optional substituent may be L s R s , where each L s is 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 each R s Independently selected from H, (C1-C6 alkyl), (C3-C8 cycloalkyl), aryl, heteroaryl, heterocycloalkyl and C1-C6 heteroalkyl. Protecting groups that can form protected derivatives of the above substituents can be found in sources such as Greene and Wuts mentioned above.

[0119] 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.

[0120] As used herein, the term "therapeutically effective amount" refers to an amount of a NLRP3 inhibitor that, when administered to a mammal in need thereof, is effective to at least partially ameliorate or at least partially prevent a condition or disease described herein.

[0121] As used herein, the term "expression" includes the process by which a polynucleotide is transcribed into mRNA and translated into a peptide, polypeptide, or protein.

[0122] The term "modulate" includes a decrease or increase in the activity or expression of a target molecule.

[0123] The term "activator" is used in this specification to refer to any molecular species that results in activation of a given receptor, whether the species itself binds to the receptor or a metabolite of the species binds to the receptor when the species is topically applied. Thus, an activator may be a ligand for the receptor, or it may be an activator that is metabolized to a ligand for the receptor, i.e., a metabolite that is formed in the tissue and is the actual ligand.

[0124] The term "patient" or "mammal" refers to a human, non-human primate, canine, feline, bovine, ovine, porcine, murine or other veterinary or laboratory mammal. One skilled in the art recognizes that a therapy that reduces the severity of pathology in one mammal is predictive of the efficacy of that therapy in another mammal.

[0125] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. Pharmaceutically acceptable salts of any of the compounds described herein are intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0126] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases which are not biologically or otherwise undesirable and 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 mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids such as arginates, gluconates, and galacturonates are also contemplated (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). The 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.

[0127] "Pharmaceutically acceptable base addition salts" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding inorganic or organic bases to the free acids. In some embodiments, pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, 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, ethylenediphenylamine, N-methylglucamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0128] As used herein, "treatment" or "treating" or "alleviating" or "improving" are used interchangeably herein. These terms refer to an approach for obtaining a beneficial or desired result, including but not limited to a therapeutic benefit and / or a prophylactic benefit. "Therapeutic benefit" refers to the eradication or amelioration of the underlying condition being treated. In addition, a therapeutic benefit can be achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying condition, such that an improvement is observed in the patient, even though the patient still suffers from the underlying condition. For a prophylactic benefit, the composition is administered to a patient at risk for developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even if a diagnosis of the disease has not yet been made.

[0129] NLRP3 modulators

[0130] NLRP3 is an intracellular signaling molecule that senses numerous pathogen-derived, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated speck-like proteins containing a caspase activation and recruitment domain (ASC). ASC then polymerizes to form large aggregates called ASC specks.

[0131] Aggregated ASC binds to the cysteine ​​protease caspase-1 to form a complex called the inflammasome. This leads to the activation of active caspase-1, which cleaves the precursor forms of the proinflammatory cytokines IL-1β and IL-18 (respectively called pro-IL-ιβ and pro-IL-18), thereby activating these cytokines. Caspase-1 also mediates a type of inflammatory cell death called pyroptosis. ASC speck aggregates can also recruit and activate caspase-8, which is able to process pro-IL-ιβ and pro-IL-18 and trigger apoptotic cell death.

[0132] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted from cells. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Through its control of the pyroptotic cell death pathway, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high mobility group protein 1 (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and release of IL-1α. In human cells, caspase-1 can also control the processing and secretion of IL-37. Many other caspase-1 substrates, such as components of the cytoskeleton and glycolytic pathways, may lead to caspase-1-dependent inflammation.

[0133] NLRP3-dependent ASC specks are released into the extracellular environment, where they can activate caspase-1, induce processing of caspase-1 substrates, and propagate inflammation. Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to shape the immune response to infection and injury. For example, IL-1β signaling induces the secretion of proinflammatory cytokines IL-6 and TNF. In the absence of T cell receptor engagement, IL-1β and IL-18 synergize with IL-23 to induce IL-17 production by memory CD4 Th17 cells and γδ T cells. IL-18 and IL-12 also synergize to induce IFN-γ production by memory T cells and NK cells, driving Th1 responses.

[0134] The inherited CAPS diseases 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, defining NLRP3 as a key component of the inflammatory process. NLRP3 has also been implicated in the pathogenesis of many complex diseases, particularly metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0135] The role of NLRP3 in central nervous system diseases is emerging, and lung diseases have also been shown to be influenced by NLRP3. In addition, NLRP3 plays a role in the development of liver disease, kidney disease, and aging. Many of these associations were defined using NLRP3 KO mice, but there are also insights into the specific activation of NLRP3 in these diseases. In type 2 diabetes (T2D), deposition of islet amylin in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0136] Current treatments for NLRP3-related diseases include biologics that target IL-1. These biologics are the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL1 receptor rilonacept. These approaches have been shown to be successful in the treatment of CAPS, and these biologics have been used in clinical trials for other IL-1β-related diseases. Small molecule inhibitors of NLRP3 offer an attractive alternative to these biologics given their potential to improve safety (minimal infection risk and ease of withdrawal compared to biologics), patient comfort, and compliance.

[0137] 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, can be used to treat NLRP3-related diseases, including but not limited to type 2 diabetes, atherosclerosis, obesity, and gout.

[0138] In some embodiments, provided herein is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof:

[0139]

[0140] in:

[0141] L is -C(R 9a )(R 9b )-, -C(O)- or -C(=N-OR 16 )-;

[0142] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C2-9 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11); or R1 and R2 are 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 replaced by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R4 and R5 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 group substitution;

[0143] R6 is

[0144] R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three R 14 Group substitution; or R 6a and R 15 together to form a bridge, the bridge being -CH2- or -CH2CH2-;

[0145] R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group consisting of: R7 and R8; or R7 and R8 are 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 by one, two or three R 14 group substitution;

[0146] R 9a and R 9b are independently selected from hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy;

[0147] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0148] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0149] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0150] Each R 13 Independently selected from 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0151] Each R 14 independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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)R13 、-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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0152] Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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(R10 )(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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group substituted; or two R 15 together to form a bridge, the bridge being -CH2- or -CH2CH2-;

[0153] R 16 Selected from hydrogen and C 1-6 alkyl; and

[0154] n is 0, 1, 2, 3 or 4.

[0155] In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a)(R 9b In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )-and R 9a Selected from hydrogen, halogen and C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )-and R 9b In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )-and R 9b Selected from hydrogen, halogen and -OH. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH2-. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(OH)-. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(CH3)-. In some embodiments, it is a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(OH)(CH3)-.

[0156] In some embodiments is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

[0157] In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )-. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )-and R 16 It is C 1-6 alkyl.

[0158] In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0159] In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0160] In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0161] In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from

[0162] In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0163] In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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, 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 In some embodiments, the 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 C 1-6 In some embodiments, the 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, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are C 1-6 In some embodiments, the compound is of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3. In some embodiments, the compound is of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, the compound is of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0164] In some embodiments, the 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 benzene 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 benzene ring is optionally replaced by one, two, or three R 14 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a benzene ring, which is optionally substituted by one, two or three R 14In some embodiments, the compound 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, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 5-membered or 6-membered heteroaryl ring, which is optionally replaced by one, two or three R 14 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5-membered or 6-membered heteroaryl ring. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-membered, 5-membered or 6-membered heterocycloalkyl ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound 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. In some embodiments, the 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, which is optionally substituted by one, two, or three R 14 In some embodiments is a compound 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.

[0165] In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OR 10In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CF3.

[0166] In some embodiments, the 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 10 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0167] In some embodiments, the 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 )(R11 In some embodiments, the compound 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, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH3. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CF3. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR 10 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OH. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(R 10 )(R 11 ).

[0168] In some embodiments, the 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, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CH3. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CF3. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OR 10 In some embodiments is a compound of Formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0169] In some embodiments, the 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, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CF3. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OR 10 In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OH. In some embodiments, the compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -N(R 10 )(R 11 ).

[0170] In some embodiments, provided herein is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0171]

[0172] in:

[0173] L is -C(R 9a )(R 9b )-, -C(O)- or -C(=N-OR 16 )-;

[0174] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 replaced by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R4 and R5 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 group substitution;

[0175] R6 is

[0176] R 6a Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 group substitution;

[0177] R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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, 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group consisting of: R7 and R8; or R7 and R8 are 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 by one, two or three R 14 group substitution;

[0178] R 9a and R 9b are independently selected from hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy;

[0179] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0180] Each R11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0181] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0182] Each R 13 Independently selected from 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0183] Each R 14 independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0184] Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0185] R 16 Selected from hydrogen and C 1-6 alkyl; and

[0186] n is 0, 1, 2, 3 or 4.

[0187] In some embodiments 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, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )-and R 9a Selected from hydrogen, halogen and C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )-and R 9b In some embodiments, the compound of formula (I), 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, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH2-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(OH)-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(CH3)-. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(OH)(CH3)-.

[0188] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

[0189] In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )-. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )-and R 16 It is C 1-6 alkyl.

[0190] In some embodiments is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6a It is C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0191] In some embodiments is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0192] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 In some embodiments, the 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, the 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, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are C 1-6 In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3. In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0193] In some embodiments are compounds 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, 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 replaced by one, two, or three R 14 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a benzene ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound 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, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 5-membered or 6-membered heteroaryl ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5-membered or 6-membered heteroaryl ring. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-membered, 5-membered or 6-membered heterocycloalkyl ring, which is optionally substituted by one, two or three R 14In some embodiments, the compound 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. In some embodiments, the 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, which is optionally substituted by one, two, or three R 14 In some embodiments is a compound 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.

[0194] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OR 10 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CF3.

[0195] In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C1-6 Haloalkyl or -OR 10 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0196] In some embodiments, the 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, the compound 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, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR 10In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OH. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(R 10 )(R 11 ).

[0197] In some embodiments, the 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, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CH3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OR 10 In some embodiments is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0198] In some embodiments, the 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, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CF3. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OR 10 In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OH. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -N(R 10 )(R 11 ).

[0199] In some embodiments, provided herein is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

[0200]

[0201] in:

[0202] L is -C(R 9a )(R 9b )-, -C(O)- or -C(=N-OR 16 )-;

[0203] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 replaced by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R4 and R5 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 group substitution;

[0204] R6 is

[0205] R 6a Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 group substitution;

[0206] R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group consisting of: R7 and R8; or R7 and R8 are 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 by one, two or three R 14 group substitution;

[0207] R 9a and R 9bare independently selected from hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy;

[0208] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0209] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0210] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0211] Each R 13 Independently selected from 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 1-9Heteroaryl is optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0212] Each R 14 independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13and -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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl,

[0213] -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0214] Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )(R11 )-、S(=O)(=NH)N(R 10 )(R 11 )、-CH2C(O)N(R 10 )(R 11 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0215] R 16 Selected from hydrogen and C 1-6 alkyl; and

[0216] n is 0, 1, 2, 3 or 4.

[0217] In some embodiments 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, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )-and R 9a Selected from hydrogen, halogen and C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )-and R 9b In some embodiments, the compound of formula (Ia), 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, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH2-. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(OH)-. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(CH3)-. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(OH)(CH3)-.

[0218] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

[0219] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )-. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )-and R 16 It is C 1-6 alkyl.

[0220] In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0221] In some embodiments, the compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, the 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, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are C 1-6 In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3. In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0222] In some embodiments is 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, 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 replaced by one, two, or three R 14 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a phenyl ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound 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, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 5-membered or 6-membered heteroaryl ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5-membered or 6-membered heteroaryl ring. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-membered, 5-membered or 6-membered heterocycloalkyl ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound 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. In some embodiments, the 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, which is optionally substituted by one, two, or three R 14 In some embodiments is a compound 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 cycloalkyl ring.

[0223] In some embodiments, the compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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 11In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OR 10 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CF3.

[0224] In some embodiments, the 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, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0225] In some embodiments, the compound of Formula (Ia), 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, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH3. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CF3. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR 10 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OH. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(R 10 )(R 11 ).

[0226] In some embodiments 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, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CH3. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CF3. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OR 10 In some embodiments is a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0227] In some embodiments 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, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CF3. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OR 10 In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OH. In some embodiments, the compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -N(R 10 )(R 11 ).

[0228] In some embodiments, provided herein is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:

[0229]

[0230] in:

[0231] L is -C(R 9a )(R 9b )-, -C(O)- or -C(=N-OR 16 )-;

[0232] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(R12 )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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 replaced by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R4 and R5 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 group substitution;

[0233] R6 is

[0234] R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group consisting of: R7 and R8; or R7 and R8 are 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 by one, two or three R 14 group substitution;

[0235] R 9a and R 9b are independently selected from hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy;

[0236] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C1-9 heteroaryl radical substitution;

[0237] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0238] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0239] Each R 13 Independently selected from 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0240] Each R 14 independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )(R11 )、-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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0241] Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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(R10 )(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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0242] R 16 Selected from hydrogen and C 1-6 alkyl; and

[0243] n is 0, 1, 2, 3 or 4.

[0244] In some embodiments 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, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )-and R 9a Selected from hydrogen, halogen and C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )-and R 9b In some embodiments, the compound of formula (Ib), 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, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH2-. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(OH)-. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -CH(CH3)-. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(OH)(CH3)-.

[0245] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

[0246] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )-. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OH)-. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(=N-OR 16 )-and R 16 It is C 1-6 alkyl.

[0247] In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0248] In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, the 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, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are C 1-6 In some embodiments, the compound is of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3. In some embodiments, the compound is of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, the compound is of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0249] In some embodiments is 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, 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 replaced by one, two, or three R 14 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a phenyl ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound 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, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 5-membered or 6-membered heteroaryl ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5-membered or 6-membered heteroaryl ring. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-membered, 5-membered or 6-membered heterocycloalkyl ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound 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. In some embodiments, the 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, which is optionally substituted by one, two, or three R 14 In some embodiments is a compound 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 cycloalkyl ring.

[0250] In some embodiments, the compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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 11In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OR 10 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CF3.

[0251] In some embodiments, the 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, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0252] In some embodiments, the compound of Formula (Ib), 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, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH3. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CF3. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR 10 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OH. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(R 10 )(R 11 ).

[0253] In some embodiments, the 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, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CH3. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CF3. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OR 10 In some embodiments is a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0254] In some embodiments, the 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, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CF3. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OR 10 In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OH. In some embodiments, the compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -N(R 10 )(R 11 ).

[0255] In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0256]

[0257]

[0258] in:

[0259] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13and -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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 replaced by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R4 and R5 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 group substitution;

[0260] R6 is

[0261] R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three R 14 Group substitution; or R 6a and R15 together to form a bridge, the bridge being -CH2- or -CH2CH2-;

[0262] R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group consisting of: R7 and R8; or R7 and R8 are 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 by one, two or three R 14 group substitution;

[0263] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0264] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0265] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0266] Each R 13 Independently selected from 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0267] Each R 14 independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0268] Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR10 、-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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group substituted; or two R 15 together form a bridge, the bridge being -CH2- or -CH2CH2-; and

[0269] n is 0, 1, 2, 3 or 4.

[0270] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0271] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0272] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0273] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from

[0274] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is

[0275] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 In some embodiments, the 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, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are C 1-6 In some embodiments, the compound is of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3. In some embodiments, the compound is of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, the compound is of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0276] In some embodiments, the 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 benzene 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 benzene ring is optionally replaced by one, two, or three R 14 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a benzene ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted phenyl ring. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 5-membered or 6-membered heteroaryl ring, which is optionally replaced by one, two or three R 14 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5-membered or 6-membered heteroaryl ring. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-membered, 5-membered or 6-membered heterocycloalkyl ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound 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. In some embodiments, the 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, which is optionally substituted by one, two, or three R 14 In some embodiments is a compound 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 cycloalkyl ring.

[0277] In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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 11In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OR 10 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CF3.

[0278] In some embodiments, the compound of formula (II), 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, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0279] In some embodiments, the compound of formula (II), 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, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH3. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CF3. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR 10 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OH. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(R 10 )(R 11 ).

[0280] In some embodiments, the 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, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CH3. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CF3. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OR 10 In some embodiments is a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0281] In some embodiments, the 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, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CF3. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OR 10 In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OH. In some embodiments, the compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -N(R 10 )(R 11 ).

[0282] In some embodiments, provided herein is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof:

[0283]

[0284] in:

[0285] R1, R2, R3, R4 and R5 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 and -CH2S(O)2N(R 10 )(R11 ), 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 replaced by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R4 and R5 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 group substitution;

[0286] R6 is

[0287] R 6a Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 group substitution;

[0288] R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group consisting of: R7 and R8; or R7 and R8 are 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 by one, two or three R 14 group substitution;

[0289] Each R 10 are independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0290] Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0291] Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0292] Each R 13 Independently selected from 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 optionally substituted by one, two or three radicals selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl radical substitution;

[0293] Each R 14 independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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)R13 、-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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group;

[0294] Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, 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(R10 )(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 )、-CH2N(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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group; and

[0295] n is 0, 1, 2, 3 or 4.

[0296] In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, the compound is of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is C 1-6 Alkyl, which is optionally substituted by one, two or three R 14In some embodiments, the compound is of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a In some embodiments, is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0297] In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0298] In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated 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 optionally substituted by one, two or three radicals selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are C 1-6 In some embodiments, the compound is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3. In some embodiments, the compound is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, the compound is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0299] In some embodiments, the 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 benzene 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 benzene ring is optionally replaced by one, two, or three R 14 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a benzene ring, which is optionally substituted by one, two or three R 14 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted phenyl ring. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 5-membered or 6-membered heteroaryl ring, which is optionally replaced by one, two or three R 14 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted 5-membered or 6-membered heteroaryl ring. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form a 4-membered, 5-membered or 6-membered heterocycloalkyl ring, which is optionally substituted by one, two or three R 14In some embodiments, the compound 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. In some embodiments, the 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, which is optionally substituted by one, two, or three R 14 In some embodiments is a compound 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 cycloalkyl ring.

[0300] In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OR 10 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is halogen. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CH3. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 In some embodiments is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CF3.

[0301] In some embodiments, the 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, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is halogen. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CH3. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -CF3. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OR 10 In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is -OH.

[0302] In some embodiments, the compound of formula (III), 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, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CH3. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6In some embodiments, the compound is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -CF3. In some embodiments, the compound is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen. In some embodiments, the compound is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is halogen. In some embodiments, the compound is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OR 10 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -OH. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is -N(R 10 )(R 11 ).

[0303] In some embodiments, the 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, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is halogen. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CH3. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -CF3. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OR 10 In some embodiments is a compound of Formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is -OH.

[0304] In some embodiments, the 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 11In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CH3. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is halogen. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is C 1-6 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -CF3. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OR 10 In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -OH. In some embodiments, the compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is -N(R 10 )(R 11 ).

[0305] In some embodiments, provided herein is a compound selected from:

[0306]

[0307]

[0308] or a pharmaceutically acceptable salt or solvate thereof.

[0309] In some embodiments, provided herein is a compound that is: or a pharmaceutically acceptable salt or solvate thereof.

[0310] In some embodiments, provided herein is a compound selected from:

[0311]

[0312] or a pharmaceutically acceptable salt or solvate thereof.

[0313] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof may be chosen by one skilled in the art to provide stable moieties and compounds.

[0314] In some embodiments, the 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, any of the compounds described above are suitable for use in any of the methods or compositions described herein.

[0315] Other forms of the compounds disclosed herein

[0316] Isomers

[0317] In addition, in some embodiments, the compounds described herein exist in the form of geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds proposed herein include all cis (cis, syn, entgegen (E)) and trans (trans, anti, zusammen (Z)) isomers and their corresponding mixtures. In some cases, the compounds exist in the form of tautomers. The compounds described herein include all possible tautomers within the formula described herein. In some cases, the compounds described herein have one or more chiral centers and each center exists in the R configuration or the S configuration. The compounds described herein include all diastereomers, enantiomers and epimers and their corresponding mixtures. In additional embodiments of the compounds and methods provided herein, enantiomers and / or mixtures of diastereomers produced by a single preparation step, combination or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatography of racemic mixtures. In some embodiments, compound as herein described is prepared as its single stereoisomer by making the racemic mixture of compound react with optically active resolving agent to form a pair of diastereomeric compounds, separate diastereoisomers and reclaim optically pure enantiomers. In some embodiments, preferably dissociable complex (for example, diastereomeric salt of crystallization). In some embodiments, diastereoisomers have different physical properties (for example, melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereoisomers are separated by chiral chromatography or preferably by separation / splitting technology based on solubility differences. In some embodiments, then optically pure enantiomer and resolving agent are reclaimed by any practical method that does not cause racemization.

[0318] Labeled compounds

[0319] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Therefore, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to the compounds described herein, but one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, such as 2 H. 3 H. 13 C. 14 C. l5 N. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds described herein that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives thereof, are within the scope of the present invention. Certain isotopically labeled compounds, for example, compounds incorporating radioactive isotopes (such as 3 H and 14 C) compounds that can be used in drug and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. 2 H) can produce certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In some embodiments, isotopically labeled compounds, their pharmaceutically acceptable salts, esters, solvates, hydrates or derivatives are prepared by any suitable method.

[0320] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0321] Pharmaceutically acceptable salts

[0322] In some embodiments, the compounds described herein exist in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0323] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a variety of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds described herein, or by separately reacting the purified free form of the compound with a suitable acid or base and isolating the salt thus formed.

[0324] Solvates

[0325] In some embodiments, the compounds described herein exist in the form of solvates. In some embodiments, methods of treating diseases by administering such solvates are described. Further described herein are methods of treating diseases by administering such solvates as pharmaceutical compositions.

[0326] Solvates contain stoichiometric or non-stoichiometric amounts of solvents, and in some embodiments, are formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed in the methods described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using an organic solvent including, but not limited to, dioxane, tetrahydrofuran, or MeOH. In addition, the compounds provided herein exist in unsolvated and solvated forms. In general, for some purposes of the compounds and methods provided herein, solvated forms are considered to be equivalent to unsolvated forms.

[0327] Synthesis of compounds

[0328] In some embodiments, the synthesis of the compounds described herein is accomplished using methods described in the chemical literature, using methods described herein, or by a combination thereof. Additionally, solvents, temperatures, and other reaction conditions may vary from those set forth herein.

[0329] In other embodiments, the starting materials and reagents used to synthesize the compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0330] In further embodiments, the compounds described herein and other related compounds having various substituents are synthesized using the techniques and materials described herein, as well as those recognized in the art, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley & Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementary Volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley & Sons, 1991), Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Edition (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Edition, Volumes A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Edition (Wiley 1999) (such disclosures are incorporated by reference). General methods for preparing compounds as disclosed herein can be derived from reactions, and reactions can be modified by using appropriate reagents and conditions to introduce various moieties present in the formulas provided herein. As a guide, the following synthetic methods can be used.

[0331] Use of protecting groups

[0332] In the described reaction, it may be necessary to protect the reactive functional groups required in the final product, such as hydroxyl, amino, imino, sulfenyl or carboxyl, to prevent them from unnecessarily participating in the reaction. Protective groups are used to block some or all of the reactive moieties and prevent such groups from participating in the chemical reaction until the protective group is removed. Preferably, each protective group can be removed in different ways. The protective group that cracks under completely different reaction conditions meets the requirement of difference removal.

[0333] Protecting groups can be removed by acid, base, reducing conditions (e.g., hydrogenolysis) and / or oxidizing conditions. Groups such as trityl, dimethoxytrityl, acetal, and tert-butyldimethylsilyl are acid unstable and can be used to protect carboxyl and hydroxyl reactive moieties in the presence of amino groups protected by Cbz groups (which can be removed by hydrogenolysis) and Fmoc groups (which are base unstable). Carboxylic acid and hydroxyl reactive moieties can be terminated with base unstable groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of acid unstable groups such as tert-butyl carbamate or acid-base stable but hydrolytically removable carbamate-terminated amines.

[0334] Carboxylic acid and hydroxyl reactive moieties may also be capped with hydrolytically removable protecting groups such as benzyl, while amine groups capable of forming hydrogen bonds with acids may be capped with base-labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds exemplified herein (including conversion to alkyl esters), or they may be capped with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be capped with fluoride-labile silylcarbamates.

[0335] Allyl-terminated groups are useful in the presence of acid- and base-protecting groups because they are stable and can subsequently be removed by metal or π-acid catalysts. For example, an allyl-terminated carboxylic acid can be treated with Pd in ​​the presence of acid-labile tert-butyl carbamate or base-labile acetamine protecting groups. 0 Catalyzed reactions remove the protection. 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, the functional group is blocked and cannot react. Once released from the resin, the functional group can react.

[0336] Capping / protecting groups can typically be selected from:

[0337]

[0338] Other protecting groups, as well as detailed descriptions of techniques suitable for the creation and removal of protecting groups, are described 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, the disclosures of which are incorporated herein by reference.

[0339] Treatment and prevention methods

[0340] In some embodiments, a method of treating a metabolic disease in a patient in need thereof comprises 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, a method of treating a metabolic disease in a patient in need thereof comprises 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 metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments, a method of treating type 2 diabetes in a patient in need thereof comprises 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, a method of treating atherosclerosis in a patient in need thereof comprises 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, a method of treating obesity in a patient in need thereof comprises 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, a method of treating gout in a patient in need thereof comprises 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.

[0341] In some embodiments, a method of treating a liver disease in a patient in need thereof comprises 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, a method of treating a liver disease in a patient in need thereof comprises 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 liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, or cirrhosis.

[0342] In some embodiments 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 I'), (I), (Ia), (Ib), (II) or (III), or a pharmaceutically acceptable salt or solvate thereof, wherein the pulmonary disease is selected from asthma, COPD and idiopathic pulmonary fibrosis.

[0343] In some embodiments, a method of treating a central nervous system disease in a patient in need thereof comprises 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 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 comprises 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, a method of treating multiple sclerosis in a patient in need thereof comprises 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, a method of treating amyotrophic lateral sclerosis in a patient in need thereof comprises 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, a method of treating multiple sclerosis in a patient in need thereof comprises 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, a method of treating Parkinson's disease in a patient in need thereof comprises 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, a method of treating Huntington's disease in a patient in need thereof comprises 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, a method of treating traumatic brain injury in a patient in need thereof comprises 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, a method of treating ischemic stroke and reperfusion in a patient in need thereof comprises 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, a method of treating stroke in a patient in need thereof comprises 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, a method of treating epilepsy in a patient in need thereof comprises 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, a method of treating depression in a patient in need thereof comprises 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.

[0344] In some embodiments is a method 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 I'), (I), (Ia), (Ib), (II), or (III), or a pharmaceutically acceptable salt or solvate thereof.

[0345] In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof comprises 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, a method of treating an inflammatory or autoimmune disease in a patient in need thereof comprises 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 rheumatoid arthritis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof comprises 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 multiple sclerosis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof comprises 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 psoriasis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof comprises 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 lupus. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof comprises 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, a method of treating an inflammatory or autoimmune disease in a patient in need thereof comprises 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 Crohn's disease. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need thereof comprises 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 ulcerative colitis.

[0346] In some embodiments, a method of treating a cardiovascular disease in a patient in need thereof comprises 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, a method of treating a cardiovascular disease in a patient in need thereof comprises 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, a method of treating atherosclerosis in a patient in need thereof comprises 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, a method of treating a stroke in a patient in need thereof comprises 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.

[0347] Pharmaceutical compositions and methods of administration

[0348] The NLRP3 inhibitors described herein are administered to a subject in a biocompatible form suitable for administration to treat or prevent a disease, disorder, or condition. 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.

[0349] 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 chosen route of administration and standard pharmaceutical practice, such as described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub. Co., Easton, PA (2005)).

[0350] Thus, provided herein is a pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt as described herein, and 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 is not harmful to the recipient (i.e., subject) of the composition.

[0351] In some embodiments, a pharmaceutical composition comprises 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 comprises a pharmaceutically acceptable carrier and a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof.

[0352] 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. 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. 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. 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. In some embodiments, a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of Formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments is a pharmaceutical composition consisting essentially of a pharmaceutically acceptable carrier and a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof.

[0353] In certain embodiments, a compound as described herein is substantially pure in that it contains less than about 5% or less than about 1% or less than about 0.1% of other small organic molecules, such as contaminating intermediates or by-products produced during one or more steps of the synthetic methods.

[0354] These formulations include those suitable for oral, topical, buccal, parenteral (eg, subcutaneous, intramuscular, intradermal, or intravenous) or aerosol administration.

[0355] Exemplary pharmaceutical compositions are used in the form of pharmaceutical preparations (e.g., solid, semisolid or liquid forms) comprising one or more disclosed compounds as active ingredients, mixed with organic or inorganic carriers or excipients suitable for external, enteral or parenteral application. In some embodiments, the active ingredients are compounded with pharmaceutically acceptable, conventional non-toxic carriers, such as for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions and any other suitable form of administration. The amount of active target compound included in the pharmaceutical composition is sufficient to produce the desired effect on the disease process or condition.

[0356] In some embodiments, the NLRP3 inhibitors described herein are administered to a subject in a biocompatible form suitable for topical administration to treat or prevent a skin disease, disorder, or condition. "Biocompatible form suitable for topical administration" refers to a form of the NLRP3 inhibitor to be administered in which any toxic effects are outweighed by the therapeutic effects of the inhibitor. 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.

[0357] Topical administration of NLRP3 inhibitors can be presented in the form of an aerosol, a semisolid pharmaceutical composition, a powder or a solution. The term "semisolid composition" refers to an ointment, cream, ointment, jelly or other pharmaceutical composition having a substantially similar consistency suitable for application to the skin. Examples of semisolid compositions are given in Chapter 17 of The Theory and Practice of Industrial Pharmacy by 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.

[0358] Dermal 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 include those that control the rate at which the drug is delivered to the skin. Patches can provide a variety of drug delivery systems, including reservoir systems or monolithic systems. For example, a reservoir design can 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 waterproof backing. Such a design delivers a uniform amount of drug over a specified time period, and the delivery rate must be less than the saturation limit of different skin types. For example, a monolithic design typically has only three layers: an adhesive layer, a polymer matrix containing the compound, and a waterproof backing. Such a design brings the skin to a saturation level of drug. Therefore, delivery is controlled by the skin. As the amount of drug in the patch decreases below the saturation level, the delivery rate decreases.

[0359] In one embodiment, the topical composition may be in 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 DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, in particular based on water-in-oil or oil-in-water microemulsions, optionally with the addition of liposomes. Suitable penetration enhancers (entrainers) include sulfoxide derivatives, such as dimethyl sulfoxide (DMSO) or decyl methyl sulfoxide (decyl-MSO) and transcutol (diethylene glycol monoethyl ether) or cyclodextrins; and 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 dodecyl urea, 1,3-didodecyl urea, 1,3-diphenyl urea; and terpenes, such as D-limonene, menthone, α-terpineol, carvone, limonene oxide or 1,8-cineole.

[0360] Ointments, pastes, emulsions and gels can also contain excipients, such as starch, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonites, silicic acid and talc, or their mixtures. Powders and sprays can also contain excipients, such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these materials. The solution of nanocrystalline antimicrobial metal can be converted into aerosols or sprays by conventional any known method for making aerosol medicines. Usually, such methods comprise pressurization or are provided for the device (usually using inert carrier gas) that pressurizes the solution container and pressurized gas is passed through a small orifice. Sprays can also contain conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0361] The carrier may also contain other pharmaceutically acceptable excipients for changing or maintaining the pH, osmotic pressure, viscosity, transparency, color, sterility, stability, dissolution rate or odor of the formulation. The anti-skin aging composition may further comprise an antioxidant, a sunscreen, a natural retinoid (e.g., retinol) and other additives commonly found in skin treatment compositions.

[0362] In some embodiments for preparing solid compositions (such as tablets), the main 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 such as water) to form a solid preformulation composition containing a homogeneous mixture of the disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is evenly dispersed throughout the composition, making it easy to subdivide the composition into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0363] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the subject compositions are mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as carboxymethylcellulose, hydroxypropyl methylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or gum arabic; (3) humectants such as Such as glycerol; (4) disintegrants, such as cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) solution retardants, such as paraffin; (6) absorption promoters, such as quaternary ammonium compounds; (7) wetting agents, for example, sodium docusate, cetyl alcohol and glyceryl monostearate; (8) absorbents, such as kaolin and bentonite; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, in some embodiments, the composition includes a buffer. In some embodiments, similar types of solid compositions are also used as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0364] In some embodiments, tablet is made by compression or molding, optionally with one or more auxiliary components. In some embodiments, binder (for example, gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surfactant or dispersant are used to prepare compressed tablets. In some embodiments, molded tablets are prepared by molding the mixture of the subject composition moistened with an inert liquid diluent in a suitable machine. In some embodiments, tablet and other solid dosage forms (such as dragees, capsules, pills and granules) are scored or prepared with coating and shell (such as enteric coating and other coatings).

[0365] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject compositions, in some embodiments, the liquid dosage forms comprise inert diluents (e.g., water or other solvents), solubilizers, and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran methanol, polyethylene glycol, and fatty acid esters of sorbitan, cyclodextrins, and mixtures thereof.

[0366] In some embodiments, suspensions contain, in addition to the subject composition, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0367] In some embodiments, powders and sprays contain, in addition to the 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 also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0368] Alternatively, compositions and compounds disclosed herein can be administered by aerosol. This is achieved by preparing aqueous aerosols, liposome preparations or solid particles containing the compound. In some embodiments, non-aqueous (e.g., fluorocarbon propellants) suspensions are used. In some embodiments, sonic nebulizers are used because they minimize exposure of the medicament to shearing, which can cause degradation of the compound contained in the subject composition. Typically, aqueous aerosols are prepared by preparing an aqueous solution or suspension of the subject composition with a conventional pharmaceutically acceptable carrier and stabilizer. Carriers and stabilizers vary with the requirements of specific subject compositions, but typically include nonionic surfactants (Tweens, Pluronics or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols are typically prepared by isotonic solutions.

[0369] Pharmaceutical compositions suitable for parenteral administration comprise a combination of a subject composition with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders for reconstitution into sterile injectable solutions or dispersions prior to use, which in some embodiments contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0370] Examples of suitable aqueous and non-aqueous carriers for pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate) and cyclodextrins. Proper fluidity can be 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.

[0371] The dosage of the composition comprising at least one compound described herein varies depending on the condition of the patient (eg, human), ie, the stage of the disease, general health, age, and other factors.

[0372] Pharmaceutical composition is used in a manner suitable for the disease to be treated (or prevented). Suitable dosage and suitable duration of application and frequency will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the concrete form of active ingredient and the method of administration. Generally speaking, suitable dosage and treatment regimen provide compositions in an amount sufficient to provide treatment and / or prevention benefit (for example, improved clinical outcome such as more frequent complete or partial remission, or longer disease-free and / or total survival period, or the alleviating of symptom severity). Optimal dose is generally determined using experimental models and / or clinical trials. In some embodiments, optimal dose depends on the patient's body mass, body weight or blood volume.

[0373] Oral dosages generally range from about 1.0 mg to about 1000 mg, 1 to 4 or more times per day.

[0374] Dosage administration may be repeated depending on the pharmacokinetic parameters of the dosage formulation and the route of administration utilized.

[0375] Formulating the composition in dosage unit form is particularly advantageous for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to a physically discrete unit suitable as a unit dose for a mammalian subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect and the required pharmaceutical carrier. The specifications of the dosage unit form depend on and are directly dependent on (a) the unique properties of the NLRP3 inhibitor and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compounds for treating individual sensitivities. The specific dosage can be readily calculated by one of ordinary skill in the art, for example, based on the patient's approximate weight or body surface area or the volume of body space to be occupied. The dosage will also be calculated based on the specific route of administration selected. Further refinement of the calculations required to determine the appropriate dosage for treatment is routinely performed by one of ordinary skill in the art. Given the activity of the NLRP3 inhibitors disclosed herein in target cell assay formulations, one of ordinary skill in the art can perform such calculations without undue experimentation. The exact dosage is determined in conjunction with standard dose-response studies. It will be understood that the actual amount of composition administered will be determined by the practitioner according to the relevant circumstances, including the condition or conditions to be 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 route of administration chosen.

[0376] The toxicity and therapeutic efficacy of such NLRP3 inhibitors can be determined in cell culture or experimental animals, for example, by using LD 50 (a dose lethal to 50% of the population) and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio LD 50 / ED 50 NLRP3 inhibitors that exhibit large therapeutic indices are preferred. Although NLRP3 inhibitors that exhibit toxic side effects may be used, care should be taken to design delivery systems that target such inhibitors to the affected tissue site in order to minimize potential damage to uninfected cells and thereby reduce side effects.

[0377] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such NLRP3 inhibitors preferably lies within the range that includes the ED with little or no toxicity. 50The dose may vary within this range depending on the dosage form and route of administration employed. For any NLRP3 inhibitor used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC determined in cell culture. 50 (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. For example, levels in plasma can be measured by high performance liquid chromatography.

[0378] Example

[0379] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. All literature citations in these examples and throughout this specification are incorporated herein by reference for all legal purposes served thereby. The starting materials and reagents used to synthesize the compounds described herein can be synthetic or can be obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0380] This article uses the standard abbreviations and acronyms as defined in J.Org.Chem.2007 72(1):23A-24A. Other abbreviations and acronyms used in this article are as follows:

[0381]

[0382] Example 1: Synthesis of 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 1)

[0383]

[0384] 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, 21 mL in THF, 42 mmol) was added. The reaction mixture was warmed to room temperature for 2 h. The reaction mixture was vigorously stirred for 5 h under open air. 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 obtain (6-chloro-4,5-dimethylpyridazine-3-yl) (pyridin-3-yl)methanone (3 g).

[0385] Step 2: Under N2, (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), PdCl2(dppf) (80 mg, 10%) and Na2CO3 (290 mg, 2.0 equiv) were combined in dioxane (20 mL) and water (5 mL). The resulting mixture was heated at 100°C for 8 h. 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).

[0386] Step 3: (6-(2-Hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (200 mg, 1.0 eq) was dissolved in MeOH (10 mL) and THF (10 mL) and the solution was cooled to 0 ° C. NaBH4 (11 mg, 0.5 eq) was added at 0 ° C. The resulting mixture was stirred at 0 ° C for 15 min. The reaction was quenched with saturated NaHCO3. The mixture was extracted with EtOAc and the EtOAc solution was concentrated in vacuo to give 2-(6-(hydroxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (201 mg), which was used without further purification.

[0387] 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 eq) in MeOH (100 mL) and water (1 mL) was added PtO (98 mg, 0.8 eq). The mixture was degassed by bubbling N gas for 20 min and then hydrogenated under H (balloon) at room temperature for 15 h. 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.

[0388] Step 5: 2-(6-(hydroxy(piperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (185 mg, 1.0 eq) was dissolved in 1,2-dichloroethane (20 mL), and HCHO (48 mg, 37% in water, 1.2 eq) and 2 drops of AcOH were added. The mixture was stirred at room temperature for 30 min and NaBH(AcO)3 (165 mg, 1.5 eq) was added. The resulting mixture was stirred at room temperature for 30 min and quenched with saturated NaHCO3, and stirred at room temperature for 10 min. The mixture was extracted with DCM (4x25 mL) and the combined DCM extracts were concentrated in vacuo. The residue was purified by silica gel chromatography to obtain 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.

[0389] Stereoisomers 1A (a mixture of two compounds) and 1B (a mixture of two compounds) were separated by C18 preparative HPLC from compound 1. Peak 1 is stereoisomer 1A, and peak 2 is stereoisomer 1B.

[0390] Stereoisomers 1A ESI-MS (EI + ,m / z):396.2.

[0391] Stereoisomers 1B ESI-MS (EI + ,m / z):396.2.

[0392] Example 2: Synthesis of (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone (Compound 2)

[0393]

[0394] Step 1: Under N2, (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), PdCl2(dppf) (82 mg, 10%), and Na2CO3 (300 mg, 2.0 equiv) were combined in dioxane (20 mL) and water (5 mL). The resulting mixture was heated at 100°C for 8 h. 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).

[0395] Step 2: (6-(2-methoxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (260 mg, 1.0 eq) was dissolved in MeOH (20 mL) and THF (20 mL). To this solution was added NaBH4 (13 mg, 0.5 eq) at 0°C. The resulting mixture was stirred at 0°C for 30 min and quenched with saturated NaHCO3. 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.

[0396] 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 eq) in MeOH (100 mL) and water (1 mL) was added PtO (117 mg, 0.8 eq) and (Boc) O (168 mg, 1.2 eq). The mixture was degassed by bubbling N gas for 20 min and then hydrogenated under H (balloon) for 1.5 h at room temperature. The H balloon was then removed and the mixture was stirred at room temperature overnight. 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).

[0397] 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 eq) in anhydrous DCM (25 mL) was added DMP (268 mg, 1.2 eq) at 0°C and stirred at 0°C for 1 h. Additional DMP (30 mg) was added and the reaction was stirred at room temperature for 30 min 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).

[0398] 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 eq) in anhydrous DCM (20 mL) was added BBr (5 eq) at 0 ° C under N . The mixture was stirred at 0 ° C for 1 h and then at room temperature for 6 h. The reaction was quenched with water at 0 ° C and stirred at room temperature for 30 min. Saturated NaHCO was added to adjust the pH to approximately 10. The mixture was extracted with DCM (3x50 mL). The combined extracts were concentrated in vacuo to give (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazine-3-yl)(piperidin-3-yl)methanone (97 mg).

[0399] Step 6: Under the reaction conditions described in Step 5 of Example 1, (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-4,5-dimethylpyridazin-3-yl)(piperidin-3-yl)methanone (56 mg) was used to produce (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.

[0400] Example 3: Synthesis of 2-(6-(1-hydroxy-1-(1-methylpiperidin-3-yl)ethyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 3)

[0401]

[0402] A solution of compound 2 (6- (2-hydroxy-4- (trifluoromethyl) phenyl) -4,5-dimethylpyridazin-3-yl) (1-methylpiperidin-3-yl) methanone (15 mg) in anhydrous THF was treated with MeMgBr (2N, 76 ul, 4.0 equiv) at 0 ° C. The mixture was stirred at room temperature for 1 h. The reaction was quenched with saturated NH4Cl and extracted with DCM (3x20 mL). The combined extracts were concentrated in vacuo and the residue was purified on 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.

[0403] Example 4: Synthesis of 2-(6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 4)

[0404]

[0405] Step 1: (6-chloro-4,5-dimethylpyridazin-3-yl)(pyridin-3-yl)methanone (1.0 g, 1.0 eq) was dissolved in MeOH (20 mL) and THF (20 mL) and cooled to 0 ° C. NaBH4 (80 mg, 0.5 eq) was added at 0 ° C. The resulting mixture was stirred at 0 ° C for 15 min. The reaction was quenched with saturated NaHCO3. 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.

[0406] Step 2: At 0 ° C, to a solution of (6-chloro-4,5-dimethylpyridazine-3-yl)(pyridin-3-yl)methanol (300 mg, 1.0 eq) in anhydrous DCM (10 mL) was added DAST (388 mg, 2.0 eq). The mixture was stirred at room temperature overnight. Additional DAST (100 mg) was added and the reaction was stirred at room temperature for another 5 h. At 0 ° C, the reaction was quenched with saturated NaHCO3 and the aqueous phase was extracted with DCM (2x20 mL). The combined extracts were concentrated in vacuo and the residue was purified on a silica gel column to obtain 3-chloro-6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazine (174 mg).

[0407] Step 3: Under N2, 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), PdCl2(dppf) (40 mg, 10%), and Na2CO3 (130 mg, 2.0 equiv) were combined in dioxane (10 mL) and water (3 mL). The resulting mixture was heated at 100°C for 8 h. 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).

[0408] 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 eq) in anhydrous DCM (25 mL) was added DMP (268 mg, 1.2 eq) at 0°C and stirred at 0°C for 1 h. Additional DMP (30 mg) was added and the reaction was stirred at room temperature for 30 min and then quenched with saturated NaHCO3. 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.

[0409] Example 5: Synthesis of 2-(4,5-dimethyl-6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 5)

[0410]

[0411] Step 1: To a solution of compound 4 (120 mg) in MeOH (40 mL) was added PtO 2 (40 mg) and degassed under vacuum, followed by hydrogenation under balloon H 2 for 15 h. The catalyst was removed by passing through a pad of celite, 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).

[0412] Step 2: Under the reaction conditions described in Step 5 of Example 1, 2-(4,5-dimethyl-6-(piperidin-3-ylmethyl)pyridazin-3-yl)-5-(trifluoromethyl)phenol (92 mg) was used to produce 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.

[0413] Example 6: Synthesis of 2-(6-(methoxy(1-methylpiperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 6)

[0414]

[0415] Step 1: To a solution of 2-(6-(fluoro(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (100 mg) in anhydrous THF (2 mL) was added 2M NaOMe (2 mL) in MeOH. The resulting mixture was heated at 90 ° C overnight in a sealed tube. The mixture was cooled and diluted with water (40 mL) and extracted with ethyl acetate (3x40 mL). The combined extracts were concentrated in vacuo. The residue was purified on a silica gel column to obtain 2-(6-(methoxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (81 mg).

[0416] Step 2: To a solution of 2-(6-(methoxy(pyridin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (60 mg) was added PtO2 (25 mg) and degassed under vacuum and hydrogenated under balloon H2 for 15 h to give 2-(6-(methoxy(piperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (42 mg).

[0417] Step 3: Under the reaction conditions described in Step 5 of Example 1, 2-(6-(methoxy(piperidin-3-yl)methyl)-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol (42 mg) was used to produce 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.

[0418] Example 7: Synthesis of 3-fluoro-5-methyl-2-(6-((1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)phenol (Compound 7)

[0419]

[0420] Step 1: To 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 N2. The mixture was stirred at room temperature for 10 min and then at 70° C. for 1 h in a sealed tube. The mixture was cooled and the solvent was 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.

[0421] Step 2: tert-Butyl 3-((9-borabicyclo[3.3.1]nonane-9-yl)methyl)piperidine-1-carboxylate (200 mg, 1.0 eq), 3,6-dibromopyridazine (300 mg, 2.0 eq), PdCl2(dppf) (40 mg, 0.1 eq) and Na2CO3 (135 mg, 2.0 eq) were combined in dioxane (15 mL) and water (5 mL). The mixture was heated at 100 ° C for 15 h. 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).

[0422] Step 3: tert-Butyl 3-((6-bromopyridazin-3-yl)methyl)piperidine-1-carboxylate (50 mg, 1.0 eq), (2-fluoro-6-hydroxy-4-methylphenyl)boronic acid (31 mg, 1.3 eq), PdCl(dppf) (9 mg, 0.1 eq) and NaCO (30 mg, 2.0 eq) were combined in dioxane (5 mL) and water (2 mL). The mixture was heated at 100° C. for 8 h. 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).

[0423] 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 min and concentrated in vacuo to give 3-fluoro-5-methyl-2-(6-(piperidin-3-ylmethyl)pyridazin-3-yl)phenol HCl salt (35 mg).

[0424] Step 5: Under the reaction conditions described in Step 5 of Example 1, 3-fluoro-5-methyl-2-(6-(piperidin-3-ylmethyl)pyridazin-3-yl)phenol (35 mg) was used to produce 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.

[0425] Example 8: Synthesis of 3-fluoro-2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-5-methylphenol (Compound 8)

[0426]

[0427] Step 1: tert-Butyl 3-((6-bromopyridazin-3-yl)methyl)piperidine-1-carboxylate (100 mg, 1.0 eq.), SeO (4.0 eq.) in CHCN (2 mL) were heated at 135°C for 8 h in a microwave reactor. 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).

[0428] Step 2: at 0 ℃, tert-butyl 3-(6-hydroxypyridazine-3-carbonyl)piperidine-1-carboxylate (40 mg, 1.0 equivalents) and DMAP (40 mg) were dissolved in DCM (2 mL) and pyridine (1 mL). Tf2O (2.0 equivalents) in DCM (1 mL) was added dropwise at 0 ℃. The resulting mixture was stirred at room temperature for 15 h. 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 obtain tert-butyl 3-(6-(((trifluoromethyl)sulfonyl)oxy)pyridazine-3-carbonyl)piperidine-1-carboxylate (26 mg).

[0429] 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), PdCl2(dppf) (0.1 equiv) and Na2CO3 (2.0 equiv) were combined in toluene (3 mL) and water (1 mL). The mixture was heated at 85°C for 8 h. 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).

[0430] 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 min. 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).

[0431] Step 5: Under the reaction conditions described in Step 5 of Example 1, 3-fluoro-2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-5-methylphenol (Compound 8) (9 mg) was produced from 3-fluoro-2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-5-methylphenol TFA salt (18 mg). ESI-MS (EI + ,m / z):332.3.

[0432] Example 9: Synthesis of 2-(4-(hydroxy(1-methylpiperidin-3-yl)methyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (Compound 9)

[0433]

[0434] 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), PdCl2(dppf) (40 mg, 0.1 equiv) and Na2CO3 (135 mg, 2.0 equiv) were combined in dioxane (15 mL) and water (5 mL). The mixture was heated at 100°C for 15 h. 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).

[0435] 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), PdCl2(dppf) (15 mg, 0.1 equiv) and Na2CO3 (48 mg, 2.0 equiv) were combined in dioxane (5 mL) and water (2 mL). The mixture was heated at 100°C for 8 h. 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).

[0436] 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 min. The mixture was concentrated in vacuo to give 2-(4-(piperidin-3-ylmethyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol TFA salt (42 mg).

[0437] Step 4: Under the reaction conditions described in Step 5 of Example 1, 2-(4-(piperidin-3-ylmethyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol TFA salt (42 mg) was used to produce 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.

[0438] Example 10: Synthesis of 2-(6-(hydroxy(pyridin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 10)

[0439]

[0440] Step 1: At 0 ° C, under N2, NaH (4.2 g, 105 mmol, 60%) was added in batches to a degassed solution of 3,6-dichloro-4-methylpyridazine (8.2 g, 50 mmol) and 3-pyridylacetonitrile (6.1 g, 52 mmol) in anhydrous DMA (60 mL). The reaction mixture was stirred at 0 ° C for 1 h. At 0 ° C, m-CPBA (12 g, 72%) was added to the solution in batches over 10 min. At 0 ° C, the reaction mixture was diluted with EtOAc (200 mL) and stirred for another 10 min. Saturated NaHCO3 (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 (3x100 mL). The organic layer water (3X 100mL) that merges, saturated NaHCO (100mL), salt solution (100mL) washing and through Na SO Drying.Solvent is concentrated in a vacuum.Solid is supersound process in EtOAc (50mL), filtered, washed with EtOAc / hexane (1: 1) (20mL), and then at 50 ℃ in EtOAc / hexane (1: 1) (50mL) slurry 30min.Mixture is cooled to room temperature and solid is removed by filtration to obtain (6-chloro-5-methyl pyridazine-3-yl) (pyridin-3-yl) ketone (A-10) (4.2g).The mother liquor that merges is concentrated in a vacuum and purified on silica gel column to obtain (6-chloro-4-methyl pyridazine-3-yl) (pyridin-3-yl) ketone (B-10) (1.3g).

[0441] Step 2: (6-chloro-5-methylpyridazine-3-yl) (pyridin-3-yl)methanone (A-10) (1.0 g, 1.0 equivalent) was dissolved in MeOH (20 mL) and THF (20 mL) and cooled to 0 ° C. NaBH4 (81 mg, 0.5 equivalent) was added at 0 ° C. The resulting mixture was stirred at 0 ° C for 15 min. The reaction was quenched with saturated NaHCO3 and then extracted with ethyl acetate. The solvent was removed in vacuo to obtain (6-chloro-5-methylpyridazine-3-yl) (pyridin-3-yl) methanol (1.0 g), which was used without further purification.

[0442] Step 3: (6-Chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (1.0 g, 1.0 eq), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (1.14 g, 1.3 eq), PdCl2(dppf) (0.28 g, 0.1 eq) and Na2CO3 (0.9 g, 2.0 eq) were combined in dioxane (20 mL) and water (5 mL). The resulting mixture was heated at 100°C for 8 h. 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.

[0443] Example 11: Synthesis of 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 11)

[0444]

[0445] 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 eq) in MeOH (150 mL) and water (1 mL) was added PtO (0.35 g, 0.8 eq) and (Boc)O (0.47 g, 1.1 eq). The mixture was degassed by bubbling N gas for 20 min and then hydrogenated under H (balloon) at room temperature for 1.5 h. The H balloon was then removed and the mixture was stirred at room temperature overnight. 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).

[0446] 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 at room temperature for 25 min. The mixture was concentrated in vacuo. The residue was suspended in saturated NaHCO and then extracted with DCM (5x20 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 a free base, which was used without further purification.

[0447] Step 3: To a solution of 2-(6-(hydroxy(piperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (180 mg, 1.0 eq) in 1,2-dichloroethane (15 mL) was added HCHO (48 mg, 37% in water, 1.2 eq) and 2 drops of AcOH. The mixture was stirred at room temperature for 30 min and NaBH(AcO)3 (165 mg, 1.5 eq) was added. The resulting mixture was stirred at room temperature for 30 min, quenched with saturated NaHCO3, and stirred at room temperature for 10 min. The mixture was extracted with DCM (4x25 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.

[0448] Example 12: Synthesis of 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)-5-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 12)

[0449]

[0450] Compound 12 was prepared by the procedure described in Example 11 starting with B-10 from Example 10. ESI-MS (EI + ,m / z):382.3.

[0451] Example 13: Synthesis of (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(pyridin-3-yl)methanone (Compound 13)

[0452]

[0453] (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), PdCl2(dppf) (8 mg, 0.1 equiv) and Na2CO3 (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 h. 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.

[0454] Example 14: Synthesis of (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone (Compound 14)

[0455]

[0456]

[0146] 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 h. 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).

[0457] 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 eq) in MeOH (250 mL) and water (2 mL) was added PtO (530 mg, 0.8 eq) and (Boc) O (720 mg, 1.1 eq). The mixture was degassed by bubbling N gas for 20 min and then hydrogenated under H (balloon) for 1.5 h at room temperature. The H balloon was then removed and the mixture was stirred at room temperature overnight. 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).

[0458] 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 eq) in anhydrous DCM (30 mL) was added DMP (1.1 g, 1.2 eq) at 0° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched with saturated NaHCO 3 . The solvent 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).

[0459] 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 eq) in anhydrous DCM (30 mL) was added BBr (5 eq) at 0°C under N. The mixture was stirred at 0°C for 1 h and then at room temperature for 6 h. The reaction was quenched with water at 0°C, stirred at room temperature for 30 min, then adjusted to pH approximately 10 by the addition of saturated NaHCO and extracted with DCM (3 x 50 mL). (Boc)O (425 mg, 1.0 eq) was added to the DCM solution and the mixture was stirred at room temperature for 1 h. 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).

[0460] 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 min and concentrated in vacuo to provide (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazine-3-yl)(piperidin-3-yl)methanone TFA salt (62 mg).

[0461] Step 6: Under the reaction conditions described in Step 5 of Example 1, (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(piperidin-3-yl)methanone TFA salt (62 mg) was used to produce (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.

[0462] Example 15: Synthesis of 2-(6-(1-hydroxy-1-(1-methylpiperidin-3-yl)ethyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 15)

[0463]

[0464] A solution of (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone (Compound 14) (22 mg, 1.0 eq) in anhydrous THF (2 mL) was treated with MeMgBr (2N, 0.12 mL, 4.0 eq) at 0°C. The mixture was stirred at room temperature for 1 h, then quenched with saturated NH4Cl and extracted with DCM (4x20 mL). The combined extracts were concentrated and the residue was purified on 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.

[0465] Example 16: Synthesis of (6-(2-hydroxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanone oxime (Compound 16)

[0466]

[0467] 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 eq) in anhydride EtOH (2 mL) was added NH2OH (1.2 eq) and 2 drops of AcOH. The resulting mixture was heated at 50 ° C for 5 h 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.

[0468] 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)

[0469]

[0470] The product of step 4 of Example 14, 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).

[0471] Under the reaction conditions described in Step 3 of Example 1, compound 17-1 (90 mg) produced an 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 Step 4 of Example 7. The resulting amine intermediate HCl salt was reductively aminated using the method described in Step 5 of Example 1 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 chemical method, compound 17B (13 mg) was produced from compound 17-1B. ESI-MS (EI+ ,m / z):382.2.

[0472] 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). Deprotection and reductive amination of compound 17-2A (38 mg) and compound 17-2B (35 mg) produced 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.

[0473] Example 18: Synthesis of 2-(6-((S)-hydroxy((R)-1-methylpiperidin-3-yl)methyl-d)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (Compound 18)

[0474]

[0475] Under the reaction conditions described in Step 3 of Example 1, and replacing d4-MeOD and NaBD4, NaBD4 (0.5 equivalents) was added to peak 17-1 (120 mg) in d4-MeOD (2 mL) at 0°C to provide the intermediate alcohol (119 mg), which was separated by a chiral column to give peak 18-1A (65 mg) and peak 18-1B (40 mg). Intermediate peak 18-1B (40 mg) was treated with 4N HCl to produce an amine intermediate, which was reductively aminated 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.

[0476] Example 19: Synthesis of 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (Compound 19)

[0477]

[0478] Step 1: Under N2, at 0°C, to a degassed solution of 3,6-dichloropyridazine (3g, 20mmol) and pyridin-3-yl-acetonitrile (2.5g, 21mmol) in DMF (30mL) was added NaH (1.68g, 42mmol, 60%) in portions. The mixture was stirred at 0°C for 1h. mCPBA (4.8g, 20mmol, 72%) was added in portions and the mixture was diluted with EtOAc (200mL). The mixture was washed with water, aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The residue was triturated with hexane / EtOAc to give (6-chloropyridazine-3-yl)(pyridin-3-yl)methanone (2.3g).

[0479] Step 2: (6-Chloropyridazin-3-yl)(pyridin-3-yl)methanol (1.0 g) was produced from (6-chloropyridazin-3-yl)(pyridin-3-yl)methanone (1.0 g) under the reaction conditions described in Step 2 of Example 10.

[0480] Step 3: (6-chloropyridazin-3-yl)(pyridin-3-yl)methanol (600 mg, 1.0 eq), (2-hydroxy-4,6-dimethylphenyl)boronic acid (585 mg, 1.3 eq), PdCl2(dppf) (160 mg, 10%) and Na2CO3 (600 mg, 2.0 eq) were combined in dioxane (30 mL) and water (5 mL). The resulting mixture was heated at 100 ° C for 8 h. 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).

[0481] Step 4: 2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (120 mg) was produced from 2-(6-(hydroxy(pyridin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (100 mg) under the reaction conditions described in Step 4 of Example 1 and used without further purification.

[0482] Step 5: Under the reaction conditions described in Step 5 of Example 1, 2-(6-(hydroxy(piperidin-3-yl)methyl)pyridazin-3-yl)-3,5-dimethylphenol (120 mg, 1.0 equiv) produced 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.

[0483] Example 20: Synthesis of 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Compound 20)

[0484]

[0485] Step 1: 3-methyl-5-(trifluoromethyl)aniline (2.63g, 15mmol) is added to concentrated H2SO4 (30mL) in a solution in water (150mL) and the mixture is cooled to 0°C. By NaNO2 (1.1g, 16mmol) in water (10mL) is added dropwise to the mixture and the reaction is stirred at 0°C for 1h. Add concentrated H2SO4 (30mL) and the mixture is heated to 90°C for 5h. The mixture is cooled to room temperature and extracted with EtOAc. The combined organic layer is washed with salt water, through Na2SO4, dried, filtered and concentrated. The residue is purified by flash chromatography to obtain 3-methyl-5-(trifluoromethyl)phenol (2.2g).

[0486] Step 2: At 0 ° C, NaH (0.96 g, 24 mmol, 60%) was added to a solution of 3-methyl-5-(trifluoromethyl)phenol (2.1 g, 12 mmol) in toluene (60 mL). The suspension was stirred at 0 ° C for 30 min. Iodine (12 mmol) was slowly added 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 2N HCl. 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 purified by flash chromatography to obtain 2-iodo-3-methyl-5-(trifluoromethyl)phenol (2.7 g).

[0487] Step 3: at 0 ℃, (chloromethoxy) methane (0.8g, 10mmol) is added dropwise to a suspension of 2-iodo-3-methyl-5-(trifluoromethyl) phenol (2.4g, 8mmol) and CsCO(3.26g, 10mmol) in DMF (10mL). Through 2h, the reaction mixture is warmed to room temperature and diluted with EtOAc (50mL). The mixture is washed with water and salt water, through NaSODrying, filtered and concentrated. Residue is purified by flash chromatography to obtain 2-iodo-1-(methoxymethoxy)-3-methyl-5-(trifluoromethyl) benzene (2.3g).

[0488] 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)2 (67 mg, 0.3 mmol) and KOAc (0.6 g, 6 mmol) in anhydrous DMF (10 mL) was stirred at 100° C. for 10 h. The mixture was diluted with EtOAc, washed with water (3 times), brine and dried over Na2SO4. 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).

[0489] 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), PdCl2(dppf) (0.1 equiv) and Na2CO3 (2.0 equiv) were combined in dioxane (10 mL) and water (2 mL). The resulting mixture was heated at 100°C for 12 h. 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).

[0490] 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 eq) in MeOH (100 mL) and water (1 mL) was added PtO (0.8 eq) and (Boc) O (1.1 eq). The mixture was degassed by bubbling N gas for 20 min and then hydrogenated under H (balloon) for 1.5 h at room temperature. The H balloon was then removed and the mixture was stirred at room temperature overnight. 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).

[0491] 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 eq) in anhydrous DCM was added DMP (1.2 eq) at 0°C. The reaction mixture was stirred at 0°C for 1 h 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).

[0492] Step 8: at 0 ℃, under N 2, 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 equivalent) in anhydrous DCM (1 mL) was added TFA (1 mL). The mixture was stirred at 0 ℃ for 1 h, and then stirred at room temperature overnight. The reaction was concentrated in a vacuum. The residue was suspended in water and adjusted to pH 10 by adding saturated NaHCO 3 , and then extracted with DCM (3x50 mL). The combined organic layers were concentrated and the residue was purified on a silica gel column to obtain (6-(2-hydroxy-6-methyl-4-(trifluoromethyl)phenyl)pyridazine-3-yl)(piperidin-3-yl)methanone (28 mg).

[0493] Step 9: Under the reaction conditions described in Step 5 of Example 1, 2-(6-(hydroxy(1-methylpiperidin-3-yl)methyl)pyridazin-3-yl)-3-methyl-5-(trifluoromethyl)phenol (Compound 20) (11 mg) was produced 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.

[0494] Example 21: Synthesis of 3-((6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidin-3-ol (Compound 21)

[0495]

[0496] 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 an 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%).

[0497] Step 2: At -50 ° C, 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. The reaction mixture was stirred at -50 ° C for 30 min, 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 h, the mixture was quenched with NH4Cl (aqueous solution) (100 mL) and then extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with brine (100 mL) and dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 3-hydroxy-3-((6-(2-methoxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidine-1-carboxylate (1.32 g, 76%).

[0498] 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 (aqueous solution) (100 mL) and then extracted with DCM (3x50 mL). The combined organic layers were washed with brine (100 mL), dried over Na SO 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.

[0499] Example 22: Synthesis of 2-(4-(1-(piperidin-3-yl)ethyl)phthalazin-1-yl)-5-(trifluoromethyl)phenol (Compound 22)

[0500]

[0501] Step 1: At -78 ° C, under nitrogen, LiHMDS (1.0M in THF) (21.8mL, 21.8mmol) is added to THF (50mL). A solution of 1-(tetrahydro-2H-pyran-4-yl)ethanone (4.5g, 19.8mmol) in THF (10mL) is added and the mixture is stirred at -78 ° C under nitrogen for 1.5h. A solution of N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (7.78g, 21.8mmol) in THF (10mL) is added over 20 minutes. The mixture is allowed to slowly warm to room temperature and stirred overnight. The reaction is quenched with NaHCO3 and the crude product is extracted with EtOAc. The combined organic extracts are washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography to give tert-butyl 3-(1-(((trifluoromethyl)sulfonyl)oxy)vinyl)piperidine-1-carboxylate (6.17 g, 87%).

[0502] 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(pinacolato)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 allowed to stir at 55° C. for 3 h. The resulting mixture was cooled to room temperature and stirred overnight. The resulting mixture was diluted with saturated aqueous NaHCO solution 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 give tert-butyl 3-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)piperidine-1-carboxylate (1.81 g, 31%).

[0503] 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 H2O (8 mL) was added 2-(4-chlorophthalazin-1-yl)-5-(trifluoromethyl)phenol (1.0 g, 3.0 mmol), Pd(PPh3)4 (346.5 mg, 0.3 mmol) and K2CO3 (829.2 mg, 6.0 mmol). The reaction mixture was stirred at 90°C under a nitrogen atmosphere for 3 h. The reaction mixture was extracted with EtOAc. The organic solution was washed with brine, dried over Na2SO4 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%).

[0504] Step 4: To a solution of tert-butyl 3-(1-(4-(2-hydroxy-4-(trifluoromethyl)phenyl)phthalazin-1-yl)ethenyl)piperidine-1-carboxylate (145 mg, 0.29 mmol) in EtOAc (5 mL) was added Pd / C (100 mg). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 1 h. The reaction mixture was filtered and washed with MeOH. The residue was concentrated under vacuum. 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%).

[0505] 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.

[0506] Example 23: Synthesis of 3-(hydroxy(6-(2-hydroxy-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)-1-methylpiperidin-4-one (Compound 23)

[0507]

[0508] Step 1: To a solution of methyl 6-chloropyridazine-3-carboxylate (30.0 g, 174 mmol) in toluene (450 mL) and H2O (50 mL) was added (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid (42.0 g, 191 mmol), Pd(dppf)Cl2 (10.0 g, 17.4 mmol) and K3PO4 (73.9 g, 348 mmol). The resulting mixture was stirred at 100 ° C for 2 h. The reaction solution was diluted with water, extracted with EtOAc, dried over Na2SO4, 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.

[0509] 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 slowly added LiBH4 (60 mL, 2 M in THF, 1.5 eq) at 0°C. The resulting mixture was stirred at room temperature under N2 for 1 h. The reaction solution was quenched with water, extracted with EtOAc, dried over Na2SO4, 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.

[0510] 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 slowly added Dess-Martin periodinane (42.4 g, 100 mmol) 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.

[0511] 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 h. 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.

[0512] Step 5: At 0 ° C, under N2, 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 dropwise BBr3 (0.5 mL). The resulting mixture was stirred at 40 ° C for 2 h. 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%, trans: cis = 2: 1) as a brown solid. ESI-MS (EI + ,m / z):382.15.

[0513] Example 24: Synthesis of (R)-(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)((R)-1-methylpiperidin-3-yl)methanol (Compound 24)

[0514]

[0515] Step 1: Under N2, in a sealed tube, 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 degassed anhydrous dioxane (25 mL) 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.

[0516] Step 2: (2-methoxy-4-(trifluoromethyl)phenyl)boric acid (3.0 g, 1.12 equivalents), Cs CO (10 g, 2.5 equivalents), Pd(PPh ) (0.7 g, 0.05 equivalents) and degassed DI water (25 mL) were added to a solution of 2-bromo-3-methylfuran. The resulting mixture was heated at 110 ° C for 8 h. The reaction mixture was cooled to room temperature and diluted with hexane (120 mL). The organic phase was separated and the aqueous phase was re-extracted with hexane (30 mL). The combined organic phases were washed with water (50 mL), brine (50 mL) and concentrated in vacuo. The residue was purified on a silica gel column to provide 2-(2-methoxy-4-(trifluoromethyl)phenyl)-3-methylfuran (1.9 g, 61%) as an oil.

[0517] Step 3: At 0 ° C, to a solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (5.0 g, 1.0 equivalent) in DMF (20 mL) was added HBTU (10.33 g, 1.25 equivalents), N, O-dimethylhydroxylamine hydrochloride (2.6 g, 1.2 equivalents) and triethylamine (9 mL, 3.0 equivalents). The resulting mixture was stirred at 0 ° C for 1 h and then at room temperature for 5 h. The reaction mixture was diluted with acetate (80 mL) and hexane (80 mL), washed with saturated NaHCO3 aqueous solution (50 mL), water (3x50 mL), HCl (0.5N, 50 mL) and brine (50 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to give (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (5.4 g, 91%) as an oil.

[0518] Step 4: Under N2, at -30 ° C, to a solution of 2-(2-methoxy-4-(trifluoromethyl)phenyl)-3-methylfuran (500 mg, 1.0 eq) in anhydrous THF (25 mL) was added dropwise n-BuLi (2.5 M, 1.25 mL, 1.6 eq) over 5 min. After stirring at -30 ° C for another 45 min, a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (850 mg, 1.6 eq) in THF (4 mL) was added dropwise over 2 min at -30 ° C. The resulting mixture was stirred at 30 ° C for 30 min and then at room temperature for 2 h. At 0 ° C, the reaction was quenched with saturated NH4Cl (30 mL) and then extracted with DCM (2x50 mL). The combined organic phases were washed with brine and concentrated in vacuo. The crude mixture was purified on a silica gel column to give (R)-tert-butyl 3-(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-carbonyl)piperidine-1-carboxylate (749 mg, 82%, 100% ee).

[0519] Step 5: To a solution of (R)-tert-butyl 3-(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-carbonyl)piperidine-1-carboxylate (150 mg, 1.0 equiv) in DMF (0.3 mL) was added formic acid (150 mg, 10 equiv) and TEA (330 mg, 10 equiv) dropwise at 0° C. The mixture was degassed by bubbling N gas for 2 min at room temperature and then the catalyst chlororuthenium (1+); [(1R,2R)-1,2-diphenyl-2-(3-phenylpropylamino)ethyl]-(4-methylphenyl)sulfonylazanide (6 mg, 0.03 equiv) was added. The gained mixture was at room temperature stirred to 15h. The mixture was diluted with DCM (25mL), washed with water, saturated NaHCO and salt water. The crude mixture was purified on silica gel column to obtain (R)-3-((R)-hydroxy (5-(2-methoxy-4-(trifluoromethyl) phenyl)-4-methylfuran-2-yl) methyl) piperidine-1-tert-butyl formate (138mg, 92%, approximately 90% de).

[0520] Step 6: A solution of tert-butyl (R)-3-((R)-hydroxy(5-(2-methoxy-4-(trifluoromethyl)phenyl)-4-methylfuran-2-yl)methyl)piperidine-1-carboxylate (80 mg, 1.0 eq) in THF (5 mL) and water (0.5 mL) was stirred at -15 ° C (acetone-ice bath) for 10 min. Solid NBS (40 mg, 1.3 eq) was added portionwise. After stirring at -15 ° C for 30 min, hydrazine hydrate (86 mg, 10 eq) was added dropwise. The resulting mixture was stirred at 0 ° C for 1 h and then at room temperature for 3 h. The reaction was quenched with saturated NaHCO3 aqueous solution (10 mL) and extracted with DCM (2x15 mL). The combined organic phases were washed with brine and concentrated in vacuo. The crude mixture was purified on silica gel to give (R)-tert-butyl 3-((R)-hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate (75 mg, 92%).

[0521] Step 7: To a solution of tert-butyl (R)-3-((R)-hydroxy(6-(2-methoxy-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)methyl)piperidine-1-carboxylate (46 mg) in DCM (1 mL) was added HCl (4N in dioxane, 1 mL). The mixture was stirred at room temperature for 20 min under N2. The solvent was...

Claims

1. A compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof: in: L is -C(R 9a )(R 9b )-, -C(O)- or -C(=N-OR 16 )-; R1, R2, R3, R4 and R5 are each independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R4 and R5 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 Group substitution; R6 is R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three R 14 Group substitution; or R 6a and R 15 together form a bridge, said bridge being -CH2- or -CH2CH2-; R7 and R8 are each independently selected from 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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group replaces; or R7 and R8 are 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 replaced by one, two or three R 14 Group substitution; R 9a and R 9b are each independently selected from hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy; Each R 10 are independently selected from 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 optionally substituted by one, two or three selected from 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 Substitution of heteroaryl groups; Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 13 Independently selected from 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 optionally substituted by one, two or three selected from 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 Substitution of heteroaryl groups; Each R 14 are independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group; Each R 15 are independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group; or two R 15 together form a bridge, said bridge being -CH2- or -CH2CH2-; R 16 Selected from hydrogen and C 1-6 Alkyl; and n is 0, 1, 2, 3 or 4.

2. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: in: L is -C(R 9a )(R 9b )-, -C(O)- or -C(=N-OR 16 )-; R1, R2, R3, R4 and R5 are each independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R4 and R5 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 Group substitution; R6 is R 6a Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 Group substitution; R7 and R8 are each independently selected from 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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group replaces; or R7 and R8 are 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 replaced by one, two or three R 14 Group substitution; R 9a and R 9b are each independently selected from hydrogen, halogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy; Each R 10 are independently selected from 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 optionally substituted by one, two or three selected from 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 Substitution of heteroaryl groups; Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 13 Independently selected from 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 optionally substituted by one, two or three selected from 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 Substitution of heteroaryl groups; Each R 14 are independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group; Each R 15 are independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group; R 16 Selected from hydrogen and C 1-6 Alkyl; and n is 0, 1, 2, 3 or 4.

3. A compound as claimed in claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is 4. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 Group substitution.

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 alkyl.

6. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3.

7. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is 8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

9. The compound of claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from:

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from 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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group substitution.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6 alkyl.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen.

14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3.

15. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen.

16. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3.

17. A compound as described in any one of claims 1 to 9, 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 Group substitution.

18. The compound of claim 17, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted benzene ring.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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 ).

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or -OH.

21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or -OR 10 .

23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen.

24. The compound of any one of claims 1 to 23, 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 ).

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 Halogenated alkyl.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or -OR 10 .

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.

28. The compound of any one of claims 1 to 27, 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 ).

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 alkyl.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(R 9a )(R 9b )-.

31. The compound of claim 30, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a is selected from hydrogen, halogen and C 1-6 alkyl.

32. The compound of claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9a It's hydrogen.

33. A compound as claimed in claim 30 or claim 31, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9b Selected from hydrogen, halogen and -OH.

34. The compound of claim 33, or a pharmaceutically acceptable salt or solvate thereof, wherein R 9b It is -OH.

35. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt or solvate thereof, wherein L is -C(O)-.

36. A compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof: in: R1, R2, R3, R4 and R5 are each independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R4 and R5 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 group substitution; R6 is R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 Cycloalkyl, wherein C 1-6 Alkyl and C 3-6 The cycloalkyl group is optionally substituted by one, two or three R 14 Group substitution; or R 6a and R 15 together form a bridge, said bridge being -CH2- or -CH2CH2-; R7 and R8 are each independently selected from 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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group replaces; or R7 and R8 are 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 replaced by one, two or three R 14 group substitution; Each R 10 are independently selected from 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 optionally substituted by one, two or three selected from 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 Substitution of heteroaryl groups; Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 13 Independently selected from 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 optionally substituted by one, two or three selected from 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 Substitution of heteroaryl groups; Each R 14 are independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group; Each R 15 are independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group; or two R 15 together form a bridge, said bridge being -CH2- or -CH2CH2-; and n is 0, 1, 2, 3 or 4.

37. A compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof: in: R1, R2, R3, R4 and R5 are each independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ); or R1 and R2 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R and R are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 or R4 and R5 are 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 group substitution; R6 is R 6a Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 group substitution; R7 and R8 are each independently selected from 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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group replaces; or R7 and R8 are 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 replaced by one, two or three R 14 group substitution; Each R 10 are independently selected from 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 optionally substituted by one, two or three selected from 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 Substitution of heteroaryl groups; Each R 11 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 12 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; Each R 13 Independently selected from 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 optionally substituted by one, two or three selected from 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 Substitution of heteroaryl groups; Each R 14 are independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted by a group; Each R 15 are independently selected from 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 )、-CH2N(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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) is substituted with a group; and n is 0, 1, 2, 3 or 4.

38. A compound as claimed in claim 36 or claim 37, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is 39. A compound as described in any one of claims 36-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is C 1-6 Alkyl, which is optionally substituted by one, two or three R 14 Group substitution.

40. The compound of any one of claims 36-39, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a is unsubstituted C 1-6 alkyl.

41. A compound as described in any one of claims 36-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3.

42. A compound as claimed in claim 36 or claim 37, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is 43. The compound of any one of claims 36-42, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

44. The compound of claim 36, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a Selected from:

45. A compound as described in any one of claims 36-44, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from 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 optionally substituted by one, two or three selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 10 and -N(R 10 )(R 11 ) group substitution.

46. ​​A compound as described in any one of claims 36-45, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

47. A compound as described in any one of claims 36-46, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen and C 1-6 alkyl.

48. The compound of any one of claims 36-47, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are hydrogen.

49. The compound of any one of claims 36-47, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen and R8 is -CH3.

50. The compound of any one of claims 36-47, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3 and R8 is hydrogen.

51. A compound as described in any one of claims 36-47, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are -CH3.

52. A compound as described in any one of claims 36-44, 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 benzene 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 benzene ring is optionally substituted by one, two or three R 14 Group substitution.

53. The compound of claim 52, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 combine to form an unsubstituted benzene ring.

54. A compound as described in any one of claims 36-53, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 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 ).

55. A compound as described in any one of claims 36-54, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or -OH.

56. The compound of any one of claims 36-55, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH.

57. A compound as described in any one of claims 36-56, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or -OR 10 .

58. The compound of any one of claims 36-57, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen.

59. A compound as described in any one of claims 36-58, 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 ).

60. A compound as described in any one of claims 36-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 Halogenated alkyl.

61. A compound as described in any one of claims 36-60, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl or -OR 10 .

62. The compound of any one of claims 36-61, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.

63. A compound as described in any one of claims 36-62, 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 ).

64. A compound as described in any one of claims 36-63, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C 1-6 alkyl.

65. A compound selected from: or a pharmaceutically acceptable salt or solvate thereof.

66. A compound selected from: or a pharmaceutically acceptable salt or solvate thereof.

67. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 66, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

68. A method of treating a metabolic disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof.

69. The method of claim 68, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout.

70. A method of treating liver disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof.

71. The method of claim 70, wherein the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, and cirrhosis.

72. A method of treating a lung disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof.

73. The method of claim 72, wherein the pulmonary disease is selected from the group consisting of asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis.

74. A method of treating a central nervous system disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound as described in any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof.

75. The method of claim 74, wherein the central nervous system disease is selected from the group consisting of 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.

76. 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 any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof.

77. The method of claim 76, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

78. A method of treating cardiovascular disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-66, or a pharmaceutically acceptable salt or solvate thereof.

79. The method of claim 78, wherein the cardiovascular disease is atherosclerosis or stroke.

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