NLRP3 modulators

Abstract

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

Description

[0001] Cross-referencing This application claims the benefit of U.S. Provisional Patent Application No. 63 / 582,159, filed September 12, 2023, and U.S. Provisional Patent Application No. 63 / 665,921, filed June 28, 2024, each of which is incorporated herein by reference in its entirety. Background Technology

[0002] The inflammasome of protein 3 (NLRP3), a member of the NOD-like receptor (NLR) family containing a thermoprotein domain, is a key component of innate immune responses and inflammatory processes. Its aberrant activity is pathogenic in inherited diseases such as cryopreservation-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. Given the potential of small-molecule inhibitors of NLRP3 in improving safety, patient comfort, and adherence, they offer an attractive alternative to these biologics. Summary of the Invention

[0003] In one respect, this article provides compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof: ; in: X is N, N(R) 7a ), C(R7) or C(O); Y is N, N(R) 8a ), C(R8) or C(O); where one of X and Y is N, N(R 7a ) or N(R 8a ); Z is -L-R6. or ; L is -C(H)(OH)-; R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 10 -SR 10 -N(R) 10 (R) 11 -C(O)OR10 -OC(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)N(R 10 (R) 11 ), -N(R 12 )C(O)OR 13 -N(R) 12 )S(O)2R 13 -C(O)R 13 -S(O)R 13 -OC(O)R 13 -C(O)N(R) 10 (R) 11 -C(O)C(O)N(R) 10 (R) 11 ), -N(R 12 )C(O)R 13 -S(O)2R 13 -S(O)2N(R) 10 (R) 11 )-、S(=O)(=NH)N(R 10 (R) 11 -CH2C(O)N(R) 10 (R) 11 ), -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 The group R1 is substituted with a group R2; 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 heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally substituted with one, two, or three R2 groups. 14Group substitution; or combination of R2 and R3 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; or combination of R3 and R4 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; or combination of R4 and R5 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 and R8 are each independently selected from hydrogen, halogen, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; R 7a and R 8a Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; or two R groups 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; n is 0, 1, 2, 3, or 4; and This indicates a single or double bond, such that all valences are satisfied.

[0004] In some embodiments, the compound is of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ia): .

[0005] In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C. 1-6Alkyl group. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is hydrogen. In some embodiments, it is a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is -CH3.

[0006] In some embodiments, the compound is of formula (I), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ib): .

[0007] In some embodiments, it is a compound of formula (I) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a Selected from hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (I) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (I) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (I) or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is hydrogen.

[0008] In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 -C(O)OR 10 or -C(O)N(R) 10 (R) 11 In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6Alkyl group. In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OH or -OCH3. In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is hydrogen. In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 or -N(R) 10 (R) 11 In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 Haloalkyl. In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is hydrogen. In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 or -N(R) 10 (R) 11 In some embodiments, it is a compound of formula (I), (Ia), or (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C. 1-6 alkyl.

[0009] On the other hand, this article provides compounds of formula (II), or pharmaceutically acceptable salts or solvates thereof: ; in: X is N, N(R) 7a ), C(R7) or C(O); Y is N, N(R) 8a), C(R8) or C(O); Z is -L-R6. or ; L is -C(H)(OH)-; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 and R8 are each independently selected from hydrogen, halogen, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; R 7a and R 8a Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; R9 is optionally superimposed by one, two, or three Rs. 14 C with substituent group 1-9 Mixed aromatics; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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)R13 -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; or two R groups 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; n is 0, 1, 2, 3, or 4; and This indicates a single or double bond, such that all valences are satisfied.

[0010] In some embodiments, the compound is of formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIa): .

[0011] In some embodiments, it is a compound of formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (II) or (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (II) or (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R8 is hydrogen. In some embodiments, it is a compound of formula (II) or (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R8 is -CH3.

[0012] In some embodiments, the compound is of formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIb): .

[0013] In some embodiments, it is a compound of formula (II) or (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II) or (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (II) or (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is hydrogen. In some embodiments, it is a compound of formula (II) or (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is -CH3.

[0014] In some embodiments, the compound is of formula (II), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIc): .

[0015] In some embodiments, it is a compound of formula (II) or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a Selected from hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (II) or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (II) or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (II) or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is hydrogen.

[0016] In some embodiments, it is a compound of formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally composed of one, two, or three R... 14 A pyridyl group substituted with a functional group. In some embodiments, it is a compound of formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally composed of one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is or In some embodiments, it is a compound of formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is indole or benzofuranyl, wherein the indole and benzofuranyl are optionally separated by one, two, or three R9 groups. 14 Group substitution. In some embodiments, it is a compound of formula (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is indole or benzofuranyl, wherein the indole and benzofuranyl are optionally replaced by one, two, or three R groups. 14 Group substitution, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), (IIa), (IIb) or (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is... , or .

[0017] In some embodiments, Z is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein Z is -L-R6. In some embodiments, Z is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R6 is In some embodiments, Z is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is In some embodiments, Z is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), a pharmaceutically acceptable salt or solvate thereof, wherein Z is In some embodiments, it is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It can be arbitrarily determined by one, two, or three Rs. 14 C with substituent group 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R 6a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R 6a It is -CH3. In some embodiments, it is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from... , .

[0018] In some embodiments, Z is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is selected from... and In some embodiments, it is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0019] On the other hand, this article provides compounds of formula (III), or pharmaceutically acceptable salts or solvates thereof: ; in: R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, and carbon. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OR9; R6 is , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 and R8 are each independently selected from hydrogen, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups, wherein the alkyl group is optionally selected from -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; Each R9 is independently a C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; or two R groups 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; and n is 0, 1, 2, 3 or 4.

[0020] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIIa): ; in: R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, and carbon. 1-6Alkyl, C 1-6 Halogenated alkyl groups and -OR9; R 6a Selected from hydrogen and C 1-6 alkyl; R7 and R8 are each independently selected from hydrogen and C. 1-6 Alkyl; and Each R9 is independently a C 1-6 Halogenated alkyl groups.

[0021] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is hydrogen. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R8 is hydrogen. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R8 is C 1-6 alkyl.

[0022] In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, C 1-6 Halogenated alkyl group and -OR9. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OR9. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is hydrogen. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is hydrogen. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is C. 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is hydrogen. In some embodiments, it is a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is hydrogen.

[0023] In another aspect described herein, there is a pharmaceutical composition comprising a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III) or (IIIa), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0024] In some embodiments, this article describes a method for treating metabolic diseases in patients in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout.

[0025] In some embodiments, a method of treating liver disease in a patient in need of it is described herein, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method of treating liver disease in a patient in need of it is described herein, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation 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.

[0026] In some embodiments, a method of treating lung disease in a patient in need of it is described herein, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the lung disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis.

[0027] In some embodiments, this article describes a method for treating a central nervous system disorder in a patient in need of it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, this article describes a method for treating a central nervous system disorder in a patient in need of it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the central nervous system disorder 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.

[0028] In some embodiments, this article describes a method for treating inflammatory or autoimmune diseases in patients in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, this article describes a method for treating inflammatory or autoimmune diseases in patients in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation 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.

[0029] In some embodiments, this article describes a method for treating cardiovascular disease in a patient in need of it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, this article describes a method for treating cardiovascular disease in a patient in need of it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the cardiovascular disease is atherosclerosis or stroke.

[0030] Incorporation All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is specifically and individually indicated to be incorporated herein by reference. Detailed Implementation

[0031] definition In the context of this disclosure, several terms will be used.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood to apply to the subject matter to which the claims are made. Where multiple definitions exist for terms herein, this section shall prevail. All patents, patent applications, publications, and published nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned herein are incorporated herein by reference. When URLs or other such identifiers or addresses are referenced, it should be understood that such identifiers may change, and specific information on the Internet may vary, but equivalent information can be found by searching the Internet. References to these demonstrate the availability and public dissemination of such information.

[0033] It should be understood that the above general description and the following detailed description are exemplary and explanatory only, and not intended to limit any of the claimed subject matter. In this application, the use of the singular includes the plural unless otherwise expressly stated. It must be noted that, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” as used in the specification and appended claims include plural references. In this application, the use of “or” means “and / or” unless otherwise stated. Furthermore, the use of the term “comprising” and other forms is non-limiting.

[0034] The chapter titles used in this article are for organizational purposes only and should not be construed as limiting the topics described.

[0035] Definitions of standard chemical terms can be found in references, including but not limited to Carey and Sundberg, *Advanced Organic Chemistry, Fourth Edition*, Volume A (2000) and Volume B (2001), Plenum Press, New York. Unless otherwise noted, standard methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology are also used.

[0036] Unless explicitly defined, the nomenclature, laboratory procedures, and techniques described herein in conjunction with analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry are generally accepted in the art. Standard techniques are used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and patient treatment. Standard techniques are used in recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipid transfection). Reaction and purification techniques can be performed, for example, using manufacturer-specified kits or as commonly performed in the art or as described herein. The foregoing techniques and procedures can generally be performed by conventional methods and are described in the various general and more specific references cited and discussed throughout this specification.

[0037] 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 therefore can be varied. 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.

[0038] As used in this article, C1-C x Including C1-C2, C1-C3...C1-C x C1-C x It refers to the number of carbon atoms that make up its specified part (excluding optional substituents).

[0039] An alkyl group is a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturation. In some embodiments, an alkyl group may have 1 to 6 carbon atoms (wherever it appears herein, a numerical range such as "1 to 6" refers to each integer within a given range; for example, "1 to 6 carbon atoms" means that an alkyl group can consist of 1, 2, 3, etc., up to 6 carbon atoms (inclusive), but this definition also covers the occurrence of the term "alkyl" without a specified numerical range). The alkyl group in the compounds described herein may be specified as "C1-C6 alkyl" or similar names. By way of example only, "C1-C6 alkyl" indicates that the alkyl chain has 1 to 6 carbon atoms, 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 may be substituted or unsubstituted. Depending on the structure, an alkyl group may be a monovalent or divalent group (i.e., alkylene).

[0040] "Alkoxy" refers to "-O-alkyl" group, where alkyl is as defined herein.

[0041] The term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only 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, the alkenyl group may have 2 to 6 carbons. The alkenyl group may be substituted or unsubstituted. Depending on the structure, the alkenyl group may be a monovalent group or a divalent group (i.e., an alkenyl group).

[0042] The term "alkynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only 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, the alkynyl group may have 2 to 6 carbons. The alkynyl group may be substituted or unsubstituted. Depending on the structure, the alkynyl group may be a monovalent group or a divalent group (i.e., an alkynyl group).

[0043] "Amino" refers to the -NH2 group.

[0044] The term "alkylamine" or "alkylamino" refers to a -N(alkyl)xHy group, wherein the alkyl group is as defined herein, and x and y are selected from the group consisting of x=1, y=1 and x=2, y=0. When x=2, the alkyl group, together with the nitrogen to which it is attached, may optionally form a cyclic ring system. "Dialkylamino" refers to a -N(alkyl)2 group, wherein the alkyl group is as defined herein.

[0045] The term "aromatic family" refers to a family containing 4n+2 elements. electron delocalization -A planar ring of an electronic system, where n is an integer. Aromatic rings can be formed of 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).

[0046] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. An aryl ring can be formed of five, six, seven, eight, nine, or more than nine carbon atoms. The aryl group can optionally be 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 or divalent group (i.e., an arylene).

[0047] "Carboxyl group" refers to -CO2H. In some embodiments, the carboxyl moiety may be replaced by a "carboxylic acid bioisostere," which is a functional group or moiety exhibiting similar physical and / or chemical properties to the carboxylic acid moiety. Carboxylic acid bioisosteres have similar biological properties to the carboxylic acid group. Compounds having a carboxylic acid moiety may have a carboxylic acid moiety exchanged with a carboxylic acid bioisostere and have similar physical and / or biological properties to compounds containing carboxylic acids. For example, in one embodiment, a carboxylic acid bioisostere ionizes at physiological pH to approximately the same degree as a carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to, those mentioned above. , , , , , , , wait.

[0048] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group, wherein each atom forming the ring (i.e., the skeleton atom) is a carbon atom. The cycloalkyl group can be saturated or partially unsaturated. The cycloalkyl group can be fused with an aromatic ring (in which case the cycloalkyl group is bonded through the carbon atoms of the non-aromatic ring). In some embodiments, the cycloalkyl group comprises a group having 3 to 10 ring atoms.

[0049] The term "heteroaryl" or "heteroarylene" refers to an aryl group comprising one or more cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. The "heteroarylene" or "heteroaryl" part containing N refers to an aromatic group in which at least one skeletal atom of the ring is a nitrogen atom.

[0050] A "heterocyclic alkyl" group or "heterocyclic aliphatic" group refers to a cycloalkyl group in which at least one skeletal ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur. The group may be fused with an aryl or heteroaryl group. The term heterocyclic also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise stated, heterocyclic alkyl 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 heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is different from the total number of atoms constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring) (including heteroatoms).

[0051] The term "halogenated" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0052] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. The halogens may be the same or they may be different. Non-limiting examples of haloalkyl groups include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, etc.

[0053] The terms "fluoroalkyl" and "fluoroalkoxy" respectively include alkyl and alkoxy groups substituted with one or more fluorine atoms. Non-limiting examples of fluoroalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, etc. Non-limiting examples of fluoroalkoxy groups include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, etc.

[0054] The term "heteroalkyl" refers to an alkyl group in which one or more skeletal chain atoms are selected from atoms other than carbon (e.g., oxygen, nitrogen, sulfur, phosphorus, silicon, or combinations thereof). Heteroatoms can be located in 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-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. Furthermore, at most two heteroatoms can be consecutive, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. In addition to the number of heteroatoms, "heteroalkyl" can have 1 to 6 carbon atoms.

[0055] The term “bond” or “single bond” refers to a chemical bond between two atoms, or, when atoms connected by a bond are considered part of a larger substructure, to a chemical bond between two parts.

[0056] The term "part" refers to a specific segment or functional group of a molecule. A chemical part is generally a recognized chemical entity that is embedded in or attached to a molecule.

[0057] As used herein, a substituent “R” appearing alone without a numerical designation refers to a substituent selected from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (by cyclic carbon bonding), and heterocycloalkyl.

[0058] "Optional" or "optionally" means that the event or situation described below may or may not occur, and the description includes instances where the event or situation occurs and instances where it does not occur.

[0059] The terms "optionally substituted" or "substituted" mean that the mentioned group can be substituted, individually and independently, by one or more additional groups selected from 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 monosubstituted and disubstituted amino groups (e.g., -NH2, -NHR, -N(R)2)) and their protected derivatives). For example, the optional substituent may be L s R s , where each L s Independently selected from bonds, -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 The protecting groups are independently selected from H, (C1-C6 alkyl), (C3-C8 cycloalkyl), aryl, heteroaryl, heterocycloalkyl, and C1-C6 heteroalkyl. Protecting groups that can form protective derivatives of the above substituents are found in sources such as Greene and Wuts mentioned above.

[0060] 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.

[0061] As used herein, the term "therapeuticly effective dose" refers to an amount of NLRP3 inhibitor that, when administered to a mammal in need, effectively at least partially improves or at least partially prevents the condition or disease described herein.

[0062] As used in this article, the term “expression” includes the process by which polynucleotides are transcribed into mRNA and translated into peptides, polypeptides, or proteins.

[0063] The term "regulation" includes a decrease or increase depending on the activity or expression of the target molecule.

[0064] The term "activator" is used in this specification to refer to any class of molecules that causes activation of a specified receptor, whether the class itself binds to the receptor upon topical application or a metabolite of the class binds to the receptor. Therefore, an activator can be a ligand of the receptor, or it can be an activator metabolized into a receptor ligand, i.e., a metabolite formed in the tissue and which is the actual ligand.

[0065] The terms "patient" or "mammal" refer to humans, non-human primates, dogs, cats, cattle, sheep, pigs, rats, or other veterinary or laboratory mammals. Those skilled in the art recognize that a therapy that reduces the severity of a pathology in one mammal has predictive significance for the efficacy of that therapy in another mammal.

[0066] "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. The pharmaceutically acceptable salts of any compound described herein are intended to cover 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.

[0067] "Pharmaceutically acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base, 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, and phosphorous acid. It also includes salts formed with organic acids such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalkanes, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and including, 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, and salicylic acid. Therefore, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate, caprylates, sebates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Salts of amino acids, such as arginine salts, gluconates, and galacturons (see, for example, Berge SM et al., "..."), are also considered. Pharmaceutical Salts,” Journal of Pharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basic compounds are prepared by contacting a free base with a sufficient amount of the desired acid to produce a salt.

[0068] "Pharmaceutically acceptable base addition salts" refer to those salts that retain the biological effectiveness and properties of the free acid and are not undesirable in biological or other respects. These salts are prepared by adding an inorganic or organic base to the free acid. In some embodiments, pharmaceutically acceptable base addition salts are formed with a metal or amine (such as alkali metals and alkaline earth metals or organic amines). Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from organic bases include, but are not limited to, salts of the following: 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-methylglucosamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. See Berge et al. above.

[0069] As used herein, the terms “treatment,” “relief,” or “improvement” are used interchangeably. These terms refer to methods of achieving a beneficial or desired outcome, including, but not limited to, therapeutic and / or preventative benefits. A “therapeutic benefit” means the eradication or improvement of an underlying condition that is being treated. Furthermore, a therapeutic benefit is achieved by the eradication or improvement of one or more physical symptoms associated with the underlying condition, resulting in an observed improvement in the patient, even though the patient still has the underlying condition. For preventative benefits, the composition is administered to a patient at risk of developing a specific disease, or to a patient who reports one or more physical symptoms of a disease, even if the disease has not yet been diagnosed.

[0070] NLRP3 regulator NLRP3 is an intracellular signaling molecule that senses many pathogen-derived, environmental, and host-derived factors. Upon activation, NLRP3 binds to apoptosis-associated spot-like proteins containing caspase activation and recruitment domains (ASC). The ASCs then aggregate to form large aggregates called ASC spots.

[0071] Aggregated ASCs associate with the cysteine ​​protease caspase-1 to form a complex called an inflammasome. This leads to the activation of active caspase-1, which cleaves the precursor forms of the pro-inflammatory cytokines IL-1β and IL-18 (referred to as pro-IL-1β and pro-IL-18, respectively), thereby activating these cytokines. Caspase-1 also mediates an inflammatory cell death process called pyroptosis. ASC dot aggregates can also recruit and activate caspase-8, which is capable of processing pro-IL-1β and pro-IL-18 and inducing apoptotic cell death.

[0072] Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, which are secreted from the cell. Active caspase-1 also cleaves gasdermin-D to trigger pyroptosis. Through its control of pyroptotic cell death pathways, caspase-1 also mediates the release of alarmin molecules such as IL-33 and high-velocity group B1 (HMGB1). Caspase-1 also cleaves intracellular IL-1R2, leading to its degradation and the 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 glycolysis pathway, may contribute to caspase-1-dependent inflammation.

[0073] NLRP3-dependent ASC spots are released into the extracellular environment, where they can activate caspase-1, induce the processing of caspase-1 substrates, and spread inflammation. Active cytokines derived from NLRP3 inflammasome activation are important drivers of inflammation and interact with other cytokine pathways to form immune responses to infection and injury. For example, IL-1β signaling induces the secretion of pro-inflammatory cytokines IL-6 and TNF. In the absence of T cell receptor involvement, IL-1β and IL-18, in conjunction with IL-23, induce the production of IL-17 by memory CD4 Th17 cells and γδ T cells. IL-18 and IL-12 also synergistically induce the production of IFN-γ by memory T cells and NK cells, thereby driving Th1 responses.

[0074] Hereditary CAPS diseases such as Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), and neonatal multisystem inflammatory diseases (NOMID) are caused by gain-of-function mutations in NLRP3, thus defining NLRP3 as a key component of inflammatory processes. NLRP3 is also involved in the pathogenesis of many complex diseases, particularly metabolic disorders such as type 2 diabetes, atherosclerosis, obesity, and gout.

[0075] The role of NLRP3 in central nervous system diseases is becoming apparent, and lung diseases have also been shown to be affected by NLRP3. Furthermore, NLRP3 plays a role in the development of liver disease, kidney disease, and aging. Many of these associations are defined using NLRP3 KO mice, but insights into the specific activation of NLRP3 in these diseases also exist. In type 2 diabetes (T2D), the deposition of pancreatic amyloid peptides in the pancreas activates NLRP3 and IL-1β signaling, leading to cell death and inflammation.

[0076] Current treatments for NLRP3-related diseases include IL-1-targeting biologics. These biologics include the recombinant IL-1 receptor antagonist anakinra, the neutralizing IL-1β antibody canakinumab, and the soluble decoy IL-1 receptor rilonacept. These approaches have proven successful in the treatment of CAPS, and these biologics have been used in clinical trials for other IL-1β-related diseases. Given the potential of small molecule inhibitors of NLRP3 for improved safety (minimized risk of infection and ease of withdrawal compared to biologics), patient comfort, and adherence, they offer an attractive alternative to these biologics.

[0077] The compounds of formulas (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa) described herein are NLRP3 modulators. The compounds of formulas (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa) described herein, as well as compositions comprising these compounds, are useful for the treatment of NLRP3-related diseases, including but not limited to type 2 diabetes, atherosclerosis, obesity, and gout.

[0078] In some embodiments, this document provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: ; in: X is N, N(R) 7a ), C(R7) or C(O); Y is N, N(R) 8a ), C(R8) or C(O); where one of X and Y is N, N(R 7a ) or N(R 8a ); Z is -L-R6. or ; L is -C(H)(OH)-; R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 The group R1 is substituted with a group R2; 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 heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally substituted with one, two, or three R2 groups. 14 Group substitution; or combination of R2 and R3 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; or combination of R3 and R4 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; or combination of R4 and R5 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 and R8 are each independently selected from hydrogen, halogen, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; R 7a and R 8a Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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)R13 -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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(R12 )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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; or two R groups 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; n is 0, 1, 2, 3, or 4; and This indicates a single or double bond, such that all valences are satisfied.

[0079] In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(R7) and Y is N. In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(R7), Y is N, and R7 is selected from hydrogen, halogen, unsubstituted C.1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(R7), Y is N, and R7 is selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(R7), Y is N, and R7 is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(R7), Y is N, and R7 is an unsubstituted C 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(R7), Y is N, and R7 is -CH3.

[0080] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N(R 7a And Y is C(O). In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N(R) 7a Y is C(O), and R 7a Selected from hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N(R 7a Y is C(O), and R 7a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is N(R 7a Y is C(O), and R 7a It is -CH2CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N(R 7a Y is C(O), and R 7a It is -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N(R 7a Y is C(O), and R 7a It is unreplaced C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N(R 7a Y is C(O), and R 7aIt is an unsubstituted cyclopropyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is N(R 7a Y is C(O), and R 7a It is hydrogen.

[0081] In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is N and Y is C(R8). In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is N, Y is C(R8), and R8 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is N, Y is C(R8), and R8 is selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is N, Y is C(R8), and R8 is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is N, Y is C(R8), and R8 is an unsubstituted C 1-6 Alkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is N, Y is C(R8), and R8 is -CH3.

[0082] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(O) and Y is N(R). 8a In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(O) and Y is N(R). 8a ), and R 8a Selected from hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(O) and Y is N(R). 8a ), and R 8a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(O) and Y is N(R). 8a ), and R 8a It is -CH2CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(O) and Y is N(R). 8a ), and R8a It is -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(O) and Y is N(R). 8a ), and R 8a It is unreplaced C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(O) and Y is N(R). 8a ), and R 8a It is an unsubstituted cyclopropyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(O) and Y is N(R). 8a ), and R 8a It is hydrogen.

[0083] In some embodiments, Z is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein Z is -L-R6. In some embodiments, Z is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R6 is... In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0084] In some embodiments, Z is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is In some embodiments, Z is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is .

[0085] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It can be arbitrarily determined by one, two, or three Rs. 14 C with substituent group 1-6Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH2CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0086] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

[0087] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from... , , In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0088] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 -C(O)OR 10 or -C(O)N(R) 10 (R) 11 In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OR 10 In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OH. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OCH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is a halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CF3.

[0089] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is a halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -CF3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OR 10 In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OH. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OCH3.

[0090] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 or -N(R) 10 (R) 11 In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -CF3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is a halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OR 10In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OH. In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OCH3. In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -N(R 10 (R) 11 ).

[0091] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is a halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -CF3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OR 10 In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OH. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OCH3.

[0092] In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 or -N(R) 10 (R) 11 In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C. 1-6Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is hydrogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -CH3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is a halogen. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -CF3. In some embodiments, it is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OR 10 In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OH. In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OCH3. In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -N(R 10 (R) 11 ).

[0093] In some embodiments, this document provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: ; in: Z is -L-R6. or ; L is -C(H)(OH)-; R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups of R1 may be substituted; or R1 and R2 may be combined to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring may optionally be substituted by one, two, or three R1 groups. 14Group substitution; or combination of R2 and R3 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; or combination of R3 and R4 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; or combination of R4 and R5 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 is selected from hydrogen, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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, C2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; or two R groups may be substituted. 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; and n is 0, 1, 2, 3 or 4.

[0094] In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is an unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3.

[0095] In some embodiments, Z is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein Z is -L-R6. In some embodiments, Z is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R6 is... In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0096] In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is .

[0097] In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It can be arbitrarily determined by one, two, or three Rs. 14 C with substituent group 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH2CH3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

[0098] In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

[0099] In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from... , , In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6 yes In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0100] In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 -C(O)OR 10 or -C(O)N(R) 10 (R) 11 In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OR 10In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OH. In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OCH3. In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is hydrogen. In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is a halogen. In some embodiments, the compound is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -CH3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CF3.

[0101] In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is a halogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -CH3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -CF3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OR 10 In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OH. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OCH3.

[0102] In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 or -N(R) 10 (R) 11 In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 Haloalkyl. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -CH3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -CF3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is a halogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OR 10 In some embodiments, the compound is of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OH. In some embodiments, the compound is of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OCH3. In some embodiments, the compound is of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -N(R 10 (R) 11 ).

[0103] In some embodiments, it 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 Halogenated alkyl or -OR 10 In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is a halogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is C. 1-6Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -CH3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -CF3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OR 10 In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OH. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OCH3.

[0104] In some embodiments, it 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 Halogenated alkyl groups, -OR 10 or -N(R) 10 (R) 11 In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is hydrogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -CH3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is a halogen. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -CF3. In some embodiments, it is a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OR 10 In some embodiments, the compound is of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OH. In some embodiments, the compound is of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OCH3. In some embodiments, the compound is of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -N(R10 (R) 11 ).

[0105] In some embodiments, this document provides a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof: ; in: Z is -L-R6. or ; L is -C(H)(OH)-; R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups of R1 may be substituted; or R1 and R2 may be combined to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring may optionally be substituted by one, two, or three R1 groups. 14 Group substitution; or combination of R2 and R3 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; or combination of R3 and R4 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; or combination of R4 and R5 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R 7a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; or two R groups 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; n is 0, 1, 2, 3 or 4.

[0106] In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a Selected from hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is -CH2CH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is -CH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 3-6Cycloalkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is an unsubstituted cyclopropyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is hydrogen.

[0107] In some embodiments, Z is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein Z is -L-R6. In some embodiments, Z is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R6 is... In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0108] In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is .

[0109] In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It can be arbitrarily determined by one, two, or three Rs. 14 C with substituent group 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6a It is -CH2CH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

[0110] In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, where n is 0.

[0111] In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from... , , In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0112] In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 -C(O)OR 10or -C(O)N(R) 10 (R) 11 In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OR 10 In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OH. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OCH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is a halogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -CH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -CF3.

[0113] In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is a halogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -CH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is C 1-6Halogenated alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -CF3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OR 10 In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OH. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OCH3.

[0114] In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 or -N(R) 10 (R) 11 In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 Haloalkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -CH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -CF3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is a halogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OR 10 In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OH. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OCH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -N(R 10 (R) 11 ).

[0115] In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is a halogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -CH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -CF3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OR 10 In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OH. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OCH3.

[0116] In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 or -N(R) 10 (R) 11 In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is hydrogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -CH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is a halogen. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is C 1-6Halogenated alkyl group. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -CF3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OR 10 In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OH. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OCH3. In some embodiments, it is a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -N(R 10 (R) 11 ).

[0117] In some embodiments, this document provides a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof: ; in: X is N, N(R) 7a ), C(R7) or C(O); Y is N, N(R) 8a ), C(R8) or C(O); Z is -L-R6. or ; L is -C(H)(OH)-; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 and R8 are each independently selected from hydrogen, halogen, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; R 7a and R 8a Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; R9 is optionally superimposed by one, two, or three Rs. 14 C with substituent group 1-9 Mixed aromatics; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 11 Independently selected from hydrogen and C1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; or two R groups 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; n is 0, 1, 2, 3, or 4; and This indicates a single or double bond, such that all valences are satisfied.

[0118] In some embodiments, the compound is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(R7) and Y is C(R8). In some embodiments, the compound is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(R7) and Y is C(R8). In some embodiments, the compound is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is C(R7) and Y is N. In some embodiments, the compound is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein X is N and Y is C(R8).

[0119] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is an unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is -CH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R8 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R8 is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R8 is an unsubstituted C 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is -CH3.

[0120] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is N(R 7a And Y is C(O). In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(O) and Y is N(R). 8a ).

[0121] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a Selected from hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is -CH2CH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is -CH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is an unsubstituted cyclopropyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a Selected from hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a It is -CH2CH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a It is -CH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a It is unreplaced C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a It is an unsubstituted cyclopropyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 8a It is hydrogen.

[0122] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is a C-terminus selected from pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl. 1-9 Heteroaryl groups, wherein pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl are optionally surrounded by one, two, or three R groups. 14 Substitution of a group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 A pyridinyl group substituted with a functional group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is composed of one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is composed of one, two, or three R groups. 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is .

[0123] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is indolyl or benzofuranyl, wherein the indolyl and benzofuranyl are optionally separated by one, two or three R9 groups. 14 Substitution of a group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 A group-substituted indole group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted indole groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted indole groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is an unsubstituted indole group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is optionally surrounded by one, two, or three R groups. 14 A benzofuranyl group substituted with a radical. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted benzofuranyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted benzofuranyl groups, wherein each R 14Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is an unsubstituted benzofuranyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is... In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is In some embodiments, it is a compound of formula (II), a pharmaceutically acceptable salt or solvate thereof, wherein R9 is... .

[0124] In some embodiments, Z is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein Z is -L-R6. In some embodiments, Z is a compound of formula (II), or a pharmaceutically acceptable salt or solvation thereof, wherein R6 is... In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0125] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is .

[0126] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It can be arbitrarily determined by one, two, or three Rs. 14 C with substituent group 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6aIt is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH2CH3. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is hydrogen. In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0127] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0128] In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from... , , In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0129] In some embodiments, this document provides a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof: ; in: Z is -L-R6. or ; L is -C(H)(OH)-; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 and R8 are each independently selected from hydrogen, halogen, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; R9 is optionally superimposed by one, two, or three Rs. 14 C with substituent group 1-9 Mixed aromatics; Each R 10Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; or two R groups may be substituted. 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; and n is 0, 1, 2, 3 or 4.

[0130] In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is hydrogen. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is an unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is -CH3. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R8 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R8 is hydrogen. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R8 is an unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is -CH3.

[0131] In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is a C-terminus selected from pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl. 1-9 Heteroaryl groups, wherein pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl are optionally surrounded by one, two, or three R groups. 14 Group substitution. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 A pyridinyl group substituted with a functional group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is composed of one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is composed of one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is... In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is .

[0132] In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is indolyl or benzofuranyl, wherein the indolyl and benzofuranyl are optionally separated by one, two, or three R9 groups. 14 Group substitution. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 A group-substituted indole group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted indole groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted indole groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is an unsubstituted indole group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is optionally surrounded by one, two, or three R groups. 14 A benzofuranyl group substituted with a radical. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted benzofuranyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted benzofuranyl groups, wherein each R 14Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is an unsubstituted benzofuranyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is... In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is In some embodiments, it is a compound of formula (IIa), a pharmaceutically acceptable salt or solvate thereof, wherein R9 is... .

[0133] In some embodiments, Z is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein Z is -L-R6. In some embodiments, Z is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R6 is... In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0134] In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is .

[0135] In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It can be arbitrarily determined by one, two, or three Rs. 14 C with substituent group 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH2CH3. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is hydrogen. In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0136] In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0137] In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from... , , In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0138] In some embodiments, this document provides a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof: ; in: Z is -L-R6. or ; L is -C(H)(OH)-; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 is selected from hydrogen, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; R9 is optionally superimposed by one, two, or three Rs. 14 C with substituent group 1-9 Mixed aromatics; Each R10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9Substitution of heteroaryl groups; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; or two R groups 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; and n is 0, 1, 2, 3 or 4.

[0139] In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is hydrogen. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is an unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3.

[0140] In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is a C-terminus selected from pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl. 1-9 Heteroaryl groups, wherein pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl are optionally surrounded by one, two, or three R groups. 14 Group substitution. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 A pyridinyl group substituted with a functional group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is composed of one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is composed of one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is... In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is .

[0141] In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is indolyl or benzofuranyl, wherein the indolyl and benzofuranyl are optionally surrounded by one, two, or three R9 groups. 14 Group substitution. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 A group-substituted indole group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted indole groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C?1-6 Alkyl group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted indole groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is an unsubstituted indole group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is optionally surrounded by one, two, or three R groups. 14 A benzofuranyl group substituted with a radical. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted benzofuranyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted benzofuranyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is an unsubstituted benzofuranyl group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is... In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is In some embodiments, it is a compound of formula (IIb), a pharmaceutically acceptable salt or solvate thereof, wherein R9 is... .

[0142] In some embodiments, Z is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein Z is -L-R6. In some embodiments, Z is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvation thereof, wherein R6 is... In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0143] In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is .

[0144] In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It can be arbitrarily determined by one, two, or three Rs. 14 C with substituent group 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH2CH3. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is hydrogen. In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0145] In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0146] In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from... , , In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is, In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0147] In some embodiments, this document provides compounds of formula (IIc), or pharmaceutically acceptable salts or solvates thereof: ; in: Z is -L-R6. or ; L is -C(H)(OH)-; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R 7a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; R9 is optionally superimposed by one, two, or three Rs. 14 C with substituent group 1-9 Mixed aromatics; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three elements selected from halogens, C, and D. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Substitution of heteroaryl groups; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two, or three groups selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 Substitution of groups; or two R groups 15 Together they form a bridge, wherein the bridge is a -CH2- or -CH2CH2- bridge; and n is 0, 1, 2, 3 or 4.

[0148] In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a Selected from hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is -CH2CH3. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7aIt is -CH3. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 3-6 Cycloalkyl. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is an unsubstituted cyclopropyl group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is hydrogen.

[0149] In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is a C-group selected from pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl. 1-9 Heteroaryl groups, wherein pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl are optionally surrounded by one, two, or three R groups. 14 Group substitution. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 A pyridinyl group substituted with a functional group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is composed of one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is composed of one, two, or three R...14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is... In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is... .

[0150] In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is indolyl or benzofuranyl, wherein the indolyl and benzofuranyl are optionally separated by one, two, or three R9 groups. 14 Group substitution. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 A group-substituted indole group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted indole groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted indole groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is an unsubstituted indole group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is optionally surrounded by one, two, or three R groups. 14 A benzofuranyl group substituted with a radical. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally replaced by one, two, or three R groups. 14 Group-substituted benzofuranyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10Is it hydrogen or unsubstituted C? 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally surrounded by one, two, or three R... 14 Group-substituted benzofuranyl groups, wherein each R 14 Independently selected from halogens, -CH3, -CF3, -OH, or -OCH3. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is an unsubstituted benzofuranyl group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R9 is... In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is... In some embodiments, it is a compound of formula (IIc), a pharmaceutically acceptable salt or solvate thereof, wherein R9 is... .

[0151] In some embodiments, Z is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein Z is -L-R6. In some embodiments, Z is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvation thereof, wherein R6 is... In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0152] In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is .

[0153] In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It can be arbitrarily determined by one, two, or three Rs. 14 C with substituent group 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH2CH3. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is hydrogen. In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0154] In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0155] In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from... , , In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0156] 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, halogens, and carbon. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OR9; R6 is , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 and R8 are each independently selected from hydrogen, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups, wherein the alkyl group is optionally selected from -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; Each R9 is independently a C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; Each R15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; or two R groups may be substituted. 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; and n is 0, 1, 2, 3 or 4.

[0157] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0158] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It can be arbitrarily determined by one, two, or three Rs. 14 C with substituent group 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is unreplaced C 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH2CH3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6aIt is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0159] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0160] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from... , , , , , , , , , , , , , , and In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

[0161] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R7 and R8 are each independently selected from hydrogen, halogen, unsubstituted C 1-6 Alkyl and C 1-6 Halogenated alkyl. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 and R8 are each independently selected from hydrogen and unsubstituted C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 and R8 are hydrogen atoms. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 and R8 are unsubstituted C atoms. 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 and R8 are -CH3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0162] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and -OR9, wherein at least one of R1, R2, R3, R4 and R5 is -OR9.

[0163] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR9. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OR9. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OCF2H. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OCF3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is a halogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -CH3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -CF3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -CH2CF3.

[0164] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is a halogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -CH3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is C 1-6Halogenated alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -CF3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OR9. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OCF2H. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OCF3.

[0165] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -CH3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -CF3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is a halogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OR9. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OCF2H. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OCF3.

[0166] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is a halogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -CH3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is C1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -CF3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OR9. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OCF2H. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OCF3.

[0167] In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is hydrogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -CH3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is a halogen. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -CF3. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OR9. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OCF2H. In some embodiments, it is a compound of formula (III), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OCF3.

[0168] In some embodiments, this document provides compounds of formula (IIIa), or pharmaceutically acceptable salts or solvates thereof: ; in: R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, and carbon. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OR9; R 6a Selected from hydrogen and C 1-6 alkyl; R7 and R8 are each independently selected from hydrogen and C.1-6 Alkyl; and Each R9 is independently a C 1-6 Halogenated alkyl groups.

[0169] In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH2CH3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is hydrogen.

[0170] In some embodiments, the compound is of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 and R8 are hydrogen. In some embodiments, the compound is of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 and R8 are C 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 and R8 are -CH3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is hydrogen and R8 is -CH3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R7 is -CH3 and R8 is hydrogen.

[0171] In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 The alkyl halogroup and -OR9, wherein at least one of R1, R2, R3, R4 and R5 is -OR9.

[0172] In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6Halogenated alkyl or -OR9. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OR9. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OCF2H. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -OCF3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is hydrogen. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is a halogen. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -CH3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -CF3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R1 is -CH2CF3.

[0173] In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is hydrogen. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is a halogen. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -CH3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -CF3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OR9. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OCF2H. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R2 is -OCF3.

[0174] In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -CH3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is C 1-6 Halogenated alkyl groups. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -CF3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is hydrogen. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is a halogen. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OR9. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OCF2H. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R3 is -OCF3.

[0175] In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is hydrogen. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is a halogen. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -CH3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is C 1-6Halogenated alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -CF3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OR9. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R4 is -OCF2H. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OCF3.

[0176] In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is hydrogen. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is C. 1-6 Alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -CH3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is a halogen. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is C 1-6 Halogenated alkyl group. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -CF3. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OR9. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OCF2H. In some embodiments, it is a compound of formula (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein R5 is -OCF3.

[0177] In some embodiments, compounds selected from the following are provided herein: or its pharmaceutically acceptable salts or solvates.

[0178] In some embodiments, compounds selected from the following are provided herein: , , , , , , , and or its pharmaceutically acceptable salts or solvates.

[0179] This document considers any combination of the groups described above for various variables. Throughout the specification, those skilled in the art can select the groups and their substituents to provide stable moieties and compounds.

[0180] In some embodiments, the therapeutic agent (e.g., a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa)) is present in the pharmaceutical composition as a pharmaceutically acceptable salt. In some embodiments, any of the above compounds is suitable for any of the methods or compositions described herein.

[0181] Other forms of the compounds disclosed herein Isomers Furthermore, in some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis (cis, syn, entgegen) E )) and trans (trans, anti, zusammen ( ZIsomers 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 formulas described herein. In some cases, the compounds described herein have one or more chiral centers and each center exists in an R configuration or an 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, mixtures of enantiomers and / or diastereomers produced by a single preparation step, combination, or tautomerization can be used for the applications described herein. In some embodiments, the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of a racemic mixture. In some embodiments, the compounds described herein are prepared as separate stereoisomers by reacting a racemic mixture of the compounds with an optically resolving agent to form a pair of diastereomers, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes (e.g., crystalline diastereomer salts) are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated by utilizing these differences. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by a separation / resolution technique based on solubility differences. In some embodiments, the optically pure enantiomers and the resolving agent are then recovered by any practical method that does not cause racemization.

[0182] Labeled compounds In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds as a pharmaceutical composition. Thus, 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 atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes incorporated into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, respectively, as follows: 2 H, 3 H, 13 C 14 C 15 N、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F and36 Cl. Compounds described herein containing the aforementioned isotopes and / or other isotopes, as well as their pharmaceutically acceptable salts, esters, solvates, hydrates, or derivatives, are within the scope of this invention. Certain isotope-labeled compounds, such as those doped with radioactive isotopes (e.g.,... 3 H and 14 Those compounds in (c) can be used for drug and / or substrate tissue distribution assays. Tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, isotopes such as deuterium (i.e., 2 Heavy isotope substitution of H) can produce certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life or reduced dose requirements. In some embodiments, the isotope-labeled compound, its pharmaceutically acceptable salt, ester, solvate, hydrate, or derivative is prepared by any suitable method.

[0183] In some embodiments, the compounds described herein are labeled in other ways, including but not limited to using chromophores or fluorescent moieties, bioluminescent labeling, or chemiluminescent labeling.

[0184] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present in the form of their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as a pharmaceutical composition.

[0185] In some embodiments, the compounds described herein have acidic or basic groups, and thus react with a variety of inorganic or organic bases and any of 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 reacting the purified free form of the compound alone with a suitable acid or base and isolating the resulting salt.

[0186] solvates In some embodiments, the compounds described herein are present in the form of solvates. In some embodiments, methods of treating diseases are performed by applying such solvates. This document further describes methods of treating diseases by applying such solvates as pharmaceutical compositions.

[0187] The solvates contain stoichiometric or non-stoichiometric amounts of solvent and, in some embodiments, are formed during crystallization with a pharmaceutically acceptable solvent such as water or ethanol. When the solvent is water, a hydrate is formed, or when the solvent is an alcohol, an alcohol is formed. The solvates of the compounds described herein are conveniently prepared or formed in the methods described herein. By way of example only, the hydrates of the compounds described herein are conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents including, but not limited to, dioxane, tetrahydrofuran, or MeOH. Furthermore, the compounds provided herein exist in both solvated and non-solvated forms. Generally, for some purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0188] Compound Synthesis In some embodiments, the synthesis of the compounds described herein is carried out using methods described in the chemical literature, methods described herein, or combinations thereof. Furthermore, the solvents, temperatures, and other reaction conditions presented herein may vary.

[0189] In other embodiments, the starting materials and reagents used to synthesize the compounds described herein are synthetic or derived from commercial sources, such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics.

[0190] In further embodiments, the compounds described herein and other related compounds with different substituents are synthesized using the techniques and materials described herein, as well as techniques and materials 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 Supplement (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, Fourth Edition (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry, Fourth Edition, Volumes A and B (Plenum 2000, 2001); and Green and Wuts, Protective Groups in Organic Synthesis, Third Edition (Wiley 1999). (All such disclosures are incorporated herein by reference) as described herein. General methods for preparing compounds as disclosed herein can be derived from reactions, and the reactions can be modified by using suitable reagents and conditions to introduce various parts present in the formulas provided herein. The following synthetic methods can be used as guidance.

[0191] In some embodiments, the compounds described herein are prepared via the general synthetic route described below.

[0192] Route A Route B Route C Route D Route E (a) (b) (c) Route F Route G Route H Route I Use of protecting groups In the described reactions, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxyl groups, required in the final product to prevent them from unnecessarily participating in the reaction. Protecting groups are used to cap some or all of the reactive moiety and prevent such groups from participating in the chemical reaction until the protecting groups are removed. Preferably, each protecting group can be removed in a different manner. Protecting groups cleaved under completely different reaction conditions satisfy the requirement of differential removal.

[0193] Protecting groups can be removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidizing conditions. Groups such as triphenylmethyl, dimethoxytriphenylmethyl, acetal, and tert-butyldimethylsilyl are acid-labile and can be used to protect the 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-labile). In the presence of acid-labile ester-terminated amines such as tert-butyl carbamate or acid- and base-stable but hydrolyzably removable urethane esters, the carboxylic acid and hydroxyl reactive moieties can be terminated with base-labile unstable groups such as, but not limited to, methyl, ethyl, and acetyl groups.

[0194] The reactive moieties of carboxylic acids and hydroxyl groups can also be capped with hydrolyzably removable protecting groups such as benzyl, while amine groups capable of forming hydrogen bonds with acids can be capped with base-unstable groups such as Fmoc. The reactive moieties of carboxylic acids can be protected by conversion to simple ester compounds (including conversion to alkyl esters) as exemplified herein, or they can be capped with oxidically removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amine groups can be capped with fluoride-unstable silylcarbamates.

[0195] Allyl-terminated groups are useful in the presence of both acid- and base-protecting groups because they are stable and can subsequently be removed by metal or π-acid catalysts. For example, allyl-terminated carboxylic acids can be degraded using Pd in ​​the presence of acid-instable tert-butyl carbamate or base-instable amine acetate protecting groups. 0 Catalytic reactions remove protection. Another form of protecting group is a resin that can attach to a compound or intermediate. As long as the residue is attached to the resin, the functional group is capped and cannot react. Once released from the resin, the functional group can react.

[0196] End-capping / protecting groups can typically be selected from: Other protecting groups, along with detailed descriptions of techniques applicable to the generation and removal of protecting groups, are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994 (such publications are incorporated herein by reference).

[0197] Treatment and prevention methods In some embodiments, a method for treating a metabolic disease in a patient in need of it includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method for treating a metabolic disease in a patient in need of it includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout. In some embodiments, a method for treating type 2 diabetes in a patient in need of it includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method for treating atherosclerosis in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method for treating obesity in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method for treating gout in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof.

[0198] In some embodiments, a method of treating liver disease in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method of treating liver disease in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the liver disease is selected from nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, or cirrhosis.

[0199] In some implementations, it is a method of treating lung disease in patients who require it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the lung disease is selected from asthma, COPD, and idiopathic pulmonary fibrosis.

[0200] In some embodiments, a method of treating a central nervous system disorder in a patient in need of such a treatment includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the central nervous system disorder 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 of such a treatment includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method of treating multiple sclerosis in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method of treating amyotrophic lateral sclerosis (ALS) in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method of treating multiple sclerosis in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method of treating Parkinson's disease in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method of treating Huntington's disease in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method of treating traumatic brain injury in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof.In some embodiments, a method for treating ischemic stroke and reperfusion in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method for treating stroke in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method for treating epilepsy in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some implementations, it is a method of treating depression in patients who require it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof.

[0201] In some implementations, it is a method of treating neurodegenerative diseases in patients who require it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof.

[0202] In some embodiments, a method for treating an inflammatory or autoimmune disease in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method for treating an inflammatory or autoimmune disease in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the disease is rheumatoid arthritis. In some embodiments, a method for treating an inflammatory or autoimmune disease in a patient in need includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the disease is multiple sclerosis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need of it includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the disease is psoriasis. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need of it includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the disease is lupus. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need of such a treatment includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the disease is intestinal bowel disease. In some embodiments, a method of treating an inflammatory or autoimmune disease in a patient in need of such a treatment includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the disease is Crohn's disease.In some implementations, it is a method of treating an inflammatory or autoimmune disease in a patient who requires it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the disease is ulcerative colitis.

[0203] In some embodiments, a method of treating cardiovascular disease in a patient in need of it includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a method of treating cardiovascular disease in a patient in need of it includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof, wherein the cardiovascular disease is atherosclerosis or stroke. In some embodiments, a method of treating atherosclerosis in a patient in need of it includes administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some implementations, it is a method of treating stroke in patients who require it, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof.

[0204] Pharmaceutical Compositions and Administration The NLRP3 inhibitors described herein are administered to subjects in a biocompatible form suitable for administration to treat or prevent diseases, symptoms, or conditions. Administration of the NLRP3 inhibitors described herein may be in any pharmacological form, including, alone or in combination with a pharmaceutically acceptable carrier, a therapeutically effective amount of the NLRP3 inhibitor.

[0205] In some 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), which is selected based on the chosen route of administration and standard pharmaceutical practice, such as that described in Remington: The Science and Practice of Pharmacy (Gennaro, 21st edition, Mack Pub. Co., Easton, PA (2005)).

[0206] Therefore, this document provides a pharmaceutical composition comprising at least one compound or pharmaceutically acceptable salt described herein, and one or more pharmaceutically acceptable carriers. A carrier (or excipient) is acceptable or suitable if it is compatible with the other components of the composition and is harmless to the recipient (i.e., the object) of the composition.

[0207] In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of formula (I), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of formula (Ia), or a pharmaceutically acceptable salt or solvation thereof. In some embodiments, a pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of formula (Ib), or a pharmaceutically acceptable salt or solvation thereof.

[0208] Another embodiment provides a pharmaceutical composition comprising essentially a pharmaceutically acceptable carrier and a compound of formula (I), (Ia), (Ib), (II), (IIa), (IIb), (IIc), (III), or (IIIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition comprises essentially 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 essentially 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 essentially a pharmaceutically acceptable carrier and a compound of formula (Ib), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition comprises essentially a pharmaceutically acceptable carrier and a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided that consists essentially of a pharmaceutically acceptable carrier and a compound of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided that consists essentially of a pharmaceutically acceptable carrier and a compound of formula (IIb), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a pharmaceutical composition is provided that consists essentially of a pharmaceutically acceptable carrier and a compound of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof.

[0209] In some embodiments, the compound as described herein is substantially pure because it contains less than about 5%, less than about 1%, or less than about 0.1% of other small organic molecules, such as contaminating intermediates or byproducts generated in one or more steps of the synthetic method.

[0210] These formulations include those suitable for oral, topical, sublingual, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) or aerosol administration.

[0211] Exemplary pharmaceutical compositions are used in the form of pharmaceutical formulations (e.g., solid, semi-solid, or liquid forms), comprising one or more of the disclosed compounds as active ingredients, mixed with an organic or inorganic carrier or excipient suitable for external, enteral, or parenteral application. In some embodiments, the active ingredient is compounded, for example, with a commonly used, pharmaceutically acceptable, non-toxic carrier for tablets, pills, capsules, suppositories, solutions, emulsions, suspensions, and any other suitable form. The amount of the active target compound contained in the pharmaceutical composition is sufficient to produce the desired effect on the course or condition of a disease.

[0212] In some implementations, the NLRP3 inhibitors described herein are administered to a subject in a biocompatible form suitable for topical application to treat or prevent skin diseases, conditions, or illnesses. "Biocompatible form suitable for topical application" means the form of the NLRP3 inhibitor to be administered in which the therapeutic effect of the inhibitor outweighs any toxic effects. The administration of the NLRP3 inhibitors described herein can be in any pharmacological form, including therapeutically effective amounts of the NLRP3 inhibitor alone or in combination with a pharmaceutically acceptable carrier.

[0213] Topical application of NLRP3 inhibitors can be in the form of aerosols, semi-solid pharmaceutical compositions, powders, or solutions. The term "semi-solid composition" refers to an ointment, cream, cream, gel, or other pharmaceutical composition with substantially similar consistency suitable for application to the skin. Examples of semi-solid compositions are given in Chapter 17 of *The Theory and Practice of Industrial Pharmacy* by Lea and Febiger (1970) and Chapter 67 of *Remington's Pharmaceutical Sciences*, 15th edition (1975), published by Mack Publishing Company.

[0214] Dermal or skin patches are another method of transdermal delivery of the therapeutic or pharmaceutical compositions described herein. Patches may provide absorption enhancers such as DMSO to increase compound absorption. Patches may include those that control the rate of drug delivery to the skin. Patches can provide a variety of drug delivery systems, including reservoir systems or monopatch systems. For example, a reservoir design may have four layers: an adhesive layer in direct contact with the skin, a control membrane to control drug molecule diffusion, a drug molecule reservoir, and a water-resistant 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 monopatch design typically has only three layers: an adhesive layer, a polymer matrix containing the compound, and a water-resistant backing. Such a design delivers a saturated amount of drug to the skin. Therefore, delivery is controlled by the skin. As the amount of drug in the patch decreases below the saturation level, the delivery rate decreases.

[0215] In one embodiment, the topical composition may, for example, take the form of a hydrogel based on polyacrylic acid or polyacrylamide; as an ointment, for example using polyethylene glycol (PEG) as a carrier, such as the standard ointment DAB 8 (50% PEG 300, 50% PEG 1500); or as an emulsion, especially a microemulsion based on water-in-oil or oil-in-water, 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 cyclodextrin; 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 dodecylurea, 1,3-bisdodecylurea, 1,3-diphenylurea; and terpenes, such as D-limonene, menthone, α-terpineol, carvone, limonene oxide, or 1,8-cineole.

[0216] Ointments, pastes, creams, and gels may also contain excipients such as starch, tragacanth gum, cellulose derivatives, polyethylene glycol, siloxanes, bentonite, silicic acid, and talc, or mixtures thereof. Powders and sprays may also contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powders, or mixtures thereof. Solutions of nanocrystalline antimicrobial metals can be converted into aerosols or sprays using any known method conventionally used to manufacture aerosol pharmaceuticals. Typically, such methods involve pressurization or providing a device for pressurizing the solution container (usually using an inert carrier gas) and passing the pressurized gas through a small orifice. Sprays may also contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0217] The carrier may also contain other pharmaceutically acceptable excipients to alter or maintain the pH, osmotic pressure, viscosity, transparency, color, sterility, stability, dissolution rate, or odor of the formulation. Anti-skin aging compositions may further include antioxidants, sunscreens, natural retinoids (e.g., retinol), and other additives commonly found in skin treatment compositions.

[0218] In some embodiments for preparing solid compositions (such as tablets), a major active ingredient is mixed with a drug carrier (e.g., conventional tableting components such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum, and other drug diluents such as water) to form a solid preform composition containing a homogeneous mixture of the disclosed compound or a non-toxic, pharmaceutically acceptable salt thereof. When these preform compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, making it easily subdividable into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0219] In solid dosage forms (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.) for oral administration, the subject composition is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or filling agents such as starch, cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as carboxymethyl cellulose, hydroxypropyl methylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, etc. Examples of ingredients include: (4) disintegrants such as crospovidone, crospovidone sodium carboxymethyl cellulose, sodium glycolate starch, agar, calcium carbonate, potato or cassava starch, alginate, certain silicates and sodium carbonate; (5) solution retardants such as paraffin; (6) absorption enhancers such as quaternary ammonium compounds; (7) wetting agents such as 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 dodecyl sulfate and mixtures thereof; and (10) colorants. In the case of capsules, tablets and pills, in some embodiments, the composition contains 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 sugars) and high molecular weight polyethylene glycol.

[0220] In some embodiments, tablets are made by compression or molding, optionally having one or more excipients. In some embodiments, compressed tablets are prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium glycolate starch or croscarmellose sodium), surfactants, or dispersants. In some embodiments, molded tablets are prepared by molding a mixture of a subject composition wetted with an inert liquid diluent in a suitable machine. In some embodiments, tablets and other solid dosage forms (such as sugar-coated pills, capsules, pellets, and granules) are scored or prepared with coatings and shells (such as enteric coatings and other coatings).

[0221] Compositions for inhalation or inhalation 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 composition, in some embodiments, the liquid dosage form comprises an inert diluent (e.g., water or other solvent), a solubilizer, and an emulsifier, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuran methanol, fatty acid esters of polyethylene glycol and sorbitol, cyclodextrins, and mixtures thereof.

[0222] In some embodiments, in addition to the subject composition, the suspension also contains suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0223] In some embodiments, in addition to the subject composition, the powder and spray also contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. In some embodiments, the spray also contains conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons (such as butane and propane).

[0224] Alternatively, the compositions and compounds disclosed herein are administered via aerosols. This is achieved by preparing aqueous aerosols, liposome formulations, or solid particles containing the compound. In some embodiments, non-aqueous (e.g., fluorocarbon propellants) suspensions are used. In some embodiments, sonic atomizers are used because they minimize the agent's exposure to shear, which can lead to degradation of the compounds contained in the subject composition. Aqueous aerosols are typically prepared by formulating an aqueous solution or suspension of the subject composition with conventionally pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the specific subject composition but typically include nonionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins such as serum albumin, sorbitol esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aerosols are typically prepared from isotonic solutions.

[0225] Pharmaceutical compositions suitable for parenteral administration comprise a combination of a subject composition with one or more pharmaceutically acceptable sterile isotonic or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders reconstituted into sterile injectable solutions or dispersions prior to use. In some embodiments, they contain antioxidants, buffers, antibacterial agents, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending agents or thickeners.

[0226] 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. For example, appropriate flowability can be maintained by using coating materials (such as lecithin), maintaining the desired particle size in the case of dispersions, and using surfactants.

[0227] The dosage of a composition containing at least one of the compounds described herein depends on the patient's (e.g., person's) condition, i.e., stage of disease, general health condition, age, and other factors.

[0228] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage, as well as the appropriate duration and frequency of administration, will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. Generally, the appropriate dosage and treatment regimen are to provide the composition in an amount sufficient to provide therapeutic and / or preventive benefits (e.g., improved clinical outcomes such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or reduction in symptom severity). The optimal dosage is typically determined using experimental models and / or clinical trials. In some embodiments, the optimal dosage depends on the patient's body mass, weight, or blood volume.

[0229] Oral doses are typically in the range of about 1.0 mg to about 1000 mg, once to four times or more daily.

[0230] The dosage can be repeated based on the pharmacokinetic parameters of the dosage formulation and the route of administration.

[0231] Formulating the composition into dosage units is particularly advantageous for ease of administration and uniformity of dosage. As used herein, dosage units refer to physically discrete units suitable as a unit dose for use as a mammalian subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect, along with the required drug delivery system. The specifications of the dosage unit form depend on and are directly dependent on (a) the unique characteristics of the NLRP3 inhibitor and the specific therapeutic effect to be achieved, and (b) the inherent limitations of techniques for combining such active compounds to treat individual sensitivities. Specific dosages can be readily calculated by those skilled in the art, for example, based on the patient's approximate weight or body surface area or volume of body space to be occupied. The dosage will also be calculated based on the chosen specific route of administration. Further refinement of the calculations required to determine the appropriate dosage for treatment is routinely performed by those skilled in the art. Given the activity of the NLRP3 inhibitors disclosed herein in target cell assay formulations, such calculations can be performed by those skilled in the art without excessive experimentation. The exact dosage is determined in conjunction with standard dose-response studies. It should be understood that the amount of composition actually applied will be determined by the practitioner based on relevant circumstances, including one or more conditions to be treated, the choice of composition to be applied, the individual patient's age, weight and response, the severity of the patient's symptoms, and the chosen route of application.

[0232] The toxicity and therapeutic efficacy of such NLRP3 inhibitors can be determined by examining cell cultures or laboratory animals, for example, using methods to determine LD50. 50 (The dose that is lethal to 50% of the population) and ED 50 The standard pharmaceutical procedure determines the dose (effective for 50% of the population). The dose-to-toxicity ratio is the therapeutic index, which can be expressed as the ratio LD50. 50 / ED 50 NLRP3 inhibitors exhibiting a high therapeutic index are preferred. While NLRP3 inhibitors exhibiting toxic side effects can be used, care should be taken to design delivery systems that target such inhibitors to the affected tissue sites in order to minimize potential damage to uninfected cells, thereby reducing side effects.

[0233] Data obtained from cell culture experiments and animal studies can be used to determine dosage ranges for human use. The dosage of such NLRP3 inhibitors is preferably within the range of ED (extracorporeal membrane oxygenation) with little or no toxicity. 50 The dosage can vary within this range depending on the dosage form and route of administration. For any NLRP3 inhibitor used in the methods described herein, the therapeutically effective dose can be estimated starting from cell culture assays. Doses can be formulated in animal models to achieve a range of circulating plasma concentrations that includes the IC50 determined in cell culture. 50(That is, the concentration of the NLRP3 inhibitor at which half of the maximum symptom suppression is achieved). Such information can be used to more accurately determine the useful dose for the human body. For example, the level in plasma can be measured by high-performance liquid chromatography.

[0234] Example The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. All references to literature in these examples and throughout this specification are incorporated herein by reference for all legal purposes served thereto. Starting materials and reagents used to synthesize the compounds described herein may be synthetic or may be available from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0235] This article uses the example of J. Org. Chem Standard abbreviations and acronyms as defined in 2007 72(1): 23A-24A. Other abbreviations and acronyms used in this paper are as follows: Example 1: Synthesis of (1-ethylpiperidin-3-yl)(6-(3-fluoro-1H-indol-6-yl)-5-methylpyridazin-3-yl)methanol (compound 10) Steps 1 and 2: At 0 °C under N2, NaH (4.2 g, 105 mmol, 60%) was added fractionally to a degassed solution of 3,6-dichloro-4-methylpyridazine (8.2 g, 50 mmol) and 3-pyridylacetonitrile (6.1 g, 52 mmol) in dry DMA (60 mL). After 1 hour at 0 °C, LCMS indicated the formation of two products, 1 and 2 (1:2 = 7:3). m-CPBA (12 g, 50 mmol, 72%) was added fractionally to the solution at 0 °C for 10 min. The reaction mixture was diluted with EtOAc (200 mL) and stirred at 0 °C for an additional 10 min. Saturated NaHCO3 (100 mL) was added to the solution at 0 °C and the mixture was stirred for 10 min. The mixture was diluted with water (200 mL), the organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 x 100 mL), saturated NaHCO3 (100 mL), and brine (100 mL), and dried over Na2SO4. The solvent was concentrated. The solid was sonicated in EtOAc (50 mL), then removed by filtration and washed with EtOAc / hexane (1:1) (20 mL) to obtain 5.2 g of solid. The solid (5.2 g) was slurried in EtOAc / hexane (1:1) (50 mL) at 500 °C for 30 min and cooled to rt. The solid was removed by filtration to obtain (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl) methyl ketone (3) (4.2 g). The combined mother liquor was concentrated under vacuum and purified by silica gel column chromatography to obtain (6-chloro-4-methylpyridazin-3-yl)(pyridin-3-yl) methyl ketone (4) (1.3 g).

[0236] Step 3: Compound 3 (1.0 g) was dissolved in MeOH (10 mL) and THF (10 mL) and then cooled under ice water. NaBH4 (81 mg) was added at 0 °C. The resulting mixture was stirred at 0 °C for 15 min. The reaction was quenched with a saturated aqueous solution of NaHCO3 and then extracted with EtOAc to give (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (5) (1.0 g), which was used without purification.

[0237] Step 4: Compound 5 (300 mg, 1.0 equivalent), 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H-indole (690 mg, 1.3 equivalent), PdCl2(dppf) (47 mg, 0.05 equivalent), and Na2CO3 (270 mg, 2.0 equivalent) were combined in dioxane (12 mL) and water (4 mL) under N2. The resulting mixture was heated at 100 °C for 12 hours. The reaction mixture was diluted with EtOAc (40 mL), washed with water and brine, and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography to give (6-(3-fluoro-1-toluenesulfonyl-1H-indol-6-yl)-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (6) (338 mg, 54% yield).

[0238] Step 5: PtO2 (118 mg, 0.8 equivalent) and (Boc)2O (162 mg, 1.1 equivalent) were added to a solution of compound 6 (330 mg, 1.0 equivalent) in MeOH (80 mL) and water (1 mL). The mixture was degassed with bubbling N2 gas for 20 min and then hydrogenated at rt under H2 (balloon) for 6 h. The catalyst was removed by filtration and the solvent was concentrated under vacuum. The crude mixture was purified by silica gel column chromatography to give tert-butyl 3-((6-(3-fluoro-1-toluenesulfonyl-1H-indol-6-yl)-5-methylpyridazin-3-yl)(hydroxy)methyl)piperidine-1-carboxylate (7) (55 mg) and tert-butyl 3-(hydroxy(5-methyl-6-(1-toluenesulfonyl-1H-indol-6-yl)pyridazin-3-yl)methyl)piperidine-1-carboxylate (8) (42 mg).

[0239] Step 6: Add a solution of dioxane (1 mL) in 4N HCl to a solution of compound 7 (55 mg) in DCM (0.5 mL). Stir the mixture at rt for 25 min. Concentrate the mixture under vacuum to obtain an intermediate amine as an HCl salt, which is used without purification. Dissolve the intermediate amine in 1,2-dichloroethane (2 mL) and MeOH (0.1 mL). Add Et3N (1.1 equivalents) and acetic acid (2 mg) to this solution. Stir the mixture at rt for 5 min, then add acetaldehyde (4.8 mg, 1.2 equivalents). Stir the mixture at rt for 5 min, and then add NaBH(OAc)3 (31 mg, 1.5 equivalents). Stir the resulting mixture at rt for 30 min and quench with a saturated aqueous solution of NaHCO3. Extract the mixture with DCM (2 × 15 mL). The crude product was purified by silica gel column chromatography to obtain (1-ethylpiperidin-3-yl)(6-(3-fluoro-1-toluenesulfonyl-1H-indol-6-yl)-5-methylpyridazin-3-yl)methanol (9) (31 mg, yield 60%).

[0240] Step 7: Add a solution of 1N TABF in THF (81 μL, 1.5 equivalent) to a solution of compound 9 (30 mg, 1.0 equivalent) in THF (1 mL). Heat the mixture under reflux for 6 hours. Add an additional 1N TABF (25 μL), and heat the resulting mixture under reflux overnight. Cool the reaction mixture, dissolve it in ethyl acetate (30 mL), and wash with saturated NaHCO3 aqueous solution (2 × 10 mL) and brine. Purify the mixture by silica gel column chromatography to give (1-ethylpiperidin-3-yl)(6-(3-fluoro-1H-indol-6-yl)-5-methylpyridazin-3-yl)methanol (10) (10 mg). LCMS: 369.2 (M+H) + .

[0241] 3-Fluoro-6-(4,4,5,5-Tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-toluenesulfonyl-1H- Synthesis of indole Step 1: Na₂CO₃ (3.6 g, 34 mmol) and Selectfluor (6 g, 17 mmol) were added to a mixture of 6-bromo-1H-indole-3-carboxylic acid (2 g, 8.3 mmol) in 1,2-dichloroethane (16 mL) and water (8 mL) at 0 °C. The mixture was heated to room temperature and stirred overnight. The reaction mixture was diluted with water and extracted with DCM. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography to give 6-bromo-3-fluoro-1H-indole (1.01 g, 56% yield).

[0242] Step 2: NaH (60%, 300 mg, 7.5 mmol) was added to a solution of 6-bromo-3-fluoro-1H-indole (1.0 g, 4.67 mmol) in DMF (10 mL) at 0 °C. After stirring for 30 min, 4-toluenesulfonyl chloride (1.2 g, 6.3 mmol) was added. After stirring for 1 hour, the mixture was diluted with EtOAc (60 mL), washed with water (4 times) and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to provide 6-bromo-3-fluoro-1-toluenesulfonyl-1H-indole (1.1 g, 64% yield).

[0243] Step 3: A mixture of 6-bromo-3-fluoro-1-toluenesulfonyl-1H-indole (1.0 g, 2.7 mmol), bis(pinacolyl)diborane (1.0 g, 4 mmol), KOAc (0.8 g, 8 mmol), and Pd(dppf)Cl2.CH2Cl2 (163 mg, 0.2 mmol) in dioxane (15 mL) was degassed and heated to 85 °C under nitrogen for 12 hours. The mixture was cooled to rt and the solids were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1-toluenesulfonyl-1H-indole (874 mg, 71% yield).

[0244] Example 2: Synthesis of (6-(1H-indol-6-yl)-5-methylpyridazin-3-yl)(1-ethylpiperidin-3-yl)methanol (compound 12) As described in steps 6 and 7 of Example 1, (6-(1H-indol-6-yl)-5-methylpyridazin-3-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (8) (42 mg) was prepared from 3-(hydroxy(5-methyl-6-(1-toluenesulfonyl-1H-indol-6-yl)pyridazin-3-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester (12) (4 mg). LCMS: 351.7 (M+H) + .

[0245] Example 3: Synthesis of (6-(benzofuran-5-yl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanol (compound 16) Step 1: (6-chloro-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (5) (200 mg, 1.0 equivalent), benzofuran-5-ylboronic acid (178 mg, 1.3 equivalent), PdCl2 (dppf) (31 mg, 0.05 equivalent), and Na2CO3 (180 mg, 2.0 equivalent) were combined in dioxane (10 mL) and water (3 mL) under N2. The resulting mixture was heated at 100 °C for 12 hours. The reaction mixture was diluted with EtOAc (60 mL), washed with water and brine, and concentrated under vacuum. The crude mixture was purified by silica gel column chromatography to give (6-(benzofuran-5-yl)-5-methylpyridazin-3-yl)(pyridin-3-yl)methanol (13) (151 mg, 56% yield).

[0246] Step 2: PtO2 (82 mg, 0.8 equivalent) and (Boc)2O (125 mg, 1.2 equivalent) were added to a solution of compound 13 (150 mg, 1.0 equivalent) in MeOH (30 mL) and water (0.3 mL). The mixture was degassed with bubbling N2 gas for 10 min and then hydrogenated at rt under H2 (balloon) for 6 h. The catalyst was removed by filtration and the solvent was concentrated under vacuum. The crude mixture was purified by silica gel column chromatography to give tert-butyl 3-((6-(benzofuran-5-yl)-5-methylpyridazin-3-yl)(hydroxy)methyl)piperidine-1-carboxylate (14) (82 mg, 41% yield).

[0247] Step 3: Add a solution of dioxane (1 mL) in 4N HCl to a solution of compound 14 (82 mg) in DCM (0.5 mL). Stir the mixture at rt for 25 min. Concentrate the mixture under vacuum to give (6-(benzofuran-5-yl)-5-methylpyridazin-3-yl)(piperidin-3-yl)methanol (15) as an HCl salt, which was used without purification.

[0248] Step 4: Compound 15 (40 mg) was dissolved in 1,2-dichloroethane (2 mL) and MeOH (0.1 mL), and Et3N (1.1 equivalent) and acetic acid (2 mg) were added. The mixture was stirred at rt for 5 min, and then formaldehyde (12 mg, 37%, 1.2 equivalent) was added. The mixture was stirred at rt for 5 min, and then NaBH(OAc)3 (32 mg, 1.5 equivalent) was added. The resulting mixture was stirred at rt for 30 min and quenched with a saturated aqueous solution of NaHCO3. The mixture was extracted with DCM (2 × 15 mL) and purified by silica gel column chromatography to give (6-(benzofuran-5-yl)-5-methylpyridazin-3-yl)(1-methylpiperidin-3-yl)methanol (16) (25 mg, 61% yield). LCMS: 338.2 (M+H) + .

[0249] Example 4: Synthesis of (6-(benzofuran-5-yl)-5-methylpyridazin-3-yl)(1-ethylpiperidin-3-yl)methanol (compound 17) Compound 15 (40 mg) was dissolved in 1,2-dichloroethane (2 mL) and MeOH (0.1 mL), and Et3N (1.1 equivalent) and acetic acid (2 mg) were added. The mixture was stirred at rt for 5 min, and then acetaldehyde (5 mg, 1.2 equivalent) was added. The mixture was stirred at rt for 5 min, and then NaBH(OAc)3 (32 mg, 1.5 equivalent) was added. The resulting mixture was stirred at rt for 30 min and quenched with a saturated aqueous solution of NaHCO3. The mixture was extracted with DCM (2 × 15 mL) and purified by silica gel column chromatography to give (6-(benzofuran-5-yl)-5-methylpyridazin-3-yl)(1-ethylpiperidin-3-yl)methanol (17) (21 mg, 48% yield). LCMS: 352.4 (M+H) + .

[0250] Example 5: Synthesis of (5-methyl-6-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)(1-methylpiperidin-3-yl)methanol (compound 21) Step 1: Compound 5 (300 mg, 1.0 equivalent), 4,4,5,5-tetramethyl-2-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborhecyclopentane (586 mg, 1.3 equivalent), PdCl2(dppf) (47 mg, 0.05 equivalent), and Na2CO3 (270 mg, 2.0 equivalent) were combined in dioxane (12 mL) and water (4 mL) under N2. The resulting mixture was heated at 100 °C for 8 hours. The reaction mixture was diluted with EtOAc (100 mL), washed with water and brine, and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give (5-methyl-6-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)(pyridin-3-yl)methanol (18) (285 mg, yield 52%).

[0251] Step 2: PtO2 (120 mg, 0.8 equivalent) and (Boc)2O (172 mg, 1.2 equivalent) were added to a solution of compound 18 (280 mg, 1.0 equivalent) in MeOH (75 mL) and water (0.8 mL). The mixture was degassed with bubbling N2 gas for 20 min and then hydrogenated at rt under H2 (balloon) for 6 h. The catalyst was removed by filtration and the solvent was concentrated under vacuum. The crude mixture was purified by silica gel column chromatography to give tert-butyl 3-(hydroxy(5-methyl-6-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidin-1-carboxylate (19) (175 mg, 50% yield).

[0252] Step 3: Add 3 mL of 4N HCl dioxane to a solution of compound 19 (150 mg) in DCM (2 mL). Stir the mixture at rt for 45 min. Concentrate the mixture under vacuum to give (5-methyl-6-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)(piperidin-3-yl)methanol (20) (132 mg) as an HCl salt, which was used without further purification.

[0253] Step 4: To a solution of compound 20 (50 mg, 1.0 equivalent) in 1,2-dichloroethane (3 mL) and MeOH (0.2 mL), Et3N (18 μL, 1.1 equivalent) and acetic acid (1 drop, about 8 mg) were added. The mixture was stirred at rt for 5 min and then formaldehyde (12 mg, 37% in water, 1.2 equivalent) was added. The mixture was stirred at rt for 30 min and then NaBH(OAc)3 (40 mg, 1.5 equivalent) was added. The resulting mixture was stirred at rt for 30 min and quenched with a saturated aqueous solution of NaHCO3. The mixture was extracted with DCM (2 × 25 mL). The crude product was purified by silica gel column chromatography to give (5-methyl-6-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)pyridazin-3-yl)(1-methylpiperidin-3-yl)methanol (21) (32 mg, 62% yield). LCMS: 448.4 (M+H) + .

[0254] 4,4,5,5-Tetramethyl-2-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-1,3,2-dioxaboron Synthesis of heterocyclic pentanes Step 1: CsF (1.8 g, 12 mmol) was slowly added to a solution of 2-bromo-5-(trifluoromethyl)benzaldehyde (2.5 g, 10 mmol) and trimethylsilyltrifluoromethane (1.7 g, 12 mmol) in THF (20 mL) at 0 °C. The mixture was heated to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc (100 mL) and washed with 1 N HCl, saturated NaHCO3, and brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography to give 1-(2-bromo-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethane-1-ol (2.5 g, 78% yield).

[0255] Step 2: Under N2 conditions, phosgene (0.86 g, 7.5 mmol) was slowly added to a suspension of imidazole (2.04 g, 30 mmol) in 1,2-dichloroethane (20 mL) under vigorous stirring. After stirring the mixture at room temperature for 30 min, a solution of 1-(2-bromo-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethane-1-ol (1.6 g, 5 mmol) in 1,2-dichloroethane (3 mL) was added. The mixture was heated to reflux for 10 min. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography to give O-(1-(2-bromo-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethyl)1H-imidazolium-1-thiocarbamate (1.8 g, 84% yield).

[0256] Step 3: To a solution of O-(1-(2-bromo-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethyl)1H-imidazolium-1-thiocarbamate (1.9 g, 4.3 mmol) in toluene (20 mL), add n-tributyltinane (1.53 g, 5.2 mmol) and AIBN (100 mg). Heat the resulting mixture at 90 °C for 2 hours to remove the solvent under vacuum. Purify the residue by silica gel column chromatography to give 1-bromo-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)benzene (0.62 g, 45% yield).

[0257] Step 4: A mixture of 1-bromo-2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)benzene (0.62 g, 2 mmol), bis(pinacol)diborane (0.76 g, 3 mmol), KOAc (0.6 g, 6 mmol), and Pd(dppf)Cl2.CH2Cl2 (81 mg, 0.1 mmol) in dioxane (10 mL) was degassed and heated to 85 °C under nitrogen for 12 hours. The mixture was cooled to rt and the solids were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 4,4,5,5-tetramethyl-2-(2-(2,2,2-trifluoroethyl)-4-(trifluoromethyl)phenyl)-1,3,2-dioxaborhecyclopentane (504 mg, 70% yield).

[0258] Example 6: Synthesis of (R)-(5-methyl-6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)((R)-1-methylpiperidin-3-yl)methanol (compound 28) Steps 1 and 2: Under N2, a solution of NBS (358 mg, 1.1 equivalent) in degassed dioxane (3 mL) was added dropwise to a solution of 3-methylfuran (150 mg, 1.0 equivalent) in degassed dioxane (3 mL). The resulting mixture was stirred at rt for 45 min to form 2-bromo-3-methylfuran (22), which was used directly. Under N2, (4-(trifluoromethyl)phenyl)boronic acid (420 mg, 1.2 equivalent), Cs2CO3 (1.5 g, 2.5 equivalent), Pd(PPh3)4 (105 mg, 0.05 equivalent), and degassed DI water (3 mL) were added to the solution of 2-bromo-3-methylfuran. The resulting mixture was heated at 80 °C for 4 h under N2. The reaction was cooled to rt and diluted with hexane (50 mL). The organic phase was separated and the aqueous phase was extracted with hexane (20 mL). The combined organic phases were washed with brine and concentrated under vacuum. The residue was purified by silica gel column chromatography to provide 3-methyl-2-(4-(trifluoromethyl)phenyl)furan (23) (280 mg, 67% yield).

[0259] Step 3: Under N2 at -30°C, n-BuLi (2.5 M, 0.75 mL, 1.7 equivalent) was added dropwise over 5 min to a solution of compound 23 (250 mg, 1.0 equivalent) in anhydrous THF (8 mL). The mixture was stirred at -30°C for an additional 45 min, and a solution of (R)-3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylic acid tert-butyl ester (425 mg, 1.4 equivalent) 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 stirred at rt for 2 h. The reaction was quenched at 0°C with saturated NH4Cl (30 mL) and then extracted with DCM (2 × 20 mL). The combined organic phases were washed with brine and concentrated under vacuum. The residue was purified by silica gel column chromatography to give (R)-3-(4-methyl-5-(4-(trifluoromethyl)phenyl)furan-2-carbonyl)piperidine-1-carboxylic acid tert-butyl ester (24) (252 mg, yield 52%).

[0260] Step 4: Formic acid (210 mg, 10 equivalents) and TEA (465 mg, 10 equivalents) were added dropwise to a solution of compound 24 (200 mg, 1.0 equivalents) in MeOH (2 mL) at 0 °C. The mixture was degassed by bubbling N2 gas for 2 min at room temperature, and then the catalyst {N-[3-(η6-phenyl)propyl]-[(1R-2R)-1,2-diphenyl-1-4-methylbenzenesulfonamide (kN')-ethyl-2-amino-(kN)]}ruthenium(II) (R,R)-Teth- (CAS# 1192620-83-9) (8.5 mg, 0.03 equivalents) was added. The resulting mixture was stirred at rt for 15 h. The mixture was diluted with DCM (25 mL) and washed with water, saturated NaHCO3 aqueous solution, and brine. The crude mixture was purified by silica gel column chromatography to give (R)-3-((R)-hydroxy(4-methyl-5-(4-(trifluoromethyl)phenyl)furan-2-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (25) (117 mg, yield 58%).

[0261] Step 5: A solution of compound 25 (115 mg, 1.0 equivalent) in THF (4 mL) and water (0.4 mL) was stirred at -15 °C (acetone-ice bath) for 10 min. Solid NBS (61 mg, 1.3 equivalent) was added in portions. After stirring at -15 °C for 30 min, hydrazine hydrate (131 mg, 10 equivalent) was added dropwise. The resulting mixture was stirred at 0 °C for 1 h, and then at rt for 1 h. The reaction was quenched with a saturated aqueous solution of NaHCO3 (10 mL) and extracted with DCM (2 × 15 mL). The combined organic phases were washed with brine and concentrated under vacuum. The residue was purified by silica gel column chromatography to give (R)-3-((R)-hydroxy(5-methyl-6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester (26) (83 mg, 70% yield).

[0262] Step 6: Add HCl (4N dioxane solution, 1 mL) to a solution of compound 26 (82 mg) in DCM (1 mL). Stir the mixture at rt for 20 min under N2. Remove the solvent under vacuum to give (R)-(5-methyl-6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)((R)-piperidin-3-yl)methanol (27) as an HCl salt.

[0263] Step 7: To a solution of compound 27 (30 mg) in 1,2-dichloroethane (2 mL) and MeOH (0.1 mL), Et3N (1.1 equivalents) and acetic acid (2 mg) were added. The mixture was stirred at rt for 5 min, and then formaldehyde (7.6 mg, 1.2 equivalents) was added. The mixture was stirred at rt for 5 min, and then NaBH(OAc)3 (32.6 mg, 1.8 equivalents) was added. The resulting mixture was stirred at rt for 30 min and quenched with a saturated aqueous solution of NaHCO3. The mixture was extracted with DCM (2 × 15 mL). The residue was purified by silica gel column chromatography to give (R)-(5-methyl-6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)((R)-1-methylpiperidin-3-yl)methanol (28) (30 mg, 96% yield). LCMS: 366.2 (M+H) + .

[0264] Example 7: Synthesis of (R)-((R)-1-ethylpiperidin-3-yl)(5-methyl-6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)methanol (compound 29) To a solution of compound 27 (35 mg) in 1,2-dichloroethane (2 mL) and MeOH (0.1 mL), Et3N (1.1 equivalents) and acetic acid (2 mg) were added. The mixture was stirred at rt for 5 min, and then acetaldehyde (5 mg, 1.2 equivalents) was added. The mixture was stirred at rt for 5 min, and then NaBH(OAc)3 (32 mg, 1.5 equivalents) was added. The resulting mixture was stirred at rt for 30 min and quenched with a saturated aqueous solution of NaHCO3. The mixture was extracted with DCM (2 × 15 mL). The residue was purified by silica gel column chromatography to give (R)-((R)-1-ethylpiperidin-3-yl)(5-methyl-6-(4-(trifluoromethyl)phenyl)pyridazin-3-yl)methanol (29) (27 mg, 75% yield). LCMS: 380.5 (M+H) + .

[0265] Example 8: Synthesis of (R)-(6-(2-(difluoromethoxy)-4-(trifluoromethyl)phenyl)-5-methylpyridazin-3-yl)((R)-1-methylpiperidin-3-yl)methanol (compound 31) To a solution of 2-(6-((R)-hydroxy((R)-1-methylpiperidin-3-yl)methyl)-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol (30) (100 mg, 1.0 equivalent) in water (2 mL) and acetonitrile (2 mL), KOH (300 mg, 20 equivalent) was added. The mixture was stirred at 0 °C for 5 min, and then diet...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof: ； in: X is N, N(R) 7a ), C(R7) or C(O); Y is N, N(R) 8a ), C(R8) or C(O); where one of X and Y is N, N(R 7a ) or N(R 8a ); Z is -L-R6. or ; L is -C(H)(OH)-; R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups of R1 may be substituted; or R1 and R2 may be combined to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring may optionally be substituted by one, two, or three R1 groups. 14 Group substitution; or combination of R2 and R3 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; or combination of R3 and R4 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; or combination of R4 and R5 to form a 4, 5, or 6-membered cycloalkyl ring, a 4, 5, or 6-membered heterocycloalkyl ring, a 5 or 6-membered heteroaromatic 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 heteroaromatic ring, or the benzene ring is optionally replaced by one, two, or three R groups. 14 Group substitution; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 and R8 are each independently selected from hydrogen, halogen, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; R 7a and R 8a Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; or two R groups may be substituted. 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; n is 0, 1, 2, 3, or 4; and This indicates a single or double bond, such that all valences are satisfied.

2. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ia): 。 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C. 1-6 alkyl.

5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen.

6. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3.

7. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (Ib): 。 8. The compound according to any one of claims 7, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a Selected from hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 Cycloalkyl.

9. The compound according to claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 1-6 alkyl.

10. The compound of claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 3-6 Cycloalkyl.

11. The compound according to claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is hydrogen.

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 -N(R) 10 (R) 11 -C(O)OR 10 or -C(O)N(R) 10 (R) 11 ).

13. The compound according to any one of claims 1-12, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 alkyl.

14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OH or -OCH3.

15. The compound according to any one of claims 1-14, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 .

16. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen.

17. The compound according to any one of claims 1-16, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 or -N(R) 10 (R) 11 ).

18. The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

19. The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 .

20. The compound according to any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.

21. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 or -N(R) 10 (R) 11 ).

22. The compound according to any one of claims 1-21, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen or C. 1-6 alkyl.

23. A compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof: ； in: X is N, N(R) 7a ), C(R7) or C(O); Y is N, N(R) 8a ), C(R8) or C(O); Z is -L-R6. or ; L is -C(H)(OH)-; R6 is , , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 and R8 are each independently selected from hydrogen, halogen, -CN, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; R 7a and R 8a Each is independently selected from hydrogen and C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; R9 is optionally superimposed by one, two, or three Rs. 14 C with substituent group 1-9 Mixed aromatics; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; or two R groups may be substituted. 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; n is 0, 1, 2, 3, or 4; and This indicates a single or double bond, such that all valences are satisfied.

24. The compound according to claim 23, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIa): 。 25. The compound according to claim 23 or 24, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

26. The compound according to any one of claims 23-25, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is selected from hydrogen and unsubstituted C. 1-6 alkyl.

27. The compound according to any one of claims 22-26, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is hydrogen.

28. The compound according to any one of claims 22-26, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is -CH3.

29. The compound according to claim 23, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIb): 。 30. The compound according to any one of claims 23-29, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen, halogen, unsubstituted C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups.

31. The compound according to any one of claims 23-30, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is selected from hydrogen and unsubstituted C. 1-6 alkyl.

32. The compound according to any one of claims 23-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen.

33. The compound according to any one of claims 23-31, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is -CH3.

34. The compound according to claim 23, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIc): 。 35. The compound according to any one of claims 34, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a Selected from hydrogen, unsubstituted C 1-6 Alkyl and unsubstituted C 3-6 Cycloalkyl.

36. The compound of claim 35, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 1-6 alkyl.

37. The compound of claim 35, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is unreplaced C 3-6 Cycloalkyl.

38. The compound of claim 35, or a pharmaceutically acceptable salt or solvate thereof, wherein R 7a It is hydrogen.

39. The compound according to any one of claims 23-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally composed of one, two, or three Rs. 14 Pyridyl groups substituted with functional groups.

40. The compound according to any one of claims 23-39, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally composed of one, two, or three R... 14 Group-substituted pyridyl groups, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 alkyl.

41. The compound according to any one of claims 23-40, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is optionally composed of one, two, or three Rs. 14 Group-substituted pyridyl groups, wherein each R 14 It is independently selected from halogen, -CH3, -CF3, -OH or -OCH3.

42. The compound according to any one of claims 23-40, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is or .

43. The compound according to any one of claims 23-38, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is indole or benzofuranyl, wherein the indole and benzofuranyl are optionally surrounded by one, two, or three R9 groups. 14 Group substitution.

44. The compound of claim 43, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is indole or benzofuranyl, wherein the indole and benzofuranyl are optionally surrounded by one, two, or three R9 groups. 14 Group substitution, wherein each R 14 Independently selected from halogens, unsubstituted C 1-6 Alkyl, C 1-6 Halogenated alkyl or -OR 10 , where R 10 Is it hydrogen or unsubstituted C? 1-6 alkyl.

45. The compound according to claim 43 or claim 44, or a pharmaceutically acceptable salt or solvate thereof, wherein R9 is , or .

46. ​​The compound according to any one of claims 1-45, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -L-R6.

47. The compound according to any one of claims 1-46, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

48. The compound according to any one of claims 1-45, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is .

49. The compound according to any one of claims 1-45, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is .

50. The compound according to any one of claims 1-49, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It can be arbitrarily determined by one, two, or three Rs. 14 C with substituent group 1-6 alkyl.

51. The compound according to any one of claims 1-50, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is unreplaced C 1-6 alkyl.

52. The compound according to any one of claims 1-51, or a pharmaceutically acceptable salt or solvate thereof, wherein R 6a It is -CH3.

53. The compound according to any one of claims 1-46, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is selected from: 。 54. The compound according to any one of claims 1-45, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is selected from: and .

55. The compound according to any one of claims 1-46, or a pharmaceutically acceptable salt or solvate thereof, wherein R6 is .

56. The compound according to any one of claims 1-55, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

57. 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, halogens, and carbon. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OR9; R6 is , , , , , , or ; R 6a Selected from hydrogen, C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. 14 Group substitution; or R 6a and R 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; R7 and R8 are each independently selected from hydrogen, halogen, and C. 1-6 Alkyl and C 1-6 Halogenated alkyl groups, wherein the alkyl group is optionally selected from -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; Each R9 is independently a C 1-6 Halogenated alkyl groups; Each R 10 Independently selected from hydrogen and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 11 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 12 Independently selected from hydrogen and C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 13 Choose C independently 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Heteroaryl groups are optionally selected from halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 One, two, or three groups of the heteroaryl group are substituted; Each R 14 Independently selected from halogens, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; Each R 15 Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -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 group, C 3-6 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl groups, -OR 10 and -N(R) 10 (R) 11 One, two, or three groups may be substituted; or two R groups may be substituted. 15 Together they form a bridge, wherein the bridge is -CH2- or -CH2CH2-; and n is 0, 1, 2, 3 or 4.

58. The compound according to claim 57, or a pharmaceutically acceptable salt or solvate thereof, having the structure of formula (IIIa): ； in: R1, R2, R3, R4, and R5 are each independently selected from hydrogen, halogens, and carbon. 1-6 Alkyl, C 1-6 Halogenated alkyl groups and -OR9; R 6a Selected from hydrogen and C 1-6 alkyl; R7 and R8 are each independently selected from hydrogen and C. 1-6 Alkyl; and Each R9 is independently a C 1-6 Halogenated alkyl groups.

59. The compound according to claim 57 or 58, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is hydrogen.

60. The compound according to any one of claims 57-59, or a pharmaceutically acceptable salt or solvate thereof, wherein R7 is C 1-6 alkyl.

61. The compound according to any one of claims 57-60, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is hydrogen.

62. The compound according to any one of claims 57-60, or a pharmaceutically acceptable salt or solvate thereof, wherein R8 is C 1-6 alkyl.

63. The compound according to any one of claims 57-62, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen, C 1-6 Halogenated alkyl groups and -OR9.

64. The compound according to any one of claims 57-63, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is -OR9.

65. The compound according to any one of claims 57-63, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is C 1-6 Halogenated alkyl groups.

66. The compound according to any one of claims 57-63, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is hydrogen.

67. The compound according to any one of claims 57-66, or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is hydrogen.

68. The compound according to any one of claims 57-67, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is C 1-6 Halogenated alkyl groups.

69. The compound according to any one of claims 57-68, or a pharmaceutically acceptable salt or solvate thereof, wherein R4 is hydrogen.

70. The compound according to any one of claims 57-69, or a pharmaceutically acceptable salt or solvate thereof, wherein R5 is hydrogen.

71. A compound selected from the following: or its pharmaceutically acceptable salts or solvates.

72. A compound selected from the following: , , , , , , , and or its pharmaceutically acceptable salts or solvates.

73. A pharmaceutical composition comprising a compound according to any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

74. A method of treating a metabolic disease in a patient who requires it, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof.

75. The method of claim 74, wherein the metabolic disease is selected from type 2 diabetes, atherosclerosis, obesity, and gout.

76. A method of treating liver disease in a patient who requires it, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1-74, or a pharmaceutically acceptable salt or solvate thereof.

77. The method of claim 76, wherein the liver disease is selected from non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH), viral hepatitis, and cirrhosis.

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

79. The method of claim 78, wherein the lung disease is selected from asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis.

80. A method of treating a central nervous system disease in a patient who requires it, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof.

81. The method of claim 80, 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.

82. A method of treating an inflammatory or autoimmune disease in a patient who requires it, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof.

83. The method of claim 82, wherein the inflammatory or autoimmune disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, inflammatory bowel disease, Crohn's disease, and ulcerative colitis.

84. A method of treating cardiovascular disease in a patient who requires it, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1-72, or a pharmaceutically acceptable salt or solvate thereof.

85. The method of claim 84, wherein the cardiovascular disease is atherosclerosis or stroke.

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