NLRP3 inhibitors

Abstract

The present invention relates to compounds of formula (A), namely NLRP3 inhibitors. The inhibitor provided by the invention can be used for treating NLRP3-related diseases or symptoms, such as autoimmune diseases and inflammatory diseases. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit NLRP3, methods of treating diseases or conditions associated with NLRP3, and methods of synthesizing such compounds. # imgabs0 #

Description

[Cross-reference to related applications]

[0001] The present invention claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 63 / 441,687, filed on January 27, 2023, entitled “NLRP3 Inhibitors,” the disclosure of which is incorporated by reference in its entirety for all purposes.

Technical field

[0002] The present invention relates to NLRP3 inhibitors. These inhibitors can be used to treat NLRP3-associated diseases or conditions, such as autoimmune diseases, Alzheimer's disease, and coronavirus infection, by inducing a persistent response. Specifically, the present invention relates to compounds and pharmaceutical compositions that inhibit NLRP3, methods for treating NLRP3-associated diseases or conditions, and methods for synthesizing such compounds. [Background Technology]

[0003] NLRP3 (NOD, LRR, and pyrin domain-containing protein 3) is an intracellular sensor that detects a wide range of microbial motifs, endogenous danger signals, and environmental stimuli, leading to the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome triggers the caspase-1-dependent release of the proinflammatory cytokines IL-1β and IL-18, as well as ectopic cell death mediated by pyroptosis.

[0004] Inflammasomes play a crucial role in innate immunity by serving as signaling platforms that process a wide range of pathogenic and cellular products associated with stress and injury. To date, the best-studied and best-characterized inflammasome is the NLRP3 inflammasome, which is composed of NLRP3 (leucine-rich repeat (NLR)-containing nucleotide-binding domain and pyrine domain-containing receptor 3), ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and procaspase-1. Activation of the NLRP3 inflammasome is mediated by a highly diverse range of stimuli. Upon activation, NLRP3 protein recruits the adaptor protein ASC, which in turn recruits procaspase-1, leading to its cleavage and activation, thereby inducing the maturation and secretion of inflammatory cytokines and pyroptosis. However, aberrant activation of the NLRP3 inflammasome is associated with a variety of diseases, including diabetes, atherosclerosis, metabolic syndrome, cardiovascular, and neurodegenerative disorders, garnering significant clinical interest in the discovery of potential inhibitors of the NLRP3 inflammasome. Recent studies have revealed various inhibitors of the NLRP3 inflammasome pathway, validated in vitro and in vivo in animal models of NLRP3-related disorders. Some of these inhibitors directly target the NLRP3 protein, while others target other components and products of the inflammasome. Directly targeting the NLRP3 protein may be a preferred option because it can prevent off-target immunosuppression and thus limit tissue damage.

[0005] Although many studies on NLRP3 inhibitors have been conducted to date, work is still ongoing to overcome major issues in patient treatment, such as NLRP3 inhibitor resistance and inhibitor specificity. [Summary of the invention]

[0006] The first aspect of the present invention relates to a compound comprising formula (A): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; R 6 Selected from H, SO2R 8 , NH2, C1-C6 alkyl, C1-C6 alkyl-C(O)-, aryl, wherein the alkyl or aryl group is optionally substituted with one or more substituents independently selected from halogen, CN, OH; R 7 is H, C1-C6 alkyl or NH2; or R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring or heteroaromatic ring; R 8 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkyl, cycloalkyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, and OH; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2; The restriction condition is that when R 5 When it is methyl, R 6 Not H or CH3CO-.

[0007] Another aspect of the present invention relates to compounds of formula (I): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; R 8 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkyl, cycloalkyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, and OH; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2.

[0008] Another aspect of the present invention relates to compounds of formula (II): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2.

[0009] Another aspect of the present invention relates to compounds of formula (III): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: W is selected from CH, N; R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2.

[0010] Another aspect of the present invention relates to compounds of formula (IV): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2.

[0011] Another aspect of the present invention relates to compounds of formula (V): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; R 6 is selected from H, C1-C6 alkyl, C1-C6 alkyl-C(O)-, aryl, wherein the alkyl or aryl group is optionally substituted with one or more substituents independently selected from halogen, CN, OH; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2; The restriction condition is that when R 5 When it is methyl, R 6 Not H or CH3CO-.

[0012] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, a diluent, or a surfactant.

[0013] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, a diluent, or a surfactant.

[0014] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, a diluent, or a surfactant.

[0015] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, a diluent, or a surfactant.

[0016] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, a diluent, or a surfactant.

[0017] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include an excipient, a diluent, or a surfactant.

[0018] Another aspect of the present invention relates to a method for treating an inflammatory disease or condition, comprising administering to a patient in need of treatment for the inflammatory disease or condition an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0019] Another aspect of the present invention relates to a method for treating an inflammatory disease or condition, comprising administering to a patient in need of treatment for the inflammatory disease or condition an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0020] Another aspect of the present invention relates to a method for treating an inflammatory disease or condition, comprising administering to a patient in need of treatment for the inflammatory disease or condition an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0021] Another aspect of the present invention relates to a method for treating an inflammatory disease or condition, comprising administering to a patient in need of treatment for the inflammatory disease or condition an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0022] Another aspect of the present invention relates to a method for treating an inflammatory disease or condition, comprising administering to a patient in need of treatment for the inflammatory disease or condition an effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0023] Another aspect of the present invention relates to a method for treating an inflammatory disease or condition, comprising administering to a patient in need of treatment for the inflammatory disease or condition an effective amount of a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0024] Another aspect of the present invention relates to a method for inhibiting NLRP3, which comprises administering to a patient in need thereof an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0025] Another aspect of the present invention relates to a method for inhibiting NLRP3, which comprises administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0026] Another aspect of the present invention relates to a method for inhibiting NLRP3, which comprises administering to a patient in need thereof an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0027] Another aspect of the present invention relates to a method for inhibiting NLRP3, which comprises administering to a patient in need thereof an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0028] Another aspect of the present invention relates to a method for inhibiting NLRP3, which comprises administering to a patient in need thereof an effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0029] Another aspect of the present invention relates to a method for inhibiting NLRP3, which comprises administering to a patient in need thereof an effective amount of a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0030] Another aspect of the present invention relates to a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting NLRP3.

[0031] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting NLRP3.

[0032] Another aspect of the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting NLRP3.

[0033] Another aspect of the present invention relates to a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting NLRP3.

[0034] Another aspect of the present invention relates to a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting NLRP3.

[0035] Another aspect of the present invention relates to a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, for use in the manufacture of a medicament for inhibiting NLRP3.

[0036] Another aspect of the present invention relates to the use of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for treating diseases and disorders associated with NLRP3.

[0037] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for treating diseases and disorders associated with NLRP3.

[0038] Another aspect of the present invention relates to the use of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for treating diseases and disorders associated with NLRP3.

[0039] Another aspect of the present invention relates to the use of a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for treating diseases and disorders associated with NLRP3.

[0040] Another aspect of the present invention relates to the use of a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for treating diseases and disorders associated with NLRP3.

[0041] Another aspect of the present invention relates to the use of a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof for treating diseases and disorders associated with NLRP3.

[0042] Another aspect of the present invention relates to a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing the diseases or conditions disclosed herein.

[0043] Another aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing the diseases or conditions disclosed herein.

[0044] Another aspect of the present invention relates to a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing the diseases or conditions disclosed herein.

[0045] Another aspect of the present invention relates to a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing the diseases or conditions disclosed herein.

[0046] Another aspect of the present invention relates to a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing the diseases or conditions disclosed herein.

[0047] Another aspect of the present invention relates to a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof, for use in the manufacture of a medicament for treating or preventing the diseases or conditions disclosed herein.

[0048] Another aspect of the present invention relates to a method for treating or preventing a disease or condition disclosed herein in a subject in need thereof. The method comprises administering to a subject in need of treatment an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0049] Another aspect of the present invention relates to a method for treating or preventing a disease or condition disclosed herein in a subject in need thereof. The method comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0050] Another aspect of the present invention relates to a method for treating or preventing a disease or condition disclosed herein in a subject in need thereof. The method comprises administering to a subject in need thereof an effective amount of a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0051] Another aspect of the present invention relates to a method for treating or preventing a disease or condition disclosed herein in a subject in need thereof. The method comprises administering to a subject in need thereof an effective amount of a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0052] Another aspect of the present invention relates to a method for treating or preventing a disease or condition disclosed herein in a subject in need thereof. The method comprises administering to a subject in need thereof an effective amount of a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0053] Another aspect of the present invention relates to a method for treating or preventing a disease or condition disclosed herein in a subject in need thereof. The method comprises administering to a subject in need thereof an effective amount of a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0054] Another aspect of the present invention relates to the use of a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for treating the diseases or conditions disclosed herein.

[0055] Another aspect of the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for treating the diseases or conditions disclosed herein.

[0056] Another aspect of the present invention relates to the use of the compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for treating the diseases or conditions disclosed herein.

[0057] Another aspect of the present invention relates to the use of the compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for treating the diseases or conditions disclosed herein.

[0058] Another aspect of the present invention relates to the use of the compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for treating the diseases or conditions disclosed herein.

[0059] Another aspect of the present invention relates to the use of a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof for treating the diseases or conditions disclosed herein.

[0060] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0061] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0062] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0063] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0064] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0065] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0066] The present invention provides NLRP3 inhibitors as therapeutic agents for treating diseases and disorders.

[0067] The present invention further provides compounds and compositions that have improved efficacy and safety profiles relative to known NLRP3 inhibitors. The present invention also provides agents that have novel mechanisms of action against NLRP3 in the treatment of various types of diseases.

[0068] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0069] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0070] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0071] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0072] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0073] The present invention further provides a method for treating a disease or condition associated with NLRP3, comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0074] The present invention further provides a method for treating blood diseases, bone diseases, cancer diseases, cardiovascular diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases, genetic diseases, immune diseases, infectious diseases, liver diseases, psychiatric diseases, metabolic diseases, muscle diseases, kidney diseases, neuronal diseases, oral diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases, and smell / taste diseases; which comprises administering to a patient suffering from at least one of such diseases or conditions a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0075] The present invention further provides a method for treating blood diseases, bone diseases, cancer diseases, cardiovascular diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases, genetic diseases, immune diseases, infectious diseases, liver diseases, psychiatric diseases, metabolic diseases, muscle diseases, kidney diseases, neuronal diseases, oral diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases, and smell / taste diseases; which comprises administering to a patient suffering from at least one of such diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0076] The present invention further provides a method for treating blood diseases, bone diseases, cancer diseases, cardiovascular diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases, genetic diseases, immune diseases, infectious diseases, liver diseases, psychiatric diseases, metabolic diseases, muscle diseases, kidney diseases, neuronal diseases, oral diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases, and smell / taste diseases; the method comprises administering to a patient suffering from at least one of such diseases or conditions a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0077] The present invention further provides a method for treating blood diseases, bone diseases, cancer diseases, cardiovascular diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases, genetic diseases, immune diseases, infectious diseases, liver diseases, psychiatric diseases, metabolic diseases, muscle diseases, kidney diseases, neuronal diseases, oral diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases, and smell / taste diseases; the method comprises administering to a patient suffering from at least one of these diseases or conditions a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0078] The present invention further provides a method for treating blood diseases, bone diseases, cancer diseases, cardiovascular diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases, genetic diseases, immune diseases, infectious diseases, liver diseases, psychiatric diseases, metabolic diseases, muscle diseases, kidney diseases, neuronal diseases, oral diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases, and smell / taste diseases; which comprises administering to a patient suffering from at least one of such diseases or conditions a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0079] The present invention further provides a method for treating blood diseases, bone diseases, cancer diseases, cardiovascular diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases, genetic diseases, immune diseases, infectious diseases, liver diseases, psychiatric diseases, metabolic diseases, muscle diseases, kidney diseases, neuronal diseases, oral diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases, and smell / taste diseases; which comprises administering to a patient suffering from at least one of such diseases or conditions a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0080] The present invention further provides methods for treating a disease, disorder, or condition selected from the group consisting of: acne vulgaris (ACNE); hereditary acral keratoderma hyaline papularis; adult-onset Still's disease (AOSD); Aicardi-Goutieres Syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthracene; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); autoimmune diseases of the cardiovascular system; autoimmune diseases of the gastrointestinal tract; autoinflammatory syndrome; Behcet's syndrome; Syndrome; Blau syndrome (BLAUS); Body mass index quantitative trait locus 11 (BMIQ11); Bone inflammatory diseases; Cerebral edema; Brucellosis; Candidiasis; Cervical lymphadenitis; Chondrocalcinosis; Chronic meningitis; Chronic recurrent multifocal osteomyelitis (CRMO); Chronic urticaria; Cinca syndrome (CINCA); Conjunctival diseases; Conjunctivitis; Connective tissue diseases; Corneal diseases; Coronavirus infections; Covid-19; Crohn's disease Disease); Cryptopyrin-associated periodic syndromes (CAPS); Cystic Fibrosis (CF); Autosomal dominant hearing loss type 34 with or without inflammation (DFNA34); Dermatitis; Diabetes mellitus; Diabetic encephalopathy; Rash (RASH); Eye disease; Familial cold autoinflammatory syndrome (FCU); Familial cold autoinflammatory syndrome type 1 (FCAS1); Familial cold autoinflammatory syndrome type 2 (FCAS2); Familial Mediterranean fever (FMF); Gout (GOUT); Hereditary periodic fever syndromes; Hidradenitis; Hidradenitis suppurativa; Essential hypertension (EHT); Hyperuricemia; Intellectual developmental disorder type 30 with speech delay and behavioral abnormalities (MRD30); Interstitial lung disease type 2 (ILD2); Hereditary keratitis (KERH); Hereditary transient corneal endotheliitis Fugax Hereditaria (KEFH); lipoprotein quantitative trait locus (LPAQTL); lymph node disease; age-related macular degeneration type 1 (ARMD1); malaria (CM); meningitis; mevalonic aciduria (MEVA); Muckle-Wells syndrome (MWS); Mycobacterium Kansasii; myocardial infarction (MCI1); kidney stones; neurologic diseases; nonalcoholic steatohepatitis (NASH);Papilitis; osteomyelitis; osteoporosis (OSTEOP); otitis media (OMS); papilledema; pericardial effusion; pericardial disease; pharyngitis; polyradiculoneuropathy; primary bacterial infections; proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); pyoderma; pyoderma gangrenosum; suppurative sterile arthritis, pyoderma gangrenosum, and acne (PAPAS); respiratory failure; salmonellosis; Schnitzler syndrome Syndrome); sebaceous gland disease; sensorineural hearing loss; serum amyloid a-amylosis; silicosis; skin disease; stomatitis; type 2 diabetes (T2D); ureteral disease; urticaria (HIVES); vulvovaginal candidiasis; Wells Syndrome, such methods comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof. ;

[0081] The present invention further provides methods for treating a disease, disorder, or condition selected from the group consisting of: acne vulgaris (ACNE); hereditary acral keratoderma hyaline papularis; adult-onset Still's disease (AOSD); Aicardi-Gautiers syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthracene; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); autoimmune diseases of the cardiovascular system; autoimmune diseases of the gastrointestinal tract; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantitative trait locus 11 (BMIQ11); and inflammatory bone diseases. ; cerebral edema; brucellosis; candidiasis; cervical lymphadenitis; chondrocalcinosis; chronic meningitis; chronic recurrent multifocal osteomyelitis (CRMO); chronic urticaria; Cinca syndrome (CINCA); conjunctival diseases; conjunctivitis; connective tissue diseases; corneal diseases; coronavirus infections; Covid-19; Crohn's disease; cryptopyrin-associated periodic syndrome (CAPS); cystic fibrosis (CF); autosomal dominant hearing loss type 34 with or without inflammation (DFNA34); dermatitis; diabetes mellitus; diabetic encephalopathy; rash (RASH); eye diseases; familial cold autoinflammatory syndrome (FCU); familial cold autoinflammatory syndrome type 1 (FCAS) 1); familial cold autoinflammatory syndrome type 2 (FCAS2); familial Mediterranean fever (FMF); gout (GOUT); hereditary periodic fever syndromes; hidradenitis; hidradenitis suppurativa; essential hypertension (EHT); hyperuricemia; autosomal dominant mental retardation type 30 with speech delay and behavioral abnormalities (MRD30); interstitial lung disease type 2 (ILD2); hereditary keratitis (KERH); hereditary transient corneal endotheliitis (KEFH); lipoprotein quantitative trait locus (LPAQTL); lymph node disease; age-related macular degeneration type 1 (ARMD1); malaria (CM); meningitis; mevalonic aciduria (MEVA); Musculoskeletal muscle atrophy (MUA) Mycobacterium kansasii syndrome (MWS); Mycobacterium kansasii disease; Myocardial infarction (MCI1); Kidney stones; Neurological diseases; Nonalcoholic steatohepatitis (NASH); Papilitis; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial disease; Pharyngitis; Polyradiculoneuropathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid a-amyloidosis; Silicosis; Skin diseases; Stomatitis;Type 2 diabetes (T2D); ureteral disease; urticaria (HIVES); vulvovaginal candidiasis; Wells syndrome, such methods comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0082] The present invention further provides methods for treating a disease, disorder, or condition selected from the group consisting of: acne vulgaris (ACNE); hereditary acral keratoderma hyaline papularis; adult-onset Still's disease (AOSD); Aicardi-Gautiers syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthracene; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); autoimmune diseases of the cardiovascular system; autoimmune diseases of the gastrointestinal tract; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantitative trait locus 11 (BMIQ11); and inflammatory bone diseases. ; cerebral edema; brucellosis; candidiasis; cervical lymphadenitis; chondrocalcinosis; chronic meningitis; chronic recurrent multifocal osteomyelitis (CRMO); chronic urticaria; Cinca syndrome (CINCA); conjunctival diseases; conjunctivitis; connective tissue diseases; corneal diseases; coronavirus infections; Covid-19; Crohn's disease; cryptopyrin-associated periodic syndrome (CAPS); cystic fibrosis (CF); autosomal dominant hearing loss type 34 with or without inflammation (DFNA34); dermatitis; diabetes mellitus; diabetic encephalopathy; rash (RASH); eye diseases; familial cold autoinflammatory syndrome (FCU); familial cold autoinflammatory syndrome type 1 (FCAS) 1); familial cold autoinflammatory syndrome type 2 (FCAS2); familial Mediterranean fever (FMF); gout (GOUT); hereditary periodic fever syndromes; hidradenitis; hidradenitis suppurativa; essential hypertension (EHT); hyperuricemia; autosomal dominant mental retardation type 30 with speech delay and behavioral abnormalities (MRD30); interstitial lung disease type 2 (ILD2); hereditary keratitis (KERH); hereditary transient corneal endotheliitis (KEFH); lipoprotein quantitative trait locus (LPAQTL); lymph node disease; age-related macular degeneration type 1 (ARMD1); malaria (CM); meningitis; mevalonic aciduria (MEVA); Musculoskeletal muscle atrophy (MUA) Mycobacterium kansasii syndrome (MWS); Mycobacterium kansasii disease; Myocardial infarction (MCI1); Kidney stones; Neurological diseases; Nonalcoholic steatohepatitis (NASH); Papilitis; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial disease; Pharyngitis; Polyradiculoneuropathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid a-amyloidosis; Silicosis; Skin diseases; Stomatitis;Type 2 diabetes (T2D); ureteral disease; urticaria (HIVES); vulvovaginal candidiasis; Wells syndrome, such methods comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0083] The present invention further provides methods for treating a disease, disorder, or condition selected from the group consisting of: acne vulgaris (ACNE); hereditary acral keratoderma hyaline papularis; adult-onset Still's disease (AOSD); Aicardi-Gautiers syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthracene; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); autoimmune diseases of the cardiovascular system; autoimmune diseases of the gastrointestinal tract; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantitative trait locus 11 (BMIQ11); and inflammatory bone diseases. ; cerebral edema; brucellosis; candidiasis; cervical lymphadenitis; chondrocalcinosis; chronic meningitis; chronic recurrent multifocal osteomyelitis (CRMO); chronic urticaria; Cinca syndrome (CINCA); conjunctival diseases; conjunctivitis; connective tissue diseases; corneal diseases; coronavirus infections; Covid-19; Crohn's disease; cryptopyrin-associated periodic syndrome (CAPS); cystic fibrosis (CF); autosomal dominant hearing loss type 34 with or without inflammation (DFNA34); dermatitis; diabetes mellitus; diabetic encephalopathy; rash (RASH); eye diseases; familial cold autoinflammatory syndrome (FCU); familial cold autoinflammatory syndrome type 1 (FCAS) 1); familial cold autoinflammatory syndrome type 2 (FCAS2); familial Mediterranean fever (FMF); gout (GOUT); hereditary periodic fever syndromes; hidradenitis; hidradenitis suppurativa; essential hypertension (EHT); hyperuricemia; autosomal dominant mental retardation type 30 with speech delay and behavioral abnormalities (MRD30); interstitial lung disease type 2 (ILD2); hereditary keratitis (KERH); hereditary transient corneal endotheliitis (KEFH); lipoprotein quantitative trait locus (LPAQTL); lymph node disease; age-related macular degeneration type 1 (ARMD1); malaria (CM); meningitis; mevalonic aciduria (MEVA); Musculoskeletal muscle atrophy (MUA) Mycobacterium kansasii syndrome (MWS); Mycobacterium kansasii disease; Myocardial infarction (MCI1); Kidney stones; Neurological diseases; Nonalcoholic steatohepatitis (NASH); Papilitis; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial disease; Pharyngitis; Polyradiculoneuropathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid a-amyloidosis; Silicosis; Skin diseases; Stomatitis;Type 2 diabetes (T2D); ureteral disease; urticaria (HIVES); vulvovaginal candidiasis; Wells syndrome, such methods comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0084] The present invention further provides methods for treating a disease, disorder, or condition selected from the group consisting of: acne vulgaris (ACNE); hereditary acral keratoderma hyaline papularis; adult-onset Still's disease (AOSD); Aicardi-Gautiers syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthracene; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); autoimmune diseases of the cardiovascular system; autoimmune diseases of the gastrointestinal tract; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantitative trait locus 11 (BMIQ11); and inflammatory bone diseases. ; cerebral edema; brucellosis; candidiasis; cervical lymphadenitis; chondrocalcinosis; chronic meningitis; chronic recurrent multifocal osteomyelitis (CRMO); chronic urticaria; Cinca syndrome (CINCA); conjunctival diseases; conjunctivitis; connective tissue diseases; corneal diseases; coronavirus infections; Covid-19; Crohn's disease; cryptopyrin-associated periodic syndrome (CAPS); cystic fibrosis (CF); autosomal dominant hearing loss type 34 with or without inflammation (DFNA34); dermatitis; diabetes mellitus; diabetic encephalopathy; rash (RASH); eye diseases; familial cold autoinflammatory syndrome (FCU); familial cold autoinflammatory syndrome type 1 (FCAS) 1); familial cold autoinflammatory syndrome type 2 (FCAS2); familial Mediterranean fever (FMF); gout (GOUT); hereditary periodic fever syndromes; hidradenitis; hidradenitis suppurativa; essential hypertension (EHT); hyperuricemia; autosomal dominant mental retardation type 30 with speech delay and behavioral abnormalities (MRD30); interstitial lung disease type 2 (ILD2); hereditary keratitis (KERH); hereditary transient corneal endotheliitis (KEFH); lipoprotein quantitative trait locus (LPAQTL); lymph node disease; age-related macular degeneration type 1 (ARMD1); malaria (CM); meningitis; mevalonic aciduria (MEVA); Musculoskeletal muscle atrophy (MUA) Mycobacterium kansasii syndrome (MWS); Mycobacterium kansasii disease; Myocardial infarction (MCI1); Kidney stones; Neurological diseases; Nonalcoholic steatohepatitis (NASH); Papilitis; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial disease; Pharyngitis; Polyradiculoneuropathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid a-amyloidosis; Silicosis; Skin diseases; Stomatitis;Type 2 diabetes (T2D); ureteral disease; urticaria (HIVES); vulvovaginal candidiasis; Wells syndrome, such methods comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0085] The present invention further provides methods for treating a disease, disorder, or condition selected from the group consisting of: acne vulgaris (ACNE); hereditary acral keratoderma hyaline papularis; adult-onset Still's disease (AOSD); Aicardi-Gautiers syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthracene; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); autoimmune diseases of the cardiovascular system; autoimmune diseases of the gastrointestinal tract; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantitative trait locus 11 (BMIQ11); and inflammatory bone diseases. ; cerebral edema; brucellosis; candidiasis; cervical lymphadenitis; chondrocalcinosis; chronic meningitis; chronic recurrent multifocal osteomyelitis (CRMO); chronic urticaria; Cinca syndrome (CINCA); conjunctival diseases; conjunctivitis; connective tissue diseases; corneal diseases; coronavirus infections; Covid-19; Crohn's disease; cryptopyrin-associated periodic syndrome (CAPS); cystic fibrosis (CF); autosomal dominant hearing loss type 34 with or without inflammation (DFNA34); dermatitis; diabetes mellitus; diabetic encephalopathy; rash (RASH); eye diseases; familial cold autoinflammatory syndrome (FCU); familial cold autoinflammatory syndrome type 1 (FCAS) 1); familial cold autoinflammatory syndrome type 2 (FCAS2); familial Mediterranean fever (FMF); gout (GOUT); hereditary periodic fever syndromes; hidradenitis; hidradenitis suppurativa; essential hypertension (EHT); hyperuricemia; autosomal dominant mental retardation type 30 with speech delay and behavioral abnormalities (MRD30); interstitial lung disease type 2 (ILD2); hereditary keratitis (KERH); hereditary transient corneal endotheliitis (KEFH); lipoprotein quantitative trait locus (LPAQTL); lymph node disease; age-related macular degeneration type 1 (ARMD1); malaria (CM); meningitis; mevalonic aciduria (MEVA); Musculoskeletal muscle atrophy (MUA) Mycobacterium kansasii syndrome (MWS); Mycobacterium kansasii disease; Myocardial infarction (MCI1); Kidney stones; Neurological diseases; Nonalcoholic steatohepatitis (NASH); Papilitis; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial disease; Pharyngitis; Polyradiculoneuropathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid a-amyloidosis; Silicosis; Skin diseases; Stomatitis;Type 2 diabetes (T2D); ureteral disease; urticaria (HIVES); vulvovaginal candidiasis; Wells syndrome, such methods comprising administering to a patient suffering from at least one of such diseases or conditions a compound of formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0086] In some aspects, the present invention provides a compound that is obtainable by or by a process for preparing a compound described herein (eg, a process comprising one or more steps described in the general procedures).

[0087] In some aspects, the present invention provides a compound that can be obtained by or by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in the syntheses of Representative Examples 1 to 9).

[0088] In some aspects, the present invention provides an intermediate described herein, which is suitable for use in a method for preparing a compound described herein (eg, the intermediate is selected from the intermediates described in the preparation section - Compounds P1 to P16).

[0089] In some aspects, the present invention provides a method of preparing a compound of the present invention.

[0090] In some aspects, the present invention provides a method for preparing a compound of the present invention, comprising one or more steps described herein.

[0091] Unless otherwise defined, all technical and scientific terms used in the present invention include the same meanings as generally understood by those skilled in the art. In this specification, unless the context clearly indicates otherwise, the singular also includes the plural. Although similar or equivalent methods and materials described in the present invention can be used for practicing or testing the present invention, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned in the present invention are incorporated by reference. The references cited in the present invention are not recognized as prior art of the claimed present invention. In the event of a conflict, this specification (including definitions) will prevail. In addition, materials, methods and examples are illustrative only and are not intended to be limiting. In the event of a conflict between the chemical structure and the name of the compound disclosed in the present invention, the chemical structure shall prevail.

[0092] Other features and advantages of the present invention will become apparent from the following detailed description and the claims of the present invention. [Specific implementation method]

[0093] The present invention provides methods for treating, preventing, or ameliorating diseases or conditions associated with NLRP3 by administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein.

[0094] The details of the present invention are described in the accompanying description below. Although methods and materials similar or equivalent to those described in the present invention can be used in the practice or testing of the present invention, illustrative methods and materials are now described. Other features, objects and advantages of the present invention will become apparent from the specification and claims of the present invention. Unless the context clearly indicates otherwise, in the specification and the accompanying claims of the present invention, singular formation also includes the plural. Unless otherwise specified, all technical and scientific terms used in the present invention include the same meanings as those generally understood by those skilled in the art in the field to which the present invention belongs. All patents and publications cited in this specification are incorporated into the present invention by reference in their entirety. definition

[0095] The articles "a" and "an" are used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. For example, "an element" refers to one element or more than one element.

[0096] Unless stated otherwise, the term "and / or" is used herein to mean either "and" or "or".

[0097] The term "optionally substituted" should be understood to mean that a given chemical moiety (e.g., an alkyl group) may (but need not) be bonded to other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may include one or more substituents other than hydrogen. For example, it may be bonded to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily include any other functional groups. Suitable substituents for optionally replacing the described groups include, but are not limited to, halogen, pendant, -OH, -CN, -COOH, -CH2CN, -O-(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH), alkyl), -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NHC(O)(C1-C6)alkyl, -C(O)NH(C1-C6)alkyl, -S(O)2(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. The substituents themselves may be optionally substituted. As used herein, "optionally substituted" also refers to substituted or unsubstituted, as described below.

[0098] As used herein, the term "substituted" means that the specified group or moiety bears one or more suitable substituents, wherein such substituents may be attached to the specified group or moiety at one or more positions. For example, a cycloalkyl-substituted aryl group may represent a cycloalkyl group attached to an atom of the aryl group via a bond or by being fused to the aryl group and sharing two or more common atoms.

[0099] As used herein, the term "unsubstituted" means that the designated group bears no substituents.

[0100] Unless otherwise specifically defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group comprising 1 to 3 aromatic rings, including monocyclic or bicyclic groups, such as phenyl, biphenyl, or naphthyl. In the case of containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be connected at a single position (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may optionally be substituted with one or more substituents (e.g., 1 to 5 substituents) at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -OP(O)(OH)2, -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH2, -NH((C-C)alkyl), -N((C-C)alkyl)2, -S(O)2-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl)2. The substituents themselves may be optionally substituted. In addition, when containing two fused rings, the aryl groups defined herein may include one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring. Exemplary ring systems of such aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, propenylnaphthyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoannulyl, and the like.

[0101] Unless otherwise expressly defined, "heteroaryl" refers to a monovalent monocyclic or polycyclic aromatic group containing 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P or B, and the remaining ring atoms being C. Polycyclic aromatic groups include two or more fused rings and may further include two or more spiro-fused rings, such as bicyclic, tricyclic, tetracyclic and similar rings. Unless otherwise expressly defined, "fused" refers to two rings sharing two ring atoms. Unless otherwise expressly defined, "spiro-fused" refers to two rings sharing one ring atom. Heteroaryl as defined herein also refers to a bicyclic heteroaromatic group, wherein the heteroatoms are selected from N, O, S, P or B. Heteroaryl as defined herein also refers to a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P or B. Heteroaryl as defined herein also refers to a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P or B. Aromatic groups are optionally independently substituted with one or more substituents described herein.Examples include, but are not limited to, furanyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxadiazolyl, pyridinyl, indolyl, thien-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazolyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thiazolyl, pheno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuranyl, benzothioalkyl, thioalkyl, tetrahydroquinolinyl, dihydrobenzothioquinolyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyridinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b] Pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridyl, furo[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazolyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5- a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]thiazolyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxadiazole, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl and their derivatives. Additionally, when containing two or more fused rings, the heteroaryl groups defined herein may include one or more saturated or partially unsaturated rings fused to one or more fully unsaturated aromatic rings.In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated rings may be further fused to the saturated or partially unsaturated rings described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein may include one or more saturated or partially unsaturated spirofused rings. Any saturated or partially unsaturated rings described herein may be optionally substituted with one or more pendant oxy groups. Exemplary ring systems of such heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, benzothioalkyl, thiobenzothioalkyl, tetrahydroquinolinyl, dihydrobenzothioalkyl, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyridin-7-yl, 8H-pyrido[3,2-b]pyridin-7-yl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridin-7-yl, 7,8-dihydro-6H-pyrido[3,2-b]pyrimidin, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrido[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxaborol-1(3H)-ol, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxaborol-9-onyl or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxaborol]-9'-onyl.

[0102] Halogen or "halo" refers to fluorine, chlorine, bromine or iodine.

[0103] An alkyl group refers to a straight or branched saturated hydrocarbon group containing 1 to 12 carbon atoms. Examples of (C1-C6)alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl (iso-propyl), isobutyl (iso-butyl), secondary butyl, tertiary butyl, isopentyl (iso-pentyl), neopentyl (neo-pentyl), and isohexyl (iso-hexyl).

[0104] "Alkoxy" refers to a straight or branched saturated hydrocarbon containing 1 to 12 carbon atoms with a terminal "O" in the chain, i.e., -O(alkyl). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, tert-butoxy, or pentoxy.

[0105] "Alkenyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, isobutenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. As defined herein, an alkenyl group can be straight or branched chain.

[0106] "Alkynyl" refers to a straight or branched chain unsaturated hydrocarbon containing 2 to 12 carbon atoms. "Alkynyl" contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, isobutynyl, pentynyl, or hexynyl. Alkynyl groups can be unsubstituted or substituted.

[0107] The term "alkylene," "alkylenyl," or "alkanediyl" refers to a divalent alkyl group. Any of the monovalent alkyl groups mentioned above can be converted to an alkylene group by removing a second hydrogen atom from the alkyl group. As defined herein, an alkylene group can also be a C1-C6 alkylene group. An alkylene group can further be a C1-C4 alkylene group. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0108] "Cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms. A polycyclic cycloalkyl group may be a fused bicyclic cycloalkyl group, a bridged bicyclic cycloalkyl group, or a spirofused bicyclic cycloalkyl group. A polycyclic cycloalkyl group contains at least one non-aromatic ring. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, norbornenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentyl, bicyclo[2.2.2]octyl, or bicyclo[2.2.2]octenyl.

[0109] "Heterocyclyl," "heterocycle," or "heterocycloalkyl" is a monocyclic or polycyclic ring containing from 3 to 24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P, or B, and wherein such ring is not aromatic. The heterocycloalkyl ring structure may be substituted with one or more substituents. The substituents themselves may be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxazolinyl, piperidinyl, oxazolinyl, thiooxazolinyl, thiooxazolinyl S-oxide, thiooxazolinyl S-dioxide, piperidinyl, azobenzene, oxazolinyl, diazolinyl, tropane, tropaneidinyl, tropaneidinyl, and homotropane.

[0110] The term "aromatic" refers to a planar ring comprising 4n+2 electrons in a conjugated system. As used herein, a "conjugated system" refers to a system of connected p orbitals comprising delocalized electrons, and the system may include lone electron pairs.

[0111] The term "haloalkyl" as used herein refers to an alkyl group as defined herein that is substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, and the like.

[0112] The term "haloalkoxy" as used herein refers to an alkoxy group as defined herein that is substituted with one or more halogens. Examples of haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, and the like.

[0113] The term "cyano" as used in the present invention refers to a substituent in which a carbon atom is bonded to a nitrogen atom via a paraffin bond, ie, C≡N.

[0114] "Spiroalkyl" or "spirocyclyl" refers to a carbon bicyclic ring system in which the two rings are connected by a single atom. The rings may differ in size and properties, or be identical in size and properties. Examples include spiropentanes, spirohexanes, spiroheptanes, spirooctanes, spirononanes, or spirodecanes. One or both rings in the spirocycle may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spirocycle may be substituted with heteroatoms such as O, N, S, or P. (C3-C 12 Spirocycloalkyl is a spirocyclic ring containing 3 to 12 carbon atoms. One or more carbon atoms may be substituted by a heteroatom.

[0115] The term "spiroheterocycloalkyl", "spiroheterocycle" or "spiroheterocyclyl" is understood to mean a spirocycle in which at least one ring is a heterocycle (eg at least one ring is furanyl, maltodyl or piperidinyl).

[0116] The term "solvate" refers to a complex formed by a solute and a solvent that includes variable stoichiometry. Such solvents for the purposes of the present invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, DMSO, and AcOH. Solvates in which water is the solvent molecule are generally referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water as well as compositions containing variable amounts of water.

[0117] The term "isomers" refers to compounds that have identical composition and molecular weight but differ in physical and / or chemical properties. The structural differences can be in their configuration (geometric isomers) or their ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, compounds of formula (A), and in particular compounds of formula (I), (II), (III), (IV), or (V), may include one or more asymmetric carbon atoms and may exist as racemates, racemic mixtures, and as individual mirror image isomers or diastereomers.

[0118] The present invention also encompasses isotopically labeled compounds of Formula I (e.g., 2 H and 14 C-labeled compounds). Deuterated (i.e., 2 H or D) and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with heavier isotopes, such as deuterium, can afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in some circumstances. Isotopically labeled compounds of formula (A), and particularly compounds of formula (I), (II), (III), (IV), or (V), can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an appropriately isotopically labeled reagent for the non-isotopically labeled reagent.

[0119] The present invention also includes pharmaceutical compositions comprising a therapeutically effective amount of the disclosed compounds and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, for example, water-soluble and water-insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium salt, calcium edetate, camphorsulfonate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, benzyl benzoate, hexafluorophosphate, hexylresorcinate, hydroxybenzo ... hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium salt, malate, maleate, mandelate, methanesulfonate, methyl bromide, methylnitrate, methylsulfate, galactarate, naphthenate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theoclate, toluenesulfonate, triethiodide, and valerate.

[0120] A "patient" or "subject" is a mammal, eg, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or a non-human primate, eg, a monkey, chimpanzee, baboon, or rhesus monkey.

[0121] When used in conjunction with a compound, an "effective amount" is an amount effective to treat or prevent a disease in a subject as described herein.

[0122] The term "carrier" as used herein encompasses vehicles, excipients, and diluents, and refers to a material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or transporting a pharmaceutical agent from one organ or part of a subject's body to another organ or part of the body.

[0123] The term "treating" with respect to a subject refers to ameliorating at least one symptom of a condition in the subject. Treatment includes curing, ameliorating or at least partially alleviating the condition.

[0124] Unless otherwise indicated, the term "disorder" is used herein to refer to, and is used interchangeably with, the terms disease, condition, or ailment.

[0125] The terms "administer," "administering," or "administration" as used herein refer to directly administering a disclosed compound or a pharmaceutically acceptable salt or composition of a disclosed compound to a subject, or administering a prodrug derivative or analog of the compound or a pharmaceutically acceptable salt or composition of the compound to a subject, which can form an equivalent amount of the active compound in the body of the subject.

[0126] As used herein, the term "prodrug" refers to a compound that can be converted in vivo by metabolic means (eg, by hydrolysis) to a disclosed compound.

[0127] The term "salt" refers to pharmaceutically acceptable salts.

[0128] The term "pharmaceutically acceptable salts" also refers to salts of compositions of the present invention that include an acidic functional group, such as a carboxylic acid functional group, and a base.

[0129] As used herein, "NLRP3 inhibitor" refers to a compound of Formula A and / or a composition comprising a compound of Formula A that inhibits NLRP3 kinase.

[0130] As used herein, "NLRP3 inhibitor" refers to a compound of Formula I and / or a composition comprising a compound of Formula I that inhibits NLRP3 kinase.

[0131] As used herein, "NLRP3 inhibitor" refers to a compound of Formula II and / or a composition comprising a compound of Formula II that inhibits NLRP3 kinase.

[0132] As used herein, "NLRP3 inhibitor" refers to a compound of Formula III and / or a composition comprising a compound of Formula III that inhibits NLRP3 kinase.

[0133] As used herein, "NLRP3 inhibitor" refers to a compound of Formula IV and / or a composition comprising a compound of Formula IV that inhibits NLRP3 kinase.

[0134] As used herein, "NLRP3 inhibitor" refers to a compound of Formula V and / or a composition comprising a compound of Formula V that inhibits NLRP3 kinase.

[0135] The amount of compound in the composition of the present invention required to achieve a therapeutic effect can be determined empirically according to conventional procedures for a particular purpose. Generally speaking, for the administration of a therapeutic agent (e.g., a compound or composition of Formula A, I, II, III, IV, V described herein (and / or additional agents)) for therapeutic purposes, such therapeutic agent is administered in a pharmacologically effective dose. "Pharmacologically effective amount," "pharmacologically effective dose," "therapeutically effective amount," or "effective amount" refers to an amount sufficient to produce a desired physiological effect or to achieve a desired result, particularly a desired result for the treatment of a condition or disease. As used herein, an effective amount will include an amount sufficient, for example, to delay the development of symptoms of a condition or disease, to alter the course of symptoms of a condition or disease (e.g., to slow the progression of symptoms of a disease), to reduce or eliminate one or more symptoms or clinical manifestations of a condition or disease, and to reverse the symptoms of a condition or disease. For example, administration of a therapeutic agent to an individual suffering from cancer provides a therapeutic benefit not only in eradicating or alleviating the underlying condition, but also in reporting a decrease in the severity or duration of symptoms associated with the disease, such as a decrease in tumor burden, a decrease in circulating tumor cells, or an increase in progression-free survival. A therapeutic benefit also includes arresting or slowing the progression of the underlying disease or condition, regardless of whether improvement is achieved. Compounds of the present invention

[0136] In one embodiment, the present invention provides a compound of formula (A) and its salts, stereoisomers, solvates, prodrugs, isotopic derivatives and tautomers: where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 and n are as described in the present invention.

[0137] It should be understood that for compounds of formula (A), R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 and n can be selected from the group described in the present invention when applicable, and the present invention is directed to any R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9Any of the groups described in and n may be combined with the present invention for R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 and any group of one or more of the rest of n.

[0138] In some embodiments, the compound comprises formula (A*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0139] In some embodiments, the compound comprises formula (A**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0140] In some embodiments, the present invention provides compounds of formula (I) and their salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers: where R 1 、R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and n are as described in the present invention.

[0141] It will be understood that for compounds of formula (I), R 1 、R 2 、R 3 、R 4 、R 5 、R 8 、R 9 and n can be selected from the group described in the present invention when applicable, and the present invention is directed to any R 1 、R 2 、R 3 、R 4 、R 5 、R 8 、R 9 Any of the groups described in and n may be combined with the present invention for R 1 、R 2 、R 3 、R 4 、R5 、R 8 、R 9 and any group of one or more of the rest of n.

[0142] In some embodiments, the compound comprises formula (I*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0143] In some embodiments, the compound comprises formula (I**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0144] In some embodiments, the present invention provides compounds of formula (II) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: where R 1 、R 2 、R 3 、R 4 、R 5 、R 9 and n are as described in the present invention.

[0145] It should be understood that for compounds of formula (II), R 1 、R 2 、R 3 、R 4 、R 5 、R 9 and n can be selected from the group described in the present invention when applicable, and the present invention is directed to any R 1 、R 2 、R 3 、R 4 、R 5 、R 9 Any of the groups described in and n may be combined with the present invention for R 1 、R 2 、R 3 、R 4 、R 5 、R 9 and any group of one or more of the rest of n.

[0146] In some embodiments, the compound comprises formula (II*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0147] In some embodiments, the compound comprises formula (II**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0148] In some embodiments, the present invention provides compounds of formula (III) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: where R 1 、R 2 、R 3 、R 4 、R 5 、R 9 , W and n are as described in the present invention.

[0149] It should be understood that for compounds of formula (III), R 1 、R 2 、R 3 、R 4 、R 5 、R 9 , W and n can be selected from the group described in the present invention when applicable, and the present invention is directed to any R 1 、R 2 、R 3 、R 4 、R 5 、R 9 , W and n described any group can be used with the present invention for R 1 、R 2 、R 3 、R 4 、R 5 、R 9 , W and any other one or more of n are combined.

[0150] In some embodiments, the compound comprises formula (III*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0151] In some embodiments, the compound comprises formula (III**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0152] In some embodiments, the present invention provides compounds of formula (IV) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: where R 1 、R 2 、R 3 、R 4 、R 5 、R 9 and n are as described in the present invention.

[0153] It will be understood that for compounds of formula (IV), R 1 、R 2 、R 3 、R 4 、R 5 、R 9 and n can be selected from the group described in the present invention when applicable, and the present invention is directed to any R 1 、R 2 、R 3 、R 4 、R 5 、R 9 Any of the groups described in and n may be combined with the present invention for R 1 、R 2 、R 3 、R 4 、R 5 、R 9 and any group of one or more of the rest of n.

[0154] In some embodiments, the compound comprises formula (IV*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0155] In some embodiments, the compound comprises formula (IV**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0156] In some embodiments, the present invention provides compounds of formula (V) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof: where R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 9 and n are as described in the present invention.

[0157] It will be understood that for compounds of formula (V), R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 9 and n can be selected from the group described in the present invention when applicable, and the present invention is directed to any R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 9 Any of the groups described in and n may be combined with the present invention for R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 9 and any group of one or more of the rest of n.

[0158] In some embodiments, the compound comprises formula (V*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0159] In some embodiments, the compound comprises formula (V**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0160] In some embodiments, the compound of formula (A) is a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0161] In some embodiments, the compound of formula (A) is a compound of formula (II) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0162] In some embodiments, the compound of formula (A) is a compound of formula (III) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0163] In some embodiments, the compound of formula (A) is a compound of formula (IV) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0164] In some embodiments, the compound of formula (A) is a compound of formula (V) or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0165] In some embodiments, the compound comprises Formula (IA): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0166] In some embodiments, the compound comprises Formula (IA-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0167] In some embodiments, the compound comprises Formula (IA-1-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0168] In some embodiments, the compound comprises Formula (IA-1-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0169] In some embodiments, the compound comprises Formula (IA-1-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0170] In some embodiments, the compound comprises Formula (IB): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0171] In some embodiments, the compound comprises formula (IB-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0172] In some embodiments, the compound comprises formula (IB-1-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0173] In some embodiments, the compound comprises Formula (IB-1-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0174] In some embodiments, the compound comprises Formula (IB-1-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0175] In some embodiments, the compound comprises formula (IB-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0176] In some embodiments, the compound comprises formula (IB-2-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0177] In some embodiments, the compound comprises Formula (IB-2-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0178] In some embodiments, the compound comprises Formula (IB-2-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0179] In some embodiments, the compound comprises formula (IB-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0180] In some embodiments, the compound comprises formula (IB-3-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0181] In some embodiments, the compound comprises Formula (IB-3-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0182] In some embodiments, the compound comprises Formula (IB-3-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0183] In some embodiments, the compound comprises formula (IB-4): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0184] In some embodiments, the compound comprises formula (IB-4-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0185] In some embodiments, the compound comprises Formula (IB-4-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0186] In some embodiments, the compound comprises Formula (IB-4-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0187] In some embodiments, the compound comprises Formula (IC): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0188] In some embodiments, the compound comprises formula (IC-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0189] In some embodiments, the compound comprises formula (IC-1-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0190] In some embodiments, the compound comprises Formula (IC-1-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0191] In some embodiments, the compound comprises formula (IC-1-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0192] In some embodiments, the compound comprises formula (IC-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0193] In some embodiments, the compound comprises formula (IC-2-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0194] In some embodiments, the compound comprises Formula (IC-2-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0195] In some embodiments, the compound comprises formula (IC-2-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0196] In some embodiments, the compound comprises formula (IC-2-Ia**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0197] In some embodiments, the compound comprises Formula (IC-2-Ib): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0198] In some embodiments, the compound comprises formula (IC-2-Ib*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0199] In some embodiments, the compound comprises formula (IC-2-Ib**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0200] In some embodiments, the compound comprises formula (IC-2-Ic): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0201] In some embodiments, the compound comprises formula (IC-2-Ic*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0202] In some embodiments, the compound comprises the formula (IC-2-Ic**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0203] In some embodiments, the compound comprises formula (IC-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0204] In some embodiments, the compound comprises formula (IC-3-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0205] In some embodiments, the compound comprises formula (IC-3-I*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0206] In some embodiments, the compound comprises formula (IC-4): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0207] In some embodiments, the compound comprises formula (IC-4-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0208] In some embodiments, the compound comprises formula (IC-4-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0209] In some embodiments, the compound comprises formula (IC-4-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0210] In some embodiments, the compound comprises formula (IC-4-Ib): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0211] In some embodiments, the compound comprises formula (IC-4-Ib*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0212] In some embodiments, the compound comprises the formula (IC-4-Ib**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0213] In some embodiments, the compound comprises formula (IC-4-Ic): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0214] In some embodiments, the compound comprises the formula (IC-4-Ic*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0215] In some embodiments, the compound comprises the formula (IC-4-Ic**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0216] In some embodiments, the compound comprises formula (IC-4-Id): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0217] In some embodiments, the compound comprises the formula (IC-4-Id*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0218] In some embodiments, the compound comprises the formula (IC-4-Id**): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0219] In some embodiments, the compound comprises formula (IC-4-Ie): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0220] In some embodiments, the compound comprises the formula (IC-4-Ie*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0221] In some embodiments, the compound comprises Formula (ID): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein each R a H, or two R a Together they form an alkanediyl group -(CH2) m -bridge, wherein m is selected from 1 and 2.

[0222] In some embodiments, the compound comprises formula (ID-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0223] In some embodiments, the compound comprises Formula (ID-1-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0224] In some embodiments, the compound comprises formula (ID-1-I*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0225] In some embodiments, the compound comprises formula (ID-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0226] In some embodiments, the compound comprises formula (ID-2-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0227] In some embodiments, the compound comprises formula (ID-2-I*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0228] In some embodiments, the compound comprises formula (ID-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0229] In some embodiments, the compound comprises formula (ID-3-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0230] In some embodiments, the compound comprises formula (ID-3-I*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0231] In some embodiments, the compound comprises Formula (IE): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0232] In some embodiments, the compound comprises Formula (IE-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0233] In some embodiments, the compound comprises Formula (IE-1-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0234] In some embodiments, the compound comprises Formula (IE-1-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0235] In some embodiments, the compound comprises Formula (IE-1-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0236] In some embodiments, the compound comprises Formula (IF): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0237] In some embodiments, the compound comprises formula (IF-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0238] In some embodiments, the compound comprises formula (IF-1-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0239] In some embodiments, the compound comprises formula (IF-1-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0240] In some embodiments, the compound comprises the formula (IF-1-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0241] In some embodiments, the compound comprises formula (IG): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0242] In some embodiments, the compound comprises formula (IG-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0243] In some embodiments, the compound comprises formula (IG-1-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0244] In some embodiments, the compound comprises formula (IG-1-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0245] In some embodiments, the compound comprises formula (IG-1-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0246] In some embodiments, the compound comprises Formula (IH): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0247] In some embodiments, the compound comprises formula (IH-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0248] In some embodiments, the compound comprises formula (IH-1-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0249] In some embodiments, the compound comprises Formula (IH-1-Ia): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0250] In some embodiments, the compound comprises formula (IH-1-Ia*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0251] In some embodiments, the compound comprises formula (II-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0252] In some embodiments, the compound comprises formula (II-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0253] In some embodiments, the compound comprises formula (II-A-1-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0254] In some embodiments, the compound comprises formula (II-A-1-I*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0255] In some embodiments, the compound comprises formula (II-A-1-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0256] In some embodiments, the compound comprises formula (II-A-1-II*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0257] In some embodiments, the compound comprises formula (II-A-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0258] In some embodiments, the compound comprises formula (II-A-2-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0259] In some embodiments, the compound comprises formula (II-A-2-I*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0260] In some embodiments, the compound comprises formula (II-A-2-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0261] In some embodiments, the compound comprises formula (II-A-2-II*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0262] In some embodiments, the compound comprises formula (II-A-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0263] In some embodiments, the compound comprises formula (II-A-3-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0264] In some embodiments, the compound comprises formula (II-A-3-I*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0265] In some embodiments, the compound comprises formula (III-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0266] In some embodiments, the compound comprises formula (III-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0267] In some embodiments, the compound comprises formula (III-A-1-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0268] In some embodiments, the compound comprises formula (III-A-1-aI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0269] In some embodiments, the compound comprises formula (III-A-1-aI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0270] In some embodiments, the compound comprises formula (III-A-1-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0271] In some embodiments, the compound comprises Formula (III-A-1-bI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0272] In some embodiments, the compound comprises formula (III-A-1-bI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0273] In some embodiments, the compound comprises formula (III-B): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0274] In some embodiments, the compound comprises formula (III-B-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0275] In some embodiments, the compound comprises formula (III-B-1-I): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0276] In some embodiments, the compound comprises formula (III-B-1-I*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0277] In some embodiments, the compound comprises formula (III-B-1-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein each R a H, or two R a Together they form an alkanediyl group -(CH2) m -bridge, wherein m is selected from 1 and 2.

[0278] In some embodiments, the compound comprises formula (III-B-1-II-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0279] In some embodiments, the compound comprises formula (III-B-1-II-a*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0280] In some embodiments, the compound comprises formula (III-B-1-II-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0281] In some embodiments, the compound comprises formula (III-B-1-II-b*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0282] In some embodiments, the compound comprises formula (III-B-1-II-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0283] In some embodiments, the compound comprises formula (III-B-1-II-c*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0284] In some embodiments, the compound comprises formula (III-B-1-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0285] In some embodiments, the compound comprises formula (III-B-1-aI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0286] In some embodiments, the compound comprises formula (III-B-1-aI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0287] In some embodiments, the compound comprises formula (III-B-1-a-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0288] In some embodiments, the compound comprises formula (III-B-1-a-II*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0289] In some embodiments, the compound comprises formula (III-B-1-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0290] In some embodiments, the compound comprises formula (III-B-1-bI): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0291] In some embodiments, the compound comprises formula (III-B-1-bI*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0292] In some embodiments, the compound comprises formula (III-B-1-b-II): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0293] In some embodiments, the compound comprises formula (III-B-1-b-II*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0294] In some embodiments, the compound comprises formula (IV-A): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0295] In some embodiments, the compound comprises formula (IV-A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0296] In some embodiments, the compound comprises formula (IV-A-1-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0297] In some embodiments, the compound comprises formula (IV-A-1-a*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0298] In some embodiments, the compound comprises formula (IV-A-1-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0299] In some embodiments, the compound comprises formula (IV-A-1-b*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0300] In some embodiments, the compound comprises formula (IV-A-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0301] In some embodiments, the compound comprises formula (IV-A-2-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0302] In some embodiments, the compound comprises formula (IV-A-2-a*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0303] In some embodiments, the compound comprises formula (IV-A-2-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0304] In some embodiments, the compound comprises formula (IV-A-2-b*): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0305] In some embodiments, the compound comprises formula (VA); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0306] In some embodiments, the compound comprises formula (VA-1); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0307] In some embodiments, the compound comprises formula (VA-1-a); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0308] In some embodiments, the compound comprises formula (VA-1-aI); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0309] In some embodiments, the compound comprises formula (VA-1-aI*); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0310] In some embodiments, the compound comprises formula (VA-1-b); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0311] In some embodiments, the compound comprises formula (VA-1-bI); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0312] In some embodiments, the compound comprises formula (VA-1-bI*); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0313] In some embodiments, the compound comprises formula (VA-1-c); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein p is an integer selected from 1, 2 and 3, and all other variables are as defined herein.

[0314] In some embodiments, the compound comprises formula (VA-1-cI); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0315] In some embodiments, the compound comprises formula (VA-1-cI*); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0316] In some embodiments, the compound comprises formula (VA-1-c-II); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0317] In some embodiments, the compound comprises formula (VA-1-c-II*); or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0318] In some embodiments, the compound comprises formula (A). In some embodiments, the compound comprises formula (I). In some embodiments, the compound comprises formula (II). In some embodiments, the compound comprises formula (III). In some embodiments, the compound comprises formula (IV). In some embodiments, the compound comprises formula (V).

[0319] In some embodiments, the compound comprises Formula (A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0320] In some embodiments, the compound comprises Formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0321] In some embodiments, the compound comprises Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0322] In some embodiments, the compound comprises Formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0323] In some embodiments, the compound comprises Formula (IV), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0324] In some embodiments, the compound comprises Formula (V), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0325] In some embodiments, the compound comprises formula (A-0): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0326] In some embodiments, the compound comprises formula (A-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein u is an integer selected from 0, 1, and all other variables are as defined herein.

[0327] In some embodiments, the compound comprises formula (A-1-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0328] In some embodiments, the compound comprises formula (A-1-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0329] In some embodiments, the compound comprises formula (A-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0330] In some embodiments, the compound comprises formula (A-134): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 10 Selected from -CH3, -CH2OH, -CH2CH3, -CH(CH3)2, -CH2OCH3, -C(CH3)2OH, -C(CH3)2OCH3, -CH2C(CH3)2OH, -CH2C(CH3)2OCH3; R 11 is selected from H, -CH3; and all other variables are as defined herein.

[0331] In some embodiments, the compound comprises formula (A-3): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein R 11 is selected from H, -CH3, and all other variables are as defined herein.

[0332] In some embodiments, the compound comprises formula (A-3-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0333] In some embodiments, the compound comprises formula (A-3-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0334] In some embodiments, the compound comprises formula (A-4-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0335] In some embodiments, the compound comprises formula (A-4-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0336] In some embodiments, the compound comprises formula (A-4-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0337] In some embodiments, the compound comprises formula (A-5): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, wherein v is an integer selected from 0 and 1; w is an integer selected from 1, 2, 3, 4, and 5; and all other variables are as defined herein.

[0338] In some embodiments, the compound comprises formula (A-5-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0339] In some embodiments, the compound comprises formula (A-5-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0340] In some embodiments, the compound comprises formula (A-5-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0341] In some embodiments, the compound comprises formula (A-5-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof, wherein v is an integer selected from 0 and 1, and all other variables are as defined herein.

[0342] In some embodiments, the compound comprises formula (A-5-d-1): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0343] In some embodiments, the compound comprises formula (A-5-d-2): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0344] In some embodiments, the compound comprises formula (A-6): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0345] In some embodiments, the compound comprises formula (A-7): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0346] In some embodiments, the compound comprises formula (A-8): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0347] In some embodiments, the compound comprises formula (A-9-a): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0348] In some embodiments, the compound comprises formula (A-9-b): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0349] In some embodiments, the compound comprises formula (A-9-c): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0350] In some embodiments, the compound comprises formula (A-9-d): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0351] In some embodiments, the compound comprises formula (A-9-e): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0352] In some embodiments, the compound comprises formula (A-10): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0353] In some embodiments, the compound comprises formula (A-11): or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative or tautomer thereof.

[0354] In some embodiments, the compound comprises formula (B): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 6 Selected from H, SO2R 8 , NH2, C1-C6 alkyl, C1-C6 alkyl-C(O)-, aryl, wherein the alkyl or aryl group is optionally substituted with one or more substituents independently selected from halogen, CN, OH; R 7 is H, C1-C6 alkyl or NH2; or R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring or heteroaromatic ring; R 8 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkyl, cycloalkyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH; or Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 12 is selected from H, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl group is optionally substituted with one or more groups selected from halogen, -OH, C1-C6 alkoxy; R 12a Selected from H, -CH3; R 12b Selected from H, -CH3; R 13 Selected from H, C1-C6 alkyl, or R 12 and R 13Together with the atoms to which it is attached and any intervening atoms, it forms a 3- to 8-membered cycloalkane or a 3- to 8-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the following: halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy.

[0355] In some embodiments, R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl.

[0356] In some embodiments, R 1 For H.

[0357] In some embodiments, R 1 is a C1-C6 alkyl group optionally substituted by one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl.

[0358] In some embodiments, R 1 is a C1-C6 alkyl group which is optionally substituted by one or more halogen groups.

[0359] In some embodiments, R 1 It is a C1-C6 alkyl group.

[0360] In some embodiments, R 1 Selected from methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0361] In some embodiments, R 1 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, and n-hexyl.

[0362] In some embodiments, R 1 It is a methyl group.

[0363] In some embodiments, R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl.

[0364] In some embodiments, R 2 For H.

[0365] In some embodiments, R 2 is a C1-C6 alkyl group optionally substituted by one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl.

[0366] In some embodiments, R 2 is a C1-C6 alkyl group which is optionally substituted by one or more halogen groups.

[0367] In some embodiments, R 2 It is a C1-C6 alkyl group.

[0368] In some embodiments, R 2 Selected from methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0369] In some embodiments, R 2 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, and n-hexyl.

[0370] In some embodiments, R 2 It is a methyl group.

[0371] In some embodiments, R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an arene, or a heteroarene, wherein the cycloalkane, heterocycle, arene, or heteroarene is optionally substituted with one or more substituents independently selected from halogen, OH, CN, C1-C6 alkyl, C1-C6 alkoxy.

[0372] In some embodiments, R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl.

[0373] In some embodiments, R 3 For H.

[0374] In some embodiments, R 3 is a C1-C6 alkyl group optionally substituted by one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl.

[0375] In some embodiments, R 3 is a C1-C6 alkyl group which is optionally substituted by one or more halogen groups.

[0376] In some embodiments, R 3 It is a C1-C6 alkyl group.

[0377] In some embodiments, R 3 Selected from methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0378] In some embodiments, R 3 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, and n-hexyl.

[0379] In some embodiments, R 3 It is a methyl group.

[0380] In some embodiments, R 3 It is -CF3.

[0381] In some embodiments, R 3 It is -CF2CF3.

[0382] In some embodiments, R 3 is C3-C4 optionally substituted by one or more substituents independently selected from the following 10 Cycloalkyl: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl.

[0383] In some embodiments, R 3 C3-C 10 Cycloalkyl.

[0384] In some embodiments, R 3 It is cyclopropyl.

[0385] In some embodiments, R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl.

[0386] In some embodiments, R 4 For H.

[0387] In some embodiments, R 4 is a C1-C6 alkyl group optionally substituted by one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl.

[0388] In some embodiments, R 4 is a C1-C6 alkyl group which is optionally substituted by one or more halogen groups.

[0389] In some embodiments, R 4 It is a C1-C6 alkyl group.

[0390] In some embodiments, R 4 Selected from methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0391] In some embodiments, R 4 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, and n-hexyl.

[0392] In some embodiments, R 4 It is a methyl group.

[0393] In some embodiments, R 4 It is -CF3.

[0394] In some embodiments, R 4 It is -CF2CF3.

[0395] In some embodiments, R 4 is C3-C4 optionally substituted by one or more substituents independently selected from the following 10 Cycloalkyl: halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl.

[0396] In some embodiments, R 4 C3-C 10 Cycloalkyl.

[0397] In some embodiments, R 4 It is cyclopropyl.

[0398] In some embodiments, R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the following: halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy.

[0399] In some embodiments, R 3 and R 4 Together with the atom to which it is attached and any intervening atoms, it forms cyclopentane.

[0400] In some embodiments, R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms

[0401] In some embodiments, R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms cyclohexane.

[0402] In some embodiments, R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms

[0403] In some embodiments, R 3 and R 4 Together with the atom to which it is attached and any intervening atoms, it forms norbornane.

[0404] In some embodiments, R 3 and R 4Together with the atoms to which it is attached and any intervening atoms, it forms

[0405] In some embodiments, R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a bicyclo[2.2.2]octane.

[0406] In some embodiments, R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms

[0407] In some embodiments, R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl.

[0408] In some embodiments, R 5 For H.

[0409] In some embodiments, R 5 It is a C1-C6 alkyl group.

[0410] In some embodiments, R 5 Selected from methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0411] In some embodiments, R 5 Selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, n-pentyl, and n-hexyl.

[0412] In some embodiments, R 5 It is a methyl group.

[0413] In some embodiments, R 5 For ethyl.

[0414] In some embodiments, R 5 for

[0415] In some embodiments, R 5 for

[0416] In some embodiments, R 5 for

[0417] In some embodiments, R 5 It is a C1-C6 alkyl group substituted with OH.

[0418] In some embodiments, R 5 It is 2-hydroxyethyl.

[0419] In some embodiments, R 5 for

[0420] In some embodiments, R 5 for

[0421] In some embodiments, R 5 for

[0422] In some embodiments, R 5 It is a C1-C6 alkyl group substituted by a C1-C6 alkoxy group.

[0423] In some embodiments, R 5 It is a C1-C6 alkyl group substituted by a methoxy group.

[0424] In some embodiments, R 5 for

[0425] In some embodiments, R 5 for

[0426] In some embodiments, R 5 for

[0427] In some embodiments, R 5 For C3-C 10 Cycloalkyl-substituted C1-C6 alkyl.

[0428] In some embodiments, R 5 for

[0429] In some embodiments, R 5 It is a C1-C6 alkyl group substituted with an aryl group.

[0430] In some embodiments, R 5 for

[0431] In some embodiments, R 5 It is a C2-C6 alkenyl group.

[0432] In some embodiments, R 5 for

[0433] In some embodiments, R 5 C3-C 10 Cycloalkyl.

[0434] In some embodiments, R 5 It is cyclopropyl.

[0435] In some embodiments, R 5 It is cyclobutyl.

[0436] In some embodiments, R 5 It is cyclopentyl.

[0437] In some embodiments, R 5 It is cyclohexyl.

[0438] In some embodiments, R 5 It is cycloheptyl.

[0439] In some embodiments, R 5 It is a 4- to 10-membered heterocyclic group.

[0440] In some embodiments, R 5 is a 4- to 10-membered heterocyclic group containing 1 to 3 heteroatoms independently selected from O, N, and S.

[0441] In some embodiments, R 5 is a 4- to 10-membered heterocyclic group containing one heteroatom selected from O, N, and S.

[0442] In some embodiments, R 5 is a 4- to 10-membered heterocyclic group containing two heteroatoms independently selected from O, N, and S.

[0443] In some embodiments, R 5 It is a 4-membered heterocyclic group containing one heteroatom selected from O, N, and S.

[0444] In some embodiments, R 5 It is a 5-membered heterocyclic group containing one heteroatom selected from O, N, and S.

[0445] In some embodiments, R 5 It is a 6-membered heterocyclic group containing one heteroatom selected from O, N, and S.

[0446] In some embodiments, R 5 for

[0447] In some embodiments, R 5 It is a 7-membered heterocyclic group containing one heteroatom selected from O, N, and S.

[0448] In some embodiments, R 5 for

[0449] In some embodiments, R 6 Selected from H, SO2R 8 , NH2, C1-C6 alkyl, C1-C6 alkyl-C(O)-, aryl, wherein the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, OH.

[0450] In some embodiments, R 6 For H.

[0451] In some embodiments, R 6 It is a C1-C6 alkyl group.

[0452] In some embodiments, R 6 is -CH3.

[0453] In some embodiments, R 6 It is -CH2CH3.

[0454] In some embodiments, R 6 for

[0455] In some embodiments, R 6 is a C1-C6 alkyl group which is optionally substituted by one or more substituents independently selected from halogen, CN, and OH.

[0456] In some embodiments, R 6 It is -CF3.

[0457] In some embodiments, R 6 It is an aryl group.

[0458] In some embodiments, R 6 for

[0459] In some embodiments, R 6 SO2R 8 .

[0460] In some embodiments, R 6 It is SO2CH3.

[0461] In some embodiments, R 6 It is SO2CH2CH3.

[0462] In some embodiments, R 6 for

[0463] In some embodiments, R6 for

[0464] In some embodiments, R 6 for

[0465] In some embodiments, R 6 It is C1-C6 alkyl-C(O)-, wherein the alkyl group is optionally substituted by one or more substituents independently selected from halogen, CN, and OH.

[0466] In some embodiments, R 6 It is CH3C(O)-.

[0467] In some embodiments, R 6 It is (CH3)2CHC(O)-.

[0468] In some embodiments, R 6 It is (CH3)3C(O)-.

[0469] In some embodiments, R 6 It is CHF2C(O)-.

[0470] In some embodiments, R 6 It is CF3C(O)-.

[0471] In some embodiments, R 6 It is CF3CF2C(O)-.

[0472] In some embodiments, R 7 It is H, C1-C6 alkyl or -NH2.

[0473] In some embodiments, R 7 For H.

[0474] In some embodiments, R 7 is -NH2.

[0475] In some embodiments, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring or heteroarene.

[0476] In some embodiments, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0477] In some embodiments, the ring Optionally substituted with one or two substituents.

[0478] In some embodiments, R6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0479] In some embodiments, the ring Optionally substituted with one or two substituents.

[0480] In some embodiments, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0481] In some embodiments, the ring Replaced as appropriate.

[0482] In some embodiments, R 8 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, and 5- to 6-membered heteroaryl, wherein the alkyl, cycloalkyl, or heteroaryl is optionally substituted by one or more substituents independently selected from halogen, CN, and OH.

[0483] In some embodiments, R 8 It is a C1-C6 alkyl group.

[0484] In some embodiments, R 8 is -CH3.

[0485] In some embodiments, R 8 It is -CH2CH3.

[0486] In some embodiments, R 8 for

[0487] In some embodiments, R 8 It is a C3-C8 cycloalkyl group.

[0488] In some embodiments, R 8 for

[0489] In some embodiments, R 8 It is a 5- to 6-membered heteroaryl group.

[0490] In some embodiments, R 8 for

[0491] In some embodiments, n is an integer selected from 0, 1, and 2.

[0492] In some embodiments, n is 0.

[0493] In some embodiments, n is 1.

[0494] In some embodiments, R 9 is selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted by one or more halogens or OH.

[0495] In some embodiments, n is 2.

[0496] In some embodiments, each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogens or OH.

[0497] In some embodiments, R 9 For OH.

[0498] In some embodiments, R 9 It is a halogen.

[0499] In some embodiments, R 9 For F.

[0500] In some embodiments, R 9 It is a C1-C6 alkyl group.

[0501] In some embodiments, R 9 It is a methyl group.

[0502] In some embodiments, R 9 is a C1-C6 alkyl group which is optionally substituted by one or more halogen groups.

[0503] In some embodiments, R 9 It is -CF3.

[0504] In some embodiments, R 9 It is a C1-C6 alkoxy group.

[0505] In some embodiments, R 9 It is a methoxy group.

[0506] In some embodiments, two R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring.

[0507] In some embodiments, R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring.

[0508] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 H, R 5is methyl, R 6 SO2CH3, R 7 For H.

[0509] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 H, R 5 is ethyl, R 6 SO2CH3, R 7 For H.

[0510] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 H, R 5 is 2-hydroxyethyl, R 6 SO2CH3, R 7 For H.

[0511] In some embodiments, R 1 H, R 2 is methyl, R 3 H, R 4 H, R 5 is methyl, R 6 SO2CH3, R 7 For H.

[0512] In some embodiments, R 1 H, R 2 is methyl, R 3 H, R 4 H, R 5 is ethyl, R 6 SO2CH3, R 7 For H.

[0513] In some embodiments, R 1 H, R 2 is methyl, R 3 H, R 4 H, R 5 is 2-hydroxyethyl, R 6 SO2CH3, R 7 For H.

[0514] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is methyl, R 6 SO2CH3, R7 For H.

[0515] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is ethyl, R 6 SO2CH3, R 7 For H.

[0516] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is 2-hydroxyethyl, R 6 SO2CH3, R 7 For H.

[0517] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is methyl, R 6 SO2CH3, R 7 For H.

[0518] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is ethyl, R 6 SO2CH3, R 7 For H.

[0519] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is 2-hydroxyethyl, R 6 SO2CH3, R 7 For H.

[0520] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0521] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0522] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0523] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 is methyl, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0524] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 is methyl, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0525] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 is methyl, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0526] In some embodiments, R 1 H, R 2 H, R 3-CF3, R 4 H, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0527] In some embodiments, R 1 H, R 2 H, R 3 -CF3, R 4 H, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0528] In some embodiments, R 1 H, R 2 H, R 3 -CF3, R 4 H, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0529] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0530] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0531] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is methyl, R 6 and R 7Together with the atoms to which it is attached and any intervening atoms, it forms

[0532] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 -CF3, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0533] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 -CF3, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0534] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 -CF3, R 5 is methyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0535] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0536] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0537] In some embodiments, R 1 H, R2 H, R 3 is methyl, R 4 H, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0538] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 is methyl, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0539] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 is methyl, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0540] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 is methyl, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0541] In some embodiments, R 1 H, R 2 H, R 3 -CF3, R 4 H, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0542] In some embodiments, R 1 H, R 2 H, R 3 -CF3, R 4 H, R 5 is ethyl, R 6 and R7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0543] In some embodiments, R 1 H, R 2 H, R 3 -CF3, R 4 H, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0544] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0545] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0546] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0547] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 -CF3, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0548] In some embodiments, R1 H, R 2 H, R 3 H, R 4 -CF3, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0549] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 -CF3, R 5 is ethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0550] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0551] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0552] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 H, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0553] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 is methyl, R5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0554] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 is methyl, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0555] In some embodiments, R 1 H, R 2 H, R 3 is methyl, R 4 is methyl, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0556] In some embodiments, R 1 H, R 2 H, R 3 -CF3, R 4 H, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0557] In some embodiments, R 1 H, R 2 H, R 3 -CF3, R 4 H, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0558] In some embodiments, R 1 H, R 2 H, R 3 -CF3, R 4 H, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0559] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0560] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0561] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 is methyl, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0562] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 -CF3, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0563] In some embodiments, R 1 H, R 2 H, R 3 H, R 4 -CF3, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0564] In some embodiments, R 1 H, R2 H, R 3 H, R 4 -CF3, R 5 is 2-hydroxyethyl, R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms

[0565] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0566] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0567] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0568] In some embodiments, the compound is selected from the group consisting of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0569] In some embodiments, the compound is selected from the compounds described in Table 1.

[0570] Table 1. Some examples of compounds of formula A

[0571] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0572] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.

[0573] In some embodiments, the compound is a salt of any acid described in Table 2 and any compound described in Table 1.

[0574] Table 2. Pharmaceutically acceptable acids that form salts with compounds of formula (A), (I) to (V).

[0575] In some embodiments, the compound is a salt of acetic acid and any one of the compounds described in Table 1.

[0576] In some embodiments, the compound is a salt of adipic acid and any one of the compounds described in Table 1.

[0577] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1.

[0578] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.

[0579] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.

[0580] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1.

[0581] In some embodiments, the compound is a salt of glutamate and any one of the compounds described in Table 1.

[0582] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1.

[0583] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1.

[0584] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.

[0585] In some aspects, the present invention provides a compound that is an isotopic derivative (eg, an isotopically labeled compound) of any one of the compounds of the formulae disclosed herein.

[0586] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0587] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0588] In some embodiments, the compound is an isotopic derivative of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0589] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0590] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by implementing the procedures disclosed in the schemes and / or examples described herein, substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0591] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0592] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0593] As used herein, the term "isotopic derivative" refers to a derivative of a compound wherein one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of Formula (I) to (V) is isotopically enriched with respect to one or more isotopes or isotopically labeled with one or more isotopes compared to the corresponding compound of Formula (I) to (V). In some embodiments, an isotopic derivative is isotopically enriched with respect to one or more isotopes selected from 2 H. 13 C. 14 C. 15 N. 18 O. 29 4. 31 P and 34 In some embodiments, an isotopic derivative is a deuterium-labeled compound (i.e., a compound with one or more atoms being enriched in or labeled with one or more atoms of S). 2 H enriched).

[0594] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0595] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0596] In some embodiments, the compound is a deuterium-labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0597] In some embodiments, the compound is a deuterium-labeled compound of any one of the compounds described in Table 1.

[0598] It is understood that a deuterium-labeled compound comprises deuterium atoms in an abundance substantially greater than the natural deuterium abundance (0.015%).

[0599] In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). As used herein, the term "deuterium enrichment factor" refers to the ratio of deuterium abundance to natural deuterium abundance.

[0600] It will be appreciated that deuterium-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by implementing the procedures disclosed in the schemes and / or examples described herein, substituting deuterium-labeled reagents for non-deuterium-labeled reagents.

[0601] The compounds of the present invention or their pharmaceutically acceptable salts or solvates containing the aforementioned deuterium atoms are within the scope of the present invention. 2 H) substitutions may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0602] In some embodiments, the compound is 18 F-labeled compound.

[0603] In some embodiments, the compound is 123 I-labeled compounds, 124 I-labeled compounds, 125 I-labeled compounds, 129 I-labeled compounds, 131 I-labeled compounds, 135 I-labeled compound or any combination thereof.

[0604] In some embodiments, the compound is 33 S-labeled compounds,34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compound or any combination thereof.

[0605] It should be understood that 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 33 S. 34 S. 35 S and / or 36 S-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, the S-labeled compounds can be prepared by performing the procedures disclosed in the processes and / or examples described herein. 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 33 S. 34 S. 35 S and / or 36 Deuterium-labeled compounds can be prepared by replacing non-isotopically labeled reagents with S-labeled reagents.

[0606] Containing the aforementioned 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 33 S. 34 S. 35 S and 36 The compounds of the present invention or their pharmaceutically acceptable salts or solvates containing one or more of the S atoms are within the scope of the present invention. 18 F. 123 I. 124 I. 125 I. 129 I. 131 I. 135 I. 33 S. 34 S. 35 S and / or 36 S) substitutions may afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0607] For the avoidance of doubt, it will be understood that where a group is defined in this specification as "described herein," that group encompasses the first and broadest definition as well as each and all specific definitions for that group.

[0608] The various functional groups and substituents that make up the compound of formula (A) are typically selected so that the molecular weight of the compound does not exceed 1000 Daltons. More typically, the molecular weight of the compound will be less than 900 Daltons, for example, less than 800 Daltons, or less than 750 Daltons, or less than 700 Daltons, or less than 650 Daltons. More preferably, the molecular weight is less than 600 Daltons, and for example, 550 Daltons or less, for example 500 Daltons or less, for example 450 Daltons or less.

[0609] Suitable pharmaceutically acceptable salts of the compounds of the present invention include, for example, acid addition salts of sufficiently basic compounds of the present invention, for example, acid addition salts with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of the present invention that are sufficiently acidic include: alkali metal salts, such as sodium salts or potassium salts; alkaline earth metal salts, such as calcium salts or magnesium salts; ammonium salts; or salts with organic bases that yield a pharmaceutically acceptable cation, such as salts with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, quinoline or quinoline-(2-hydroxyethyl)amine.

[0610] It is to be understood that the compounds of any one of the formulae disclosed herein and any pharmaceutically acceptable salts thereof encompass stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of such compounds.

[0611] As used herein, the term "isomerism" refers to compounds that have the same molecular formula but differ in the sequence of bonding of the atoms or the arrangement of the atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers." Stereoisomers that are not mirror images of one another are termed "diastereomers," and stereoisomers that are non-superimposable mirror images of one another are termed "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomer forms with opposite chirality is termed a "racemic mixture."

[0612] As used herein, the term "chiral center" refers to a carbon atom that is bonded to four different substituents.

[0613] As used herein, the term "chiral isomer" refers to a compound containing at least one chiral center. Compounds containing more than one chiral center can exist as individual diastereomers or as a mixture of diastereomers (referred to as a "diastereomeric mixture"). When a chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center in question. The substituents attached to the chiral center in question are ordered according to the ordering rules of Cahn, Ingold, and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0614] As used herein, the term "geometric isomers" refers to diastereoisomers that exist as mirror images of each other around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). The names of these configurations are distinguished by the prefixes cis and trans or Z and E, which indicate whether the groups are on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0615] It should be understood that the compounds of the present invention may be described as different chiral or geometric isomers. It should also be understood that when a compound includes chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of the present invention, and the naming of the compound does not exclude any isomeric form. It should be understood that not all isomers may include the same level of activity.

[0616] It is to be understood that the structures and other compounds discussed herein include all atropisomers thereof. It is also to be understood that not all atropisomers may exhibit the same level of activity.

[0617] As used herein, the term "atropisomer" is a stereoisomer in which the atoms of the two isomers differ in their arrangement in space. Atropisomers exist due to restricted rotation caused by steric hindrance of rotation of bulky groups around a central bond. Such atropisomers typically exist as a mixture; however, recent advances in chromatographic techniques have made it possible to separate mixtures of two atropisomers under selected circumstances.

[0618] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. This conversion causes the formal migration of hydrogen atoms and is accompanied by the exchange of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric groups in solution. In solutions where tautomerization may occur, chemical equilibrium of the tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be mutually converted by tautomerization is called tautomerism. Among the various possible types of tautomerism, two are generally observed. In keto-enol tautomerism, simultaneous shifts of electrons and hydrogen atoms occur. The ring-chain tautomerism exhibited by glucose occurs because the aldehyde group (-CHO) in the sugar chain molecule reacts with a hydroxyl group (-OH) in the same molecule to produce a cyclic (ring-shaped) form.

[0619] It is understood that the compounds of the present invention may be depicted as different tautomers. It is also understood that when a compound comprises tautomeric forms, all tautomeric forms are intended to be included within the scope of the present invention, and the naming of the compound does not exclude any tautomeric form. It is understood that certain tautomers may comprise higher levels of activity than other tautomers.

[0620] Compounds that have the same molecular formula but differ in the nature or order of the bonding of their atoms or in the spatial arrangement of their atoms are called "isomers". Isomers that differ in the spatial arrangement of their atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are called "mirror image isomers". When a compound includes an asymmetric center, for example, when it is bonded to four different groups, a pair of mirror image isomers may exist. Mirror image isomers can be characterized by the absolute configuration of their asymmetric center and described by the R and S ordering rules of Cahn and Prelog, or described by the way the molecule rotates the plane of polarization and designated as right-handed or left-handed (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual mirror image isomers or as mixtures thereof. A mixture containing equal proportions of mirror image isomers is called a "racemic mixture".

[0621] The compounds of the present invention may include one or more asymmetric centers; such compounds can therefore be prepared as individual (R) or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of specific compounds in this specification and the claims of the present invention is intended to include individual mirror image isomers and mixtures thereof (racemic mixtures or other mixtures). Methods for determining stereochemistry and separating stereoisomers are well known in the art (see "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 2001 Chapter 4), for example, by synthesizing from optically active starting materials or by resolving racemic forms. Some compounds of the present invention may include geometric isomer centers (E and Z isomers). It should be understood that the present invention encompasses all optical non-mirror image isomers and geometric isomers and mixtures thereof, including inflammasome inhibitory activity.

[0622] The present invention also encompasses compounds of the present invention as defined herein containing one or more isotopic substitutions.

[0623] It should be understood that, if applicable, compounds of any formula described herein include the compounds themselves, as well as salts thereof, and solvates thereof. For example, salts can be formed between anions and positively charged groups (e.g., amine groups) on substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamates, nitrates, phosphates, citrates, methanesulfonates, trifluoroacetates, glutamates, glucuronates, glutarates, malate, maleates, succinates, fumarates, tartrates, toluenesulfonates, salicylates, lactates, naphthylsulfonates, and acetates (e.g., trifluoroacetates).

[0624] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming a pharmaceutically acceptable salt. Similarly, salts can also be formed between cations and negatively charged groups (e.g., carboxylates) on substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations (e.g., tetramethylammonium or diethylamine). Substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0625] It should be understood that the compounds of the present invention (e.g., salts of the compounds) can exist in hydrated or non-hydrated (anhydrous) forms or in the form of solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0626] As used herein, the term "solvate" refers to a solvent addition form containing either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap solvent molecules in a crystalline solid state at fixed molar ratios, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more water molecules with a molecule of a substance, wherein the water remains in its molecular state as HO.

[0627] As used herein, the term "analog" refers to a compound that is structurally similar to another compound but has a slightly different composition (e.g., due to the replacement of an atom with an atom of a different element or due to the presence of a specific functional group, or the replacement of one functional group with another). Thus, an analog is a compound that is similar or equivalent in function and appearance, but not similar or equivalent in structure or origin to a reference compound.

[0628] As used herein, the term "derivative" refers to a compound that includes a common core structure and is substituted with various groups as described herein.

[0629] As used herein, the term "bioisostere" refers to a compound produced by exchanging one atom or group of atoms for another broadly similar atom or group of atoms. The purpose of bioisosteric replacement is to produce a new compound that has similar biological properties to the parent compound. Bioisosteric replacement can be based on physical chemistry or topology. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonamides, tetrazoles, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0630] It will also be understood that certain compounds of any of the formulae disclosed herein may exist in solvated as well as unsolvated forms (e.g., hydrated forms). Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It will be understood that the present invention encompasses all such solvated forms that possess inflammasome inhibitory activity.

[0631] It should also be understood that certain compounds of any of the formulae disclosed herein may exhibit polymorphism, and the present invention encompasses all such forms or mixtures thereof that possess inflammasome inhibitory activity. It is generally known that crystalline materials can be analyzed using conventional techniques such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0632] Compounds of any of the formulae disclosed herein may exist in a variety of different tautomeric forms, and reference to a compound of formula (A), (I), (II), or (III) includes all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms and only one is specifically described or shown, formula (A), (I), (II), or (III) encompasses all other tautomeric forms. Examples of tautomeric forms include keto, enol, and enolate forms, such as the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / thiol, and nitro / acid nitro.

[0633] The compounds containing amine functional groups of any one of the formulas disclosed in the present invention can also form N-oxides. The compounds of formula (I) or (II) containing amine functional groups mentioned in the present invention also include N-oxides. If the compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of nitrogen atoms of tertiary amines or nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or peracid (such as peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, edited by Jerry March, 4th edition, Wiley Interscience, p. 36. More specifically, N-oxides can be prepared by the procedure of LW Deany (Syn. Comm. 1977, 7, 509-514), wherein the amine compound reacts with meta-chloroperbenzoic acid (m-CPBA), for example, in an inert solvent (such as dichloromethane).

[0634] The compounds of any of the formulae disclosed herein can be administered as prodrugs, which decompose in the human or animal body to release the compounds of the invention. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the invention. Prodrugs can be formed when the compounds of the invention contain suitable groups or substituents to which property-modifying groups can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide groups in any of the formulae disclosed herein.

[0635] Thus, the present invention includes those compounds of any of the formulae disclosed herein as defined above, which are useful in organic synthesis and which are useful in the human or animal body by cleavage of their prodrugs. Thus, the present invention includes those compounds of any of the formulae disclosed herein produced by organic synthesis, as well as such compounds produced in the human or animal body by metabolism of a precursor compound, i.e., the compounds of any of the formulae disclosed herein may be synthetically produced compounds or metabolically produced compounds.

[0636] Suitable pharmaceutically acceptable prodrugs of the compounds of any of the formulae disclosed herein are prodrugs that are suitable for administration to humans or animals without undue pharmacological activity and without undue toxicity based on sound medical judgment. Various forms of prodrugs have been described, for example, in the following literature: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", edited by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Vol. 14; and h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0637] Suitable pharmaceutically acceptable prodrugs of the compounds of any of the formulae disclosed herein that include a hydroxyl group are, for example, in vivo cleavable esters or ethers thereof. In vivo cleavable esters or ethers of the compounds of any of the formulae disclosed herein that contain a hydroxyl group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxyl compound. Suitable pharmaceutically acceptable esters of hydroxyl-forming groups include, for example, inorganic esters of phosphates (including aminophosphocyclic esters). Other suitable pharmaceutically acceptable ester-forming groups of hydroxyl groups include C1-C 10 Alkanoyl, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl; C1-C 10Alkoxycarbonyl groups include, for example, ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, (N-aminoquinoline)methyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups, such as acetoxymethyl and pivaloyloxymethyl.

[0638] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein that include a carboxyl group are, for example, in vivo cleavable amides thereof or esters thereof, such as amides formed with: an amine, such as ammonia; C 1-4 Alkylamines such as methylamine; (C1-C4 alkyl)2-amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine; C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine; phenyl-C1-C4 alkylamines such as benzylamine; and amino acids such as glycine.

[0639] Suitable pharmaceutically acceptable prodrugs of compounds of any of the formulae disclosed herein that include an amine group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amine group include, for example, C1-C 10 In some embodiments, the present invention relates to amides formed by alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, (N-aminolinoyl)methyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0640] The in vivo effects of the compounds of any of the formulae disclosed herein may be partially exerted by one or more metabolites formed in the human or animal body after administration of the compounds of any of the formulae disclosed herein. As stated above, the in vivo effects of the compounds of any of the formulae disclosed herein may also be exerted by the metabolism of precursor compounds (prodrugs). Methods for synthesizing compounds

[0641] The compounds of the present invention can be prepared by a variety of methods, including standard chemical methods. Suitable synthetic routes are depicted in the schemes given below.

[0642] Compounds of formula (A), particularly formula (I), formula (II), formula (III), formula (IV) or formula (V), can be prepared by methods known in the art of organic synthesis as shown in the following synthetic scheme sections. In the processes described below, it should be fully understood that protective groups for sensitive or reactive groups are used as needed according to general principles or chemical methods. Protective groups are manipulated according to standard methods for organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999). Such groups are removed at the appropriate stage of compound synthesis using methods that are obvious to those skilled in the art. Those skilled in the art will recognize the selection process for the presence or absence of stereocenters in compounds of formula (A), (I) to (III) as well as the reaction conditions and order. Therefore, the present invention encompasses two possible stereoisomers (unless otherwise specified in the synthesis) and includes not only racemic compounds but also individual mirror image isomers and / or diastereomers. When a compound is required to be in the form of a single mirror image isomer or diastereomer, it can be obtained by stereospecific synthesis or by resolving the final product or any suitable intermediate. Resolution of final products, intermediates, or starting materials can be achieved by any suitable method known in the art. See, for example, EL Elliel, SH Wilen, and LN Mander, "Stereochemistry of Organic Compounds" (Wiley-Interscience, 1994).

[0643] The compounds described in the present invention can be prepared from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic processes. Preparation of compounds

[0644] The compounds of the present invention can be prepared in a variety of ways familiar to those skilled in the art of organic synthesis. By way of example, the compounds of the present invention can be synthesized using the methods described below and synthetic methods known in the art of organic synthesis chemistry or variations thereof as understood by those skilled in the art. Suitable methods include, but are not limited to, the methods described below. The compounds of the present invention can be synthesized by following the steps outlined in the general procedures, which include different orders of assembling intermediates or compounds. The starting materials are commercially available or prepared by known procedures in the reported literature or as described below. General Procedures

[0645] In general, compounds of formula (A) can be prepared according to the reaction sequence presented in Scheme 1.

[0646] Process 1

[0647] It must be understood that any compound in Scheme 1, any substituent in such compounds, may be further modified at any step in the sequence presented to provide modified derivatives of such compounds that can be used to prepare compounds of Formula (A), particularly Formula (I), Formula (II), Formula (III), Formula (IV) or Formula (V).

[0648] All reagents may be commercially available compounds themselves or products synthesized from commercially available reagents. For preparation, such reagents may be used in one-step or multi-step synthetic procedures, including but not limited to the procedures described in the preparation section of the present invention.

[0649] It will be apparent to those skilled in the art that any of the compounds of formula (A), (I), (II), (III), (IV) or (V) obtained according to the procedures described above can be the subject of further transformations and modifications to obtain other compounds of formula (A), (I), (II), (III), (IV) or (V). Biological analysis

[0650] Once a compound designed, selected, and / or optimized by the methods described above is prepared, it can be characterized using a variety of assays known to those skilled in the art to determine whether the compound comprises biological activity. For example, a molecule can be characterized by conventional assays (including but not limited to those described below) to determine whether it comprises the predicted activity, binding activity, and / or binding specificity.

[0651] In addition, high-throughput screening can be used to accelerate the analysis performed using such assays. Thus, the activity of the molecules described herein can be rapidly screened using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput analysis can use one or more different analytical techniques, including but not limited to the following analytical techniques.

[0652] Various in vitro or in vivo biological assays can be used to detect the effects of the compounds of the invention. Such in vitro or in vivo biological assays can include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. Pharmaceutical compositions

[0653] In some aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention as an active ingredient. In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound of the formula described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0654] As used herein, "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0655] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances that may also serve as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material. The carrier in a powder is generally a finely powdered solid that is a mixture comprising a finely powdered active ingredient. The active ingredient in a tablet is generally mixed in a suitable proportion with a carrier having the desired binding capacity and compacted into the desired shape and size. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter, and the like. In addition to the active ingredient, a solid form preparation may also contain colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0656] Liquid formulations are also suitable for oral administration, including liquid formulations, including emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. This category includes solid form formulations that are intended to be converted into liquid form formulations just before use. Emulsions can be prepared in solution, for example, in a propylene glycol aqueous solution or can contain emulsifiers such as lecithin, sorbitan monooleate, or gum arabic. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions can be prepared by dispersing the finely powdered active ingredient in water in the presence of a viscous substance, such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0657] The compounds of the present invention can be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and can be presented in unit dosage form in ampoules, prefilled syringes, small volume infusions, or in multi-dose containers with preservatives added. The composition can be in the form of a suspension, solution, or emulsion in such an oily or aqueous vehicle, such as a solution in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents, or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain a compounding agent such as a preservative, a wetting agent, an emulsifying or suspending agent, a stabilizer, and / or a dispersant. Alternatively, the active ingredient may be in the form of a powder obtained by aseptic isolation of sterile solids or by lyophilization from a solution constituted with a suitable vehicle (e.g., sterile, pyrogen-free water) prior to use.

[0658] The compounds of the present invention can be formulated for oral administration in the form of tablets, capsules (each of which includes sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present invention can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical art.

[0659] The formulations of the present invention may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0660] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, random methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfobutyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, random methylated γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0661] Any suitable chelating agent may be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium ethylenediaminetetraacetate, trisodium ethylenediaminetetraacetate, and tetrasodium ethylenediaminetetraacetate, and mixtures thereof.

[0662] Any suitable preservative may be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, butylparaben, and sorbic acid, and mixtures thereof.

[0663] In some embodiments, examples of preservatives include those selected from the group consisting of quaternary ammonium salts, such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, and butylparaben and sorbic acid, and mixtures thereof.

[0664] The aqueous vehicle may also include a tonicity agent to adjust tonicity (osmotic pressure). The tonicity agent may be selected from the group consisting of glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride, and sodium chloride, and mixtures thereof. In some embodiments, the tonicity agent is selected from the group consisting of glycols (e.g., propylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0665] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives (e.g., methylcellulose, ethylcellulose, hydroxyethylcellulose), polyethylene glycols (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropylmethylcellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopol, e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0666] To adjust the formulation to an acceptable pH (typically from about 5.0 to about 9.0, more preferably from about 5.5 to about 8.5, and particularly from about 6.0 to about 8.5, from about 7.0 to about 8.5, from about 7.2 to about 7.7, from about 7.1 to about 7.9, or from about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or a metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, with sodium hydroxide and / or hydrochloric acid being preferred. Such acidic and / or alkaline pH adjusters are added to adjust the formulation to an acceptable target pH range. Therefore, it is not necessary to use both an acid and a base; depending on the formulation, the addition of either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0667] The aqueous vehicle may also contain a buffer to stabilize the pH. When used, the buffer is selected from the group consisting of: phosphate buffers (e.g., sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (e.g., boric acid or salts thereof, including disodium tetraborate), citrate buffers (e.g., citric acid or salts thereof, including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0668] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (Tyloxapol), polyethylene glycol 40 stearate, fatty acid glycol esters, fatty acid glycerides, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0669] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be encapsulated in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be combined with excipients and used in the form of tablets, dragees, or capsules. Oral compositions can also be prepared using a fluid carrier used as a mouthwash, wherein the compound in the fluid carrier is orally administered and rinsed and expectorated or swallowed. Pharmaceutically compatible binders and / or adjuvant substances can be included as part of the composition. Tablets, pills, capsules, dragees, and the like may contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose; a disintegrant such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetener such as sucrose or saccharin; or a flavoring such as peppermint, methyl salicylate, or orange flavor.

[0670] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound of the present invention as defined above, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0671] In some embodiments, the pharmaceutical compositions described herein may further comprise one or more additional pharmaceutically active agents.

[0672] The compositions of the present invention may be in a form suitable for oral use (e.g., in the form of tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., in the form of finely divided powders or liquid aerosols), administration by insufflation (e.g., in the form of finely divided powders), or parenteral administration (e.g., in the form of sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or in the form of suppositories for rectal administration).

[0673] The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents and / or preservatives.

[0674] A therapeutically effective amount of a compound of the invention for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with a NLRP3-associated condition as described herein.

[0675] A therapeutically effective amount of a compound of the invention for use in therapy is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with a NLRP3-associated condition as described herein.

[0676] According to well-known medical principles, the dosage of the compounds of formula (A), (I), (II), (III), (IV), (V) for therapeutic or preventive purposes will naturally vary depending on the nature and severity of the disease, the age and sex of the animal or individual, and the route of administration. How to use

[0677] In some aspects, the present invention provides a method of inhibiting NLRP3 (eg, in vitro or in vivo) comprising contacting a cell with a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0678] In some aspects, the present invention provides a method for treating or preventing a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0679] In some aspects, the present invention provides a method of treating a disease or condition disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0680] In some embodiments, the disease or disorder is associated with NLRP3. In some embodiments, the disease or disorder is a disease or disorder involving NLRP3.

[0681] The compounds of the present invention can also be used to treat diseases associated with NLRP3. For example, diseases and conditions treatable according to the methods of the present invention include acne vulgaris (ACNE); hereditary acrokeratoderma hyaline papularis; adult-onset Still's disease (AOSD); Aicardi-Gautiers syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthracis; aphthous stomatitis; arthritis; arthritis; aseptic meningitis; asthma (ASTHMA); cardiovascular autoimmune diseases; gastrointestinal autoimmune diseases; autoinflammatory syndrome; Behcet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantitative trait locus 11 (BMIQ11); bone disease Inflammatory diseases; cerebral edema; brucellosis; candidiasis; cervical lymphadenitis; chondrocalcinosis; chronic meningitis; chronic recurrent multifocal osteomyelitis (CRMO); chronic urticaria; Cinca syndrome (CINCA); conjunctival diseases; conjunctivitis; connective tissue diseases; corneal diseases; coronavirus infections; Covid-19; Crohn's disease; cryptopyrin-associated periodic syndrome (CAPS); cystic fibrosis (CF); autosomal dominant hearing loss type 34 with or without inflammation (DFNA34); dermatitis; diabetes mellitus; diabetic encephalopathy; rash (RASH); eye diseases; familial cold autoinflammatory syndrome (FCU); familial cold autoinflammatory syndrome Familial cold autoinflammatory syndrome type 1 (FCAS1); familial cold autoinflammatory syndrome type 2 (FCAS2); familial Mediterranean fever (FMF); gout (GOUT); hereditary periodic fever syndromes; hidradenitis; hidradenitis suppurativa; essential hypertension (EHT); hyperuricemia; autosomal dominant mental retardation type 30 with speech delay and behavioral abnormalities (MRD30); interstitial lung disease type 2 (ILD2); hereditary keratitis (KERH); hereditary transient corneal endotheliitis (KEFH); lipoprotein quantitative trait locus (LPAQTL); lymph node disease; age-related macular degeneration type 1 (ARMD1); malaria (CM); meningitis Mevalonic aciduria (MEVA); Muir-Wei syndrome (MWS); Mycobacterium kansasii; Myocardial infarction (MCI1); Kidney stones; Neurological diseases; Nonalcoholic steatohepatitis (NASH); Papilitis; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial disease; Pharyngitis; Polyradiculoneuropathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Pyogenic sterile arthritis, pyoderma gangrenosum, and acne vulgaris (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss;Serum amyloid-α amyloidosis; silicosis; skin diseases; stomatitis; type 2 diabetes (T2D); ureteral diseases; urticaria (HIVES); vulvovaginal candidiasis; Wells syndrome.

[0682] The treatment method comprises administering to a patient suffering from at least one of such diseases or conditions a compound of formula (A) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer or pharmaceutical composition thereof.

[0683] In some embodiments, the treatment comprises administering to a patient suffering from at least one of such diseases or conditions a compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0684] In some embodiments, the treatment method comprises administering to a patient suffering from at least one of such diseases or conditions a compound of formula (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0685] In some embodiments, the treatment method comprises administering to a patient suffering from at least one of such diseases or conditions a compound of formula (III) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0686] In some embodiments, the treatment comprises administering to a patient suffering from at least one of such diseases or conditions a compound of formula (IV) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0687] In some embodiments, the treatment comprises administering to a patient suffering from at least one of such diseases or conditions a compound of Formula (V) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0688] In some embodiments, the disease or disorder is an autoimmune disease.

[0689] In some embodiments, the disease or condition is acne vulgaris (ACNE).

[0690] In some embodiments, the disease or condition is acrokeratosis.

[0691] In some embodiments, the disease or condition is hereditary papules hyaline.

[0692] In some embodiments, the disease or disorder is Adult Onset Still's Disease (AOSD).

[0693] In some embodiments, the disease or disorder is Acardi-Gautiers syndrome (AGS).

[0694] In some embodiments, the disease or disorder is familial Alzheimer's disease type 1 (AD1).

[0695] In some embodiments, the disease or disorder is amyloidosis.

[0696] In some embodiments, the disease or disorder is amyotrophic lateral sclerosis type 1 (ALS1).

[0697] In some embodiments, the disease or condition is anthrax.

[0698] In some embodiments, the disease or condition is aphthous stomatitis.

[0699] In some embodiments, the disease or condition is arthritis.

[0700] In some embodiments, the disease or disorder is an arthropathy.

[0701] In some embodiments, the disease or condition is aseptic meningitis.

[0702] In some embodiments, the disease or disorder is asthma (ASTHMA).

[0703] In some embodiments, the disease or disorder is an autoimmune disease of the cardiovascular system.

[0704] In some embodiments, the disease or disorder is a gastrointestinal autoimmune disease.

[0705] In some embodiments, the disease or disorder is an autoinflammatory syndrome.

[0706] In some embodiments, the disease or disorder is Behçet's syndrome (BD).

[0707] In some embodiments, the disease or disorder is Blau syndrome (BLAUS).

[0708] In some embodiments, the disease or condition is body mass index quantitative trait locus 11 (BMIQ11).

[0709] In some embodiments, the disease or disorder is an inflammatory disease of the bone.

[0710] In some embodiments, the disease or condition is cerebral edema.

[0711] In some embodiments, the disease or condition is brucellosis.

[0712] In some embodiments, the disease or condition is candidiasis.

[0713] In some embodiments, the disease or condition is cervical lymphadenitis.

[0714] In some embodiments, the disease or disorder is chondrocalcinosis.

[0715] In some embodiments, the disease or condition is chronic meningitis.

[0716] In some embodiments, the disease or disorder is chronic recurrent multifocal osteomyelitis (CRMO).

[0717] In some embodiments, the disease or condition is chronic urticaria.

[0718] In some embodiments, the disease or disorder is Cinca syndrome (CINCA).

[0719] In some embodiments, the disease or disorder is a conjunctival disease.

[0720] In some embodiments, the disease or condition is conjunctivitis.

[0721] In some embodiments, the disease or disorder is a connective tissue disease.

[0722] In some embodiments, the disease or disorder is a corneal disease.

[0723] In some embodiments, the disease or disorder is a coronavirus infection.

[0724] In some embodiments, the disease or condition is Covid-19.

[0725] In some embodiments, the disease or disorder is Crohn's disease.

[0726] In some embodiments, the disease or disorder is cryopyrin-associated periodic syndrome (CAPS).

[0727] In some embodiments, the disease or disorder is cystic fibrosis (CF).

[0728] In some embodiments, the disease or disorder is deafness autosomal dominant type 34 with or without inflammation (DFNA34).

[0729] In some embodiments, the disease or condition is dermatitis.

[0730] In some embodiments, the disease or condition is diabetes.

[0731] In some embodiments, the disease or disorder is diabetic encephalopathy.

[0732] In some embodiments, the disease or condition is rash (RASH).

[0733] In some embodiments, the disease or condition is an ocular disease.

[0734] In some embodiments, the disease or disorder is familial cold autoinflammatory syndrome (FCU).

[0735] In some embodiments, the disease or disorder is familial cold autoinflammatory syndrome type 1 (FCAS1).

[0736] In some embodiments, the disease or disorder is familial cold autoinflammatory syndrome type 2 (FCAS2).

[0737] In some embodiments, the disease or disorder is Familial Mediterranean fever (FMF).

[0738] In some embodiments, the disease or disorder is gout (GOUT).

[0739] In some embodiments, the disease or disorder is hereditary periodic fever syndrome.

[0740] In some embodiments, the disease or condition is hidradenitis.

[0741] In some embodiments, the disease or condition is hidradenitis suppurativa.

[0742] In some embodiments, the disease or condition is essential hypertension (EHT).

[0743] In some embodiments, the disease or condition is hyperuricemia.

[0744] In some embodiments, the disease or disorder is autosomal dominant mental retardation type 30 (MRD30) with speech delay and behavioral abnormalities.

[0745] In some embodiments, the disease or disorder is interstitial lung disease type 2 (ILD2).

[0746] In some embodiments, the disease or condition is hereditary keratitis renal (KERH).

[0747] In some embodiments, the disease or disorder is hereditary transient corneal endotheliitis (KEFH).

[0748] In some embodiments, the disease or disorder is a lipoprotein quantitative trait locus (LPAQTL).

[0749] In some embodiments, the disease or disorder is a lymph node disease.

[0750] In some embodiments, the disease or disorder is age-related macular degeneration type 1 (ARMD1).

[0751] In some embodiments, the disease or disorder is malaria (CM).

[0752] In some embodiments, the disease or condition is meningitis.

[0753] In some embodiments, the disease or disorder is mevalonic aciduria (MEVA).

[0754] In some embodiments, the disease or disorder is Muir-Weiel syndrome (MWS).

[0755] In some embodiments, the disease or condition is Mycobacterium kansasii disease.

[0756] In some embodiments, the disease or condition is myocardial infarction (MCI1).

[0757] In some embodiments, the disease or condition is kidney stones.

[0758] In some embodiments, the disease or disorder is a neurological disease.

[0759] In some embodiments, the disease or disorder is nonalcoholic steatohepatitis (NASH).

[0760] In some embodiments, the disease or condition is papillitis.

[0761] In some embodiments, the disease or disorder is osteomyelitis.

[0762] In some embodiments, the disease or condition is osteoporosis (OSTEOP).

[0763] In some embodiments, the disease or condition is otitis media (OMS).

[0764] In some embodiments, the disease or condition is papilledema.

[0765] In some embodiments, the disease or condition is pericardial effusion.

[0766] In some embodiments, the disease or disorder is pericardial disease.

[0767] In some embodiments, the disease or condition is pharyngitis.

[0768] In some embodiments, the disease or condition is polyradiculoneuropathy.

[0769] In some embodiments, the disease or condition is a primary bacterial infectious disease.

[0770] In some embodiments, the disease or disorder is proteasome-associated autoinflammatory syndrome type 1 (PRAAS1).

[0771] In some embodiments, the disease or disorder is pyoderma.

[0772] In some embodiments, the disease or condition is pyoderma gangrenosum.

[0773] In some embodiments, the disease or disorder is suppurative sterile arthritis, pyoderma gangrenosum and acne (PAPAS).

[0774] In some embodiments, the disease or condition is respiratory failure.

[0775] In some embodiments, the disease or condition is salmonellosis.

[0776] In some embodiments, the disease or disorder is Schnitzler syndrome.

[0777] In some embodiments, the disease or disorder is a sebaceous gland disease.

[0778] In some embodiments, the disease or disorder is sensorineural hearing loss.

[0779] In some embodiments, the disease or disorder is serum amyloid a-amyloidosis.

[0780] In some embodiments, the disease or condition is silicosis.

[0781] In some embodiments, the disease or disorder is a skin disease.

[0782] In some embodiments, the disease or condition is stomatitis.

[0783] In some embodiments, the disease or disorder is type 2 diabetes (T2D).

[0784] In some embodiments, the disease or disorder is a ureteral disease.

[0785] In some embodiments, the disease or condition is hives (HIVES).

[0786] In some embodiments, the disease or condition is vulvovaginal candidiasis.

[0787] In some embodiments, the disease or disorder is Wells syndrome.

[0788] In some aspects, the present invention provides a method for treating or preventing an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0789] In some aspects, the present invention provides a method of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0790] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use (eg, in vitro or in vivo) in inhibiting NLRP3.

[0791] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or condition disclosed herein.

[0792] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a disease or condition disclosed herein.

[0793] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating or preventing an autoimmune disease in a subject in need thereof.

[0794] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating or preventing a coronavirus infection in a subject in need thereof.

[0795] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating an autoimmune disease in a subject in need thereof.

[0796] In some aspects, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a coronavirus infection in a subject in need thereof.

[0797] In some aspects, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for inhibiting NLRP3 (eg, in vitro or in vivo).

[0798] In some aspects, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a disease or condition disclosed herein.

[0799] In some aspects, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or condition disclosed herein.

[0800] In some aspects, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing an autoimmune disease in a subject in need thereof.

[0801] In some aspects, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a coronavirus infection in a subject in need thereof.

[0802] In some aspects, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an autoimmune disease in a subject in need thereof.

[0803] In some aspects, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a coronavirus infection in a subject in need thereof.

[0804] The present invention provides compounds that act as (e.g., in vitro or in vivo) NLRP3 inhibitors. Accordingly, the present invention provides a method of inhibiting NLRP3 in vitro or in vivo, the method comprising contacting a cell with a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt thereof.

[0805] In some embodiments, the NLRP3 inhibitor is a compound of the invention.

[0806] The efficacy of the compounds of the present invention can be determined by industry-recognized assays / disease models according to standard procedures elucidated therefor as described in the art and within current general knowledge.

[0807] The present invention also provides a method of treating a disease or condition involving NLRP3 in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound as defined herein, or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

[0808] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Ways to apply

[0809] The compounds of the invention, or pharmaceutical compositions comprising such compounds, may be administered to a subject by any suitable route of administration, whether systemically / peripherally or locally (ie, at the desired site of action).

[0810] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, for example, an aerosol (e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcutaneous, intraarticular, subarachnoid, and intrasternal; by, for example, subcutaneous or intramuscular implantation of a reservoir or pouch. Examples General synthetic procedures and examples for the preparation of compounds.

[0811] All reagents were commercially available and used without further purification. Yields refer to purified and spectroscopically pure compounds. Thin layer chromatography (TLC) was performed using Merck TLC aluminum foil silica gel 60F 254 The chromatography was performed on a 100 nm plate and observed by fluorescence quenching under UV light. Flash chromatography was performed using silica gel (Chromatorex, MB 70-40 / 75, 40-75 μm) purchased from Fuji Silysia Chemicals. NMR spectra were recorded for 1 H was measured on a Varian-400MR operating at 400 MHz. Chemical shifts are reported in ppm with the solvent resonance as the internal standard. Data are reported as follows: s = singlet, br. = broad, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets; coupling constants in Hz; integration. Purity was recorded on a Waters e2695 Separation Module / 2998 PDA Detector HPLC system (column: XBridge C18, 5 μm, 4.6 mm (ID) × 150 mm (L), eluent: a mixture of mobile phases A and B, mobile phase A: 100% acetonitrile; mobile phase B: pure water containing 0.1% formic acid and 10 mM NH4OAc, flow rate: 0.5 mL / min, detection: UV, 254 nm).

[0812] The abbreviations used in the following examples and elsewhere in this invention are: AA acetic acid ACN acetonitrile aq. water-based anh. anhydrous br. Broad peak BSA bovine serum albumin BTMA·ICl2 Benzyltrimethylammonium dichloroiodide d Doublet DCM dichloromethane DIPA diisopropylamine DIPEA N,N-Diisopropylethylamine DMAP dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EA Ethyl acetate eq equivalent FA Formic acid FBS fetal bovine serum h hour HPLC High pressure (or high performance) liquid chromatography LCMS liquid chromatography mass spectrometry m multiplet M Moore MHz Megahertz min NBS N-bromosuccinimide NMR Nuclear Magnetic Resonance Pd2(dba)3-(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2xDCM [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane q quartet rt room temperature s single peak s solid sat. saturated t temperature, triplet TEA triethylamine THF Tetrahydrofuran TLC thin layer chromatography Synthesis of building blocks Synthesis of (2-(methylsulfonylamino)-4-(trifluoromethyl)phenyl)boronic acid (P2)

[0813] Preparation 1. N-(2-Bromo-5-(trifluoromethyl)phenyl)methanesulfonamide (P1). To a stirred solution of 2-bromo-5-(trifluoromethyl)aniline (5.0 g, 20.83 mmol, 1.0 eq) in pyridine (20 mL) was added MsCl (2.5 mL, 31.24 mmol, 1.5 eq) at 0 ° C. The resulting reaction mixture was stirred at 0 ° C to ambient temperature for 4 hours. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated under reduced pressure, and the crude reaction mass was diluted with chloroform and extracted with water (3×100 mL). The combined organic layers were washed with 1N HCl (100 mL) and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was subjected to combi-flash chromatography using a mixture of EtOAc (10→13%) and hexane as eluent to give 2.5 g of the title compound (37%) as an off-white solid. Analytical data: 1 H NMR (400MHz, CDCl3), δ: 7.92 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 8.4, 1.6 Hz, 1H), 6.92 (br.s, 1H), 3.07 (s, 3H). LCMS(ESI): C8H7BrF3NO2S[M+H] + The calculated value is 317.9, and the experimental value is 318.1.

[0814] Preparation 2. (2-(Methylsulfonamido)-4-(trifluoromethyl)phenyl)benzoic acid (P2). To a stirred solution of P2 (2.0 g, 6.28 mmol, 1.0 eq) in 1,4-dioxane (25.0 mL) was added KOAc (2.1 g, 22.00 mmol, 3.5 eq) and bis(pinacolato)diboron (2.3 g, 9.43 mmol, 1.5 eq) at ambient temperature. The resulting reaction mixture was degassed with argon for 15 minutes and Pd(PPh3)2Cl2 (440 mg, 0.629 mmol, 0.1 eq) was added at ambient temperature, and the reaction mixture was stirred at 100°C for 3 hours. The progress of the reaction was monitored by TLC and LCMS. After the starting material was complete, the reaction mixture was diluted with DCM (150 mL), filtered through a bed of celite, and the filtrate was concentrated under reduced pressure to give 2.0 g of the title compound (crude) as a brown gummy liquid. Note: The crude material was carried on to the next step without further purification. Analytical data: LCMS (ESI): C 21 H 23 BFN3O3[MH] + The calculated value is 282.1, and the experimental value is 282.1. Synthesis of (R)-6-chloro-N-(1-ethylpiperidin-3-yl)-5-methylpiperidin-3-amine (P5).

[0815] Preparation 3. (R)-3-((6-chloro-5-methyl-3-thiazolin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (P3) and (R)-3-((6-chloro-4-methyl-3-thiazolin-3-yl)amino)-piperidine-1-carboxylic acid tert-butyl ester (P3a). To a stirred solution of 3,6-dichloro-4-methylpyridine (5.0 g, 30.673 mmol, 1.0 eq) in DMSO (20 mL) was added DIPEA (27.3 mL, 153.36 mmol, 5.0 eq) followed by (R)-tert-butyl 3-aminopiperidine-1-carboxylate (7.97 g, 39.87 mmol, 1.3 eq) and the resulting reaction mixture was stirred at 140 ° C to ambient temperature for 24 hours. The progress of the reaction was monitored by TLC and LCMS. After the starting material was completed, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was flash chromatographed using 15-20% EA / petroleum ether as the eluent to afford P3 and P3a. Analytical information of P3: Yield of P3, 2.5 g (24.2%) of the title compound as a light brown solid. 1 H NMR (400MHz, DMSO-d6), δ: 6.88 (d, J=7.2Hz, 1H), 6.81 (br.s, 1H), 4.03-3.60 (m, 3H), 3.24-2.92(m,2H),2.19(s,3H),1.98(br.s,1H),1.74(br.s,1H),1.43-1.15(m,11H). LCMS(ESI):C 15 H 23 ClN4O2[M+H] + The calculated value is 327.1, and the experimental value is 327.3. Analytical data of P3a: Yield of P3a, 1.14 g (14%) of the title compound as a light brown solid. 1H NMR(400MHz,DMSO-d6),δ:7.33(s,1H),6.03(br.s,1H),4.02-3.94(m,1H),3.82-3.65(m,1H), 3.30-2.80(m,2H),2.10(s,3H),1.98-1.94(m,1H),1.74-1.72(br.s,2H),1.46-1.15(m,11H). LCMS(ESI):C 15 H 23 ClN4O2[M+H] + The calculated value is 327.1, and the experimental value is 327.3.

[0816] Preparation 4. (R)-6-Chloro-5-methyl-N-(piperidin-3-yl)piperidin-3-amine (P4). To a stirred solution of (R)-tert-butyl 3-((6-chloro-5-methylthiazolin-3-yl)amino)piperidine-1-carboxylate (P3, 2.5 g, 7.669 mmol, 1.0 eq) in methanol (5.0 mL) was added 4N HCl in MeOH (10 mL) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the volatiles were concentrated under reduced pressure. The residue was triturated with diethyl ether and dried to afford 1.7 g of the title compound as an off-white solid (97.7%). Note: The crude material was carried on to the next step without further purification. Analytical data: 1 H NMR(400MHz,DMSO-d6),δ:9.54(s,1H),9.21(br.s,1H),8.98(br.s,1H),7.32(s,1H),4.26(br.s,1H),3. 38-3.12(m,2H),2.94-2.90(m,2H),2.33(s,3H),2.01-1.90(m,2H),1.80-1.71(m,1H),1.66-1.58(m,1H). LCMS (ESI): C 10 H 15 ClN4[M+H] + The calculated value is 227.1, and the experimental value is 227.3.

[0817] Preparation 5. (R)-6-Chloro-N-(1-ethylpiperidin-3-yl)-5-methylpiperidin-3-amine (P5). To a stirred solution of (R)-6-chloro-5-methyl-N-(piperidin-3-yl)thiazolin-3-amine (P4, 500 mg, 2.212 mmol, 1.0 eq) in DCE (5.0 mL) was added AcOH (27 mg, 0.442 mmol, 0.2 eq) and 30% acetaldehyde solution (5.0 mL) at ambient temperature. The resulting reaction mixture was stirred at the same temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was quenched with saturated NaHCO (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was flash chromatographed using a mixture of MeOH (5 → 10%) / DCM as an eluent to give 450 mg of the title compound (95.7%) as an off-white solid. Analytical data: 1 H NMR (400MHz, DMSO-d6), δ: 6.80 (s, 1H), 6.77 (d, J = 8.0Hz, 1H), 3.95-3.88 (m, 1H), 2.89-2.97 (m, 1H), 2.63-2.61 (m, 1H), 2.32 (q, J = 4.0Hz, 2 H),2.17(s,3H),1.99(t,J=9.6Hz,1H),1.89-1.80(m,2H),1.70-1.65(m,1H),1.54-1.44(m,1H),1.31-1.28(m,1H),1.03(t,J=7.0Hz,3H). LCMS(ESI):C 12 H 19 ClN4[M+H] + The calculated value is 255.1, and the experimental value is 255.3. Synthesis of (R)-2-(3-((6-chloro-5-methylthiazolin-3-yl)amino)piperidin-1-yl)ethan-1-ol (P6)

[0818] Preparation 6. (R)-2-(3-((6-chloro-5-methylpiperidin-3-yl)amino)piperidin-1-yl)ethan-1-ol (P6). To a stirred solution of (R)-6-chloro-5-methyl-N-(piperidin-3-yl)thiazolin-3-amine (P4, 500 mg, 2.212 mmol, 1.0 eq) in ACN (5.0 mL) was added potassium carbonate (612 mg, 4.425 mmol, 2.0 eq) and 2-bromoethan-1-ol (412 mg, 3.31 mmol, 1.5 eq) at ambient temperature. The resulting reaction mixture was stirred at 70 ° C for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After the starting material was completed, the reaction mixture was quenched with water (50 mL) and extracted with EA (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was flash chromatographed using a mixture of (5→25%) MeOH / DCM as the eluent to give 400 mg of the title compound as an off-white solid (66.0%). Analytical data: 1 H NMR (400MHz, DMSO-d6), δ: 6.80 (br.s, 1H), 6.77 (br.s, 1H), 4.34 (t, J = 5.2Hz, 1H) ,4.09(dd,J=10.4Hz,5.2Hz,1H),3.93(t,J=4.0Hz,1H),3.48(dd,J=11.2Hz,5.6H z,2H),3.15(d,J=4.8Hz,2H),2.86(d,J=11.2Hz,1H),2.67-2.61(m,1H),2.41-2. 32(m,2H),2.18(s,3H),2.15-1.99(m,1H),1.79-1.77(m,1H),1.76-1.67(m,1H). LCMS (ESI): C 12 H 19 ClN4O[M+H] + The calculated value is 271.1, and the experimental value is 271.3. Synthesis of (R)-6-chloro-N-(1-ethylpiperidin-3-yl)-4-methylpiperidin-3-amine (P8)

[0819] Preparation 7. (R)-6-Chloro-4-methyl-N-(piperidin-3-yl)piperidin-3-amine (P7). To a stirred solution of (R)-3-((6-chloro-4-methylthiazolin-3-yl)amino)piperidine-1-carboxylic acid tributyl ester (P3a, 1.3 g, 3.988 mmol, 1.0 eq) in methanol (5.0 mL) was added 4N HCl in MeOH (5 mL) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the volatiles were concentrated under reduced pressure. The residue was triturated with diethyl ether and dried to give 900 mg of the title compound as an off-white solid (crude material). Note: The crude material was carried on to the next step without further purification. Analytical data: 1 H NMR(400MHz,DMSO-d6),δ:9.46(br.s,1H),7.52(s,1H),6.82(br.s,1H),4.41(br.s,1H),3.41-3.3 3(m,1H),3.20-3.14(m,1H),2.97-2.84(m,2H),2.20(s,3H),1.98-1.91(m,2H),1.75-1.65(m,2H). LCMS(ESI):C 10 H 15 ClN4[M+H] + The calculated value is 227.1, and the experimental value is 227.2.

[0820] Preparation 8. (R)-6-Chloro-N-(1-ethylpiperidin-3-yl)-4-methylpiperidin-3-amine (P8). To a stirred solution of (R)-6-chloro-4-methyl-N-(piperidin-3-yl)thiazolin-3-amine (P7, 500 mg, 2.205 mmol, 1.0 eq) in DCE (5.0 mL) was added AcOH (27 mg, 0.442 mmol, 0.2 eq) and 30% aqueous acetaldehyde (5.0 mL) at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was quenched with saturated NaHCO (20 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was flash chromatographed using a mixture of MeOH (5 → 10%) / DCM as an eluent to give 450 mg of the title compound (80%) as an off-white solid. Analytical data: 1H NMR (400MHz, DMSO-d6), δ: 7.29 (s, 1H), 5.95 (d, J = 8.0Hz, 1H), 4.16-4.09 (m, 1H), 2.96 (d, J = 8.4Hz, 1H), 2.70 (d, J=11.2Hz,1H),2.34(q,J=7.2Hz,2H),2.09(s,3H),1.95-1.83(m,3H),1.56-1.33(m,3H),0.97(t,J=9.6Hz,3H). LCMS(ESI):C 12 H 19 ClN4[M+H] + The calculated value is 255.1, and the experimental value is 255.3. Synthesis of (R)-2-(3-((6-chloro-4-methylthiazolin-3-yl)amino)piperidin-1-yl)ethan-1-ol (P9)

[0821] Preparation 9. (R)-2-(3-((6-chloro-4-methylpiperidin-3-yl)amino)piperidin-1-yl)ethan-1-ol (P9). To a stirred solution of (R)-6-chloro-4-methyl-N-(piperidin-3-yl)thiazolin-3-amine (P3a, 500 mg, 2.212 mmol, 1.0 eq) in ACN (5.0 mL) was added potassium carbonate (612 mg, 4.425 mmol, 2.0 eq) and 2-bromoethan-1-ol (412 mg, 3.31 mmol, 1.5 eq) at ambient temperature. The resulting reaction mixture was stirred at 60 ° C for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After the starting material was completed, the reaction mixture was quenched with water (50 mL) and extracted with EA (3×50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was flash chromatographed using a mixture of (5→25%) MeOH / DCM as the eluent to give 350 mg of the title compound as an off-white solid (58.0%). Analytical data: 1H NMR (400MHz, DMSO-d6), δ: 7.29 (s, 1H), 5.95 (d, J = 7.6Hz, 1H), 4.36 (br.s, 1H), 4.14-4.10 (m, 1H), 3.49 (br.s, 2H), 2.93 (d, J = 8.8Hz, 1 H),2.70-2.68(m,1H),2.40(t,J=6.4Hz,2H),2.09(s,3H),2.07-2.02(m,1H),1.83-1.80(m,1H),1.68-1.64(m,1H),1.53-1.39(m,1H). LCMS(ESI):C 12 H 19 ClN4O[M+H] + The calculated value is 271.1, and the experimental value is 271.2. (R)-6-chloro-5-methyl-N-(1-methylpiperidin-3-yl)-3-amine (P10) and (R)-6-chloro-4-methyl-N-(1-methylpiperidin-3-yl)-3-amine Synthesis of (P10a)

[0822] Preparation 10. (R)-2-(3-((6-chloro-4-methylpiperidin-3-yl)amino)piperidin-1-yl)ethan-1-ol (P10). To a stirred solution of 3,6-dichloro-4-methylpyridine (1.0 g, 6.13 mmol, 1.0 eq) in DMSO (10.0 mL) in a sealed tube was added DIPEA (15.8 g, 122.6 mmol, 20 eq) and (R)-1-methylpiperidin-3-amine (2.3 g, 12.26 mmol, 2.0 eq) at ambient temperature. The resulting reaction mixture was stirred at 165 ° C for 48 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was quenched with ice water (30 mL) and adjusted to pH approximately 10 to 12 using NaHCO 3 , followed by extraction with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was subjected to combined flash chromatography using a mixture of 0-10% MeOH-DCM as the eluent to afford 700 mg of a mixture of regioisomers P10 and P10a (47%), which was further purified by SFC purification to afford P10 (180 mg) (12.2%) and P10a (130 mg) (8.8%) as off-white solids. Analysis data: P10: 1H NMR (400MHz, CDCl3), δ: 6.53(s,1H),5.2(br.s,1H),4.05(br.s,1H),2.54-2.42(m,3H),2.26(s,7H),1.8-1.7(m,7H),1.7(s,3H). LCMS(ESI):C 11 H 17 ClN4[M+H] + Calculated value: 241.11, experimental value 241.35. P10a: 1 H NMR (400MHz, DMSO-d6), δ: 7.30 (d, J = 0.8Hz, 1H), 5.95 (d, J = 8.0Hz, 1H), 4.16-4.09 (m, 1H), 2.88(d,J=8.0Hz,1H),2.60(d,J=10.4Hz,1H),2.16(s,3H),2.09(s,3H),1.88-1.65(m,8H). LCMS(ESI):C 11 H 17 ClN4[M+H] + The calculated value is 241.11, and the experimental value is 241.36. Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1H-indazole (P13)

[0823] Preparation 11. 3-Bromo-2-fluoro-6-(trifluoromethyl)benzaldehyde (P11). To a stirred solution of DIPA (2.39 g, 23.66 mmol, 1.1 eq) in anhydrous THF (50 mL) was added n-BuLi (1.6 M, 13.5 mL, 21.6 mmol, 1.0 eq) at 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 30 minutes. Afterwards, a solution of 1-bromo-2-fluoro-4-(difluoromethyl)benzene (5.0 g, 20.57 mmol, 1.0 eq) in THF (50 mL) was added at -78 ° C. and stirred for 1 hour at -78 ° C. DMF (1.9 mL, 24.69 mmol, 1.2 eq) was then added at -78 ° C. and the reaction mixture was stirred at 0 ° C for 30 minutes. The reaction progress was monitored by TLC and LCMS. After the starting material was completed, the reaction mixture was quenched with AcOH (50 mL), followed by addition of ice water (100 mL) and extraction with diethyl ether (2 × 100 mL). The combined organic layers were washed sequentially with diluted HCl solution (0.2 M, 100 mL), water (100 mL), brine solution (100 mL), and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a light yellow liquid (5.0 g crude) (100%). Note: The crude material was carried on to the next step without further purification. Analytical data: 1 H NMR (400MHz, CDCl3), δ: 10.38 (s, 1H), 7.92-7.88 (m, 1H), 7.5 (d, J = 8.4Hz, 1H).

[0824] Preparation 12. 7-Bromo-4-(trifluoromethyl)-1H-indazole (P12). To a stirred solution of 3-bromo-2-fluoro-6-(difluoromethyl)benzaldehyde (P11, 5.0 g, 18.4 mmol, 1.0 eq) in DME (50 mL) was added N-methylhydroxylamine hydrochloride (1.54 g, 18.4 mmol, 1.0 eq) and K2CO3 (2.8 g, 20.29 mmol, 1.1 eq) at ambient temperature. The reaction mixture was stirred at 40 ° C for 4 to 5 hours. The reaction progress was monitored by TLC and LCMS. After the completion of the starting material, the reaction mixture was filtered and washed with DME (40 mL). The filtrate was concentrated under reduced pressure to obtain an intermediate. To the intermediate was added monohydrate hydrazine (50 mL, 92.24 mmol, 5.0 eq) at ambient temperature. The resulting reaction mixture was refluxed at 100 ° C for 12 hours. The reaction progress was monitored by TLC and LCMS. After the completion of the starting material, all volatiles were evaporated under reduced pressure and extracted with EtOAc (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.The residue was subjected to combined flash chromatography using 10-20% EtOAc / petroleum ether as eluent to afford 1.5 g of the title compound (P12, 31%) as a light yellow solid. Analytical data: 1 H NMR (400MHz, DMSO-d6), δ: 14.11 (s, 1H), 8.34 (s, 1H), 7.81 (d, J = 7.6Hz, 1H), 7.48 (d, J = 7.6Hz, 1H). LCMS(ESI): C8H4BrF3N2[M+H] + The calculated value is 264.95, and the experimental value is 265.07.

[0825] Preparation 13. 7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1H-indazole (P13). To a stirred solution of 7-bromo-4-(trifluoromethyl)-1H-indazole (P12, 1.5 g, 5.68 mmol, 1.0 eq) in 1,4-dioxane (30.0 mL) was added bis(pinacolato)diboron (2.88 g, 11.36 mmol, 2.0 eq) and KOAc (2.78 g, 28.4 mmol, 5.0 eq) at ambient temperature. The reaction mixture was degassed with Ar for 10 minutes, and PdCl2(dppf)xDCM (0.416 g, 0.56 mmol, 0.1 eq) was added at ambient temperature. The reaction mixture was stirred at 110 ° C for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After the starting material was consumed, the reaction mixture was cooled to room temperature, filtered through a pad of celite and washed with diethyl ether (2×50 mL). The filtrate was washed with water (100 mL) and extracted with diethyl ether (3×50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure.The residue was triturated with n-hexane at -78°C and filtered to give 1.2 g of the title compound (P13, 79%) as a light yellow solid. Analytical data: 1 H NMR (400MHz, DMSO-d6), δ: 13.1 (s, 1H), 8.22 (br.s, 1H), 7.81 (d, J = 6.8Hz, 1H), 7.54 (d, J = 7.2Hz, 1H), 1.38 (s, 12H). LCMS(ESI):C 14 H 16 BF3N2O2[M+H] + The calculated value is 231.05, and the experimental value is 231.06. Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1H-indazole (P16)

[0826] Preparation 14. (R)-tert-butyl(1-(2-hydroxyethyl)piperidin-3-yl)carbamate (P14). To a stirred solution of tertiary butyl-(R)-piperidin-3-ylcarbamate (10.0 g, 50.0 mmol, 1.0 eq) in ACN (150 mL) was added NaCO (10.5 g, 100.0 mmol, 2.0 eq), 2-bromoethanol (9.3 g, 75.0 mmol, 1.5 eq) at 0 ° C. The resulting reaction mixture was stirred at ambient temperature for 12 hours. The reaction progress was monitored by TLC and LCMS. After the completion of the starting material, the reaction mixture was filtered through a bed of celite and washed with EtOAc (100 mL). The filtrate was concentrated under reduced pressure. The residue was subjected to combined flash chromatography using a mixture of 1-2% MeOH / DCM as an eluent to give 8.0 g of the title compound P14 (65%) as an off-white solid. Analytical data: 1 H NMR (400MHz, DMSO-d6), δ: 6.68 (d, J=8.0Hz, 1H), 4.36 (bs, 1H), 4.09-4.08 (m, 1H), 3.44 (qt, J=5.6Hz, 2H), 3.31 (bs, 1H), 3.16 (d, J=6.0 Hz,1H),2.74-2.72(m,1H),2.60(bs,1H),2.35(t,J=5.6Hz,1H),1.94-1.81(m,1H),1.64-1.56(m,2H),1.37(s,9H),1.15-1.12(m,1H). LCMS(ESI):C 12 H 24 N2O3[M+H] + Calculated value: 245.18, experimental value 245.38.

[0827] Preparation 15. (R)-2-(3-aminopiperidin-1-yl)ethan-1-ol hydrochloride (P15). To a stirred solution of (R)-(1-(2-hydroxyethyl)piperidin-3-yl)carbamic acid tert-butyl ester (P14, 8.0 g, 32.62 mmol, 1.0 eq) in 1,4-dioxane (40 mL) was added 1,4-dioxane (160 mL) containing 4N HCl at 0 ° C. The resulting reaction mixture was stirred at ambient temperature for 24 hours. The progress of the reaction was monitored by TLC. After the starting material was completed, all volatiles were evaporated under reduced pressure. The residue was triturated with diethyl ether to give 4.0 g of the title compound P15 (85%) as an off-white solid. Analytical data: 1H NMR(400MHz,DMSO-d6),δ:3.81-3.75(m,2H),3.74-3.71(m,1H),3.56(s,3H),3.39-3.34(m,2 H),3.22(bs,1H),3.07-2.98(m,2H),2.96-2.89(m,2H),2.09-2.00(m,1H),1.91-1.86(m,2H). LCMS(ESI):C7H 16 N2O[M+H] + Calculated value: 145.13, experimental value 145.28.

[0828] Preparation 16. (R)-6-Chloro-N-(1-ethylpiperidin-3-yl)-5-methylpiperidin-3-amine (P16) and (R)-6-chloro-N-(1-ethylpiperidin-3-yl)-4-methylpiperidin-3-amine (P16A). To a stirred solution of 3,6-dichloro-4-methylpyrrolidone (P15, 4.0 g, 24.5 mmol, 1.0 eq) in DMSO (40.0 mL) was added DIPEA (63.43 g, 490.76 mmol, 20 eq) and (R)-2-(3-aminopiperidin-1-yl)ethan-1-ol (6.3 g, 29.4 mmol, 1.2 eq) in a sealed tube at ambient temperature. The resulting reaction mixture was stirred at 165 ° C for 48 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was quenched with ice water (150 mL) and the pH was adjusted to about 10 to 12 with NaHCO solution, followed by extraction with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography using 0-10% MeOH / DCM as eluent to give 1.5 g of the title compound as a mixture of regioisomers (40%). Further SFC purification gave P16 (200 mg, 3.0%) and P16A (180 mg, 2.7%) as off-white solids. Analysis data: P16: 1 H NMR (400MHz, CDCl3), δ: 6.55 (s, 1H), 5.17 (br.s, 1H), 4.04 (br.s, 1H), 3.67-3.61 (m, 1H ),2.76-2.74(m,1H),2.58-2.32(m,5H),2.27(s,5H),1.76(br.s,2H),1.62(br.s,2H). LCMS(ESI):C 12 H 19 ClN4O[M+H] +Calculated value: 271.12, experimental value 271.19. P16A: 1 H NMR(400MHz, CDCl3), δ:7.01(s,1H),4.71(br.s,1H),4.48(br.s,1H),3.67-3.6 1(m,2H),2.78-2.60(m,1H),2.60-2.52(m,5H),2.06(s,5H),1.74-1.63(m,3H). LCMS(ESI):C 12 H 19 ClN4O[M+H] + Calculated value: 271.12, experimental value 271.35. Synthesis of N-(3-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide (P19)

[0829] Preparation 17. 2-Iodo-3-methyl-5-(trifluoromethyl)aniline (P17). To a stirred solution of 3-methyl-5-(trifluoromethyl)aniline (2.5 g, 14.27 mmol, 1.0 eq) in DCM (25 mL) and MeOH (5 mL) was added BTMA·ICl2 (9.93 g, 28.54 mmol, 2.0 eq) and CaCO3 (3.57 g, 35.68 mmol, 2.5 eq) at ambient temperature. The resulting reaction mixture was stirred at this temperature for 18 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was filtered and washed with DCM (80 mL). The filtrate was washed with saturated Na2S2O3 solution (2×60 mL), water (40 mL) and dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure at 45°C. The residue was flash chromatographed over silica gel (230-400 mesh) using a mixture of EtOAc (10→20%) and hexanes as eluent to afford 1.5 g of the title compound P17 as a yellow liquid (35%). Analytical data: 1 H NMR (400MHz, CDCl3), δ: 6.86-6.85 (m, 1H), 6.78-6.77 (m, 1H), 4.37 (br.s, 2H), 2.46 (s, 3H); LCMS (ESI): C8H8F3IN [M+H] + The calculated value is 301.9, and the experimental value is 301.9.

[0830] Preparation 18. N-(2-iodo-3-methyl-5-(trifluoromethyl)phenyl)methanesulfonamide (P18). To a stirred solution of P17 (1.8 g, 5.979 mmol, 1.0 eq) in pyridine (20 mL) was added MsCl (2.3 mL, 29.89 mmol, 5.0 eq) at 0 ° C. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 × 60 mL). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure at 45 ° C. Using a mixture of EtOAc (15 → ​​20%) and hexane as an eluent, the residue was flash chromatographed through silica gel (230 to 400 mesh) to give 1.7 g of the title compound P18 (75%) as an off-white solid. Analytical data: 1 H NMR (400MHz, CDCl3), δ: 7.50 (br.s, 1H), 7.12 (br.s, 1H), 2.92 (s, 3H), 2.48 (s, 3H); LCMS (ESI): C9H 10 F3INO2S[M+H] + The calculated value is 379.9, and the experimental value is 380.2.

[0831] Preparation 19. N-(3-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide (P19). To a stirred solution of P18 (0.5 g, 1.31 mmol, 1.0 eq) and bis(pinacolato)diboron (670 mg, 2.63 mmol, 2.0 eq) in 1,4-dioxane (10 mL) was added KOAc (388 mg, 3.95 mmol, 3.0 eq) at ambient temperature. The reaction mixture was degassed with a stream of nitrogen for 15 minutes. Subsequently, Pd(dppf)Cl2·DCM (46 mg, 0.066 mmol, 0.05 eq) was added at this temperature. The reaction mixture was heated to 100°C and stirred at 100°C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was cooled to ambient temperature and filtered through a pad of celite; the pad was washed with 10% MeOH in DCM (40 mL). The filtrate was evaporated under reduced pressure at 40°C. The residue was triturated with hexane (2×30 mL) and decanted. The decanted hexane layer was concentrated under reduced pressure to obtain 0.8 g of the title compound P19 (crude) as a yellow liquid. Analytical data: LCMS (ESI): C 15 H21 BF3NO4S[M+H] + The calculated value is 380.12, and the experimental value is 380.18. Synthesis of (R)-6-chloro-N-(1-methylpiperidin-3-yl)-3-amine (P20)

[0832] Preparation 20. (R)-6-Chloro-N-(1-methylpiperidin-3-yl)piperidin-3-amine (P20). To a stirred solution of 3,6-dichlorophenoxyethanol (0.5 g, 3.35 mmol, 1.0 eq) in DMSO (10.0 mL) was added DIPEA (1.78 mL, 10.06 mmol, 3.0 eq) followed by (R)-1-methylpiperidin-3-amine (0.38 g, 3.35 mmol, 1.0 eq) at ambient temperature. The resulting reaction mixture was stirred at 110 ° C for 16 hours. The reaction progress was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was quenched with water (30 mL) and extracted with 10% MeOH in DCM (2×40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure at 45 ° C to give a residue. The residue was flash chromatographed over silica gel (230-400 mesh) using a mixture of 5% Et3N in MeOH (10→20%) and DCM as eluent to afford 220 mg of the title compound P20 as an off-white solid (28%). Analytical data: 1 H NMR (400MHz, CD3OD), δ: 8.53 (s, 1H), 7.33 (d, J = 9.6Hz, 1H), 6.93 (d, J = 9.6Hz, 1H), 4.20-4.15 (m, 1H), 3.24-3.17 ( m,2H),2.64(s,3H),2.05-1.95(m,2H),1.82-1.77(m,1H),1.59-1.52(m,1H),1.30(t,J=7.2Hz,4H); LCMS(ESI): C 10 H 15 ClN4[M+H] + Calculated value: 227.1, experimental value 227.3. Synthesis of (R)-6-chloro-N-(1-ethylpiperidin-3-yl)piperidin-3-amine (P23)

[0833] Preparation 21. (R)-tert-butyl(1-ethylpiperidin-3-yl)carbamate (P21). To a stirred solution of (R)-piperidin-3-ylcarbamic acid tert-butyl ester (5.0 g, 25.0 mmol, 1.0 eq) in ACN (75 mL) was added KCO (4.14 g, 30.0 mmol, 1.2 eq) at 0 ° C., followed by iodoethane (4.28 g, 27.5 mmol, 1.1 eq). The resulting reaction mixture was stirred at ambient temperature for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After the completion of the starting material, the reaction mixture was filtered through a celite bed and washed with DCM (30 mL). The filtrate was evaporated under reduced pressure at 40 ° C to obtain a residue. The residue was flash chromatographed on silica gel (230 to 400 mesh) using a mixture of MeOH (1 → 2%) and DCM as an eluent to give 2.5 g of the title compound P21 (43%) as a light yellow liquid. Analytical data: 1 H NMR (400MHz, CDCl3), δ: 5.06 (br.s, 1H), 3.79 (s, 1H), 2.78-2.25 (m, 6H), 1.77-1.55 (m, 3H), 1.44 (s, 9H), 1.12 (t, J = 6.8Hz, 3H); LCMS (ELSD) (ESI): C 12 H 24 N2O2[M+H] + Calculated value: 229.18, experimental value 229.25.

[0834] Preparation 22. (R)-1-Ethylpiperidin-3-amine hydrochloride (P22). To a stirred solution of (R)-(1-ethylpiperidin-3-yl)carbamic acid tert-butyl ester (P21, 2.5 g, 10.95 mmol, 1.0 eq) in 1,4-dioxane (12.5 mL) was added 1,4-dioxane (25 mL) containing 4 M HCl at 0 ° C. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The reaction progress was monitored by TLC and LCMS. After the starting material was completed, the reaction mixture was concentrated under reduced pressure at 40 ° C to obtain a residue. The residue was triturated with diethyl ether (20 mL) and dried to give 2.0 g of the title compound P22 (crude material) as a yellow solid. Analytical data: 1H NMR(400MHz,DMSO-d6),δ:8.71(br.s,3H),3.60-3.56(m,2H),3.45-3.42(m,1H),3.21-3.02(m,2H ),2.98-2.66(m,2H),2.17-1.75(m,3H),1.62-1.48(m,1H),1.25(t,J=7.2Hz,3H); LCMS(ESI): C7H 17 ClN2[M-HCl+H] + Calculated value: 129.13, experimental value: 129.18.

[0835] Preparation 23. (R)-6-Chloro-N-(1-ethylpiperidin-3-yl)piperidin-3-amine (P23). To a stirred solution of 3,6-dichlorophenoxyethanol (0.5 g, 3.35 mmol, 1.0 eq) in DMSO (5.0 mL) was added DIPEA (1.75 mL, 10.06 mmol, 3.0 eq) at ambient temperature, followed by P22 (607 mg, 3.69 mmol, 1.1 eq). The resulting reaction mixture was stirred at 120 ° C for 16 hours. The reaction progress was monitored by TLC and LCMS. After the starting material was completed, the reaction mixture was quenched with water (30 mL) and extracted with 10% MeOH in DCM (2×40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure at 45 ° C to obtain a residue. The residue was flash chromatographed on silica gel (230 to 400 mesh) using a mixture of 5% Et3N in MeOH (10→20%) and DCM as the eluent to give 300 mg of the title compound P23 (37%) as a light brown solid. Analytical data: 1 H NMR(400MHz, CD3OD), δ:7.37(d,J=9.6Hz,1H),6.96(d,J=9.6Hz,1H),4.28-4.21(m,1H),3.72-3.54(m,1H),3.16 -3.07(m,2H),2.95-2.72(m,2H),2.17-2.03(m,2H),1.93-1.84(m,1H),1.76-1.61(m,1H),1.31(t,J=7.6Hz,4H). LCMS(ESI):C 11 H 17 ClN4[M+H] + Calculated value: 241.1, experimental value 241.36. (R)-6-chloro-N-(1-ethylpiperidin-3-yl)-5-methylpiperidin-3-amine and (R)-6-chloro-N-(1-ethylpiperidin-3-yl)-4-methylpiperidin-3-amine (P24 and Synthesis of P24A)

[0836] Preparation 24. (R)-6-Chloro-N-(1-ethylpiperidin-3-yl)-5-methylpiperidin-3-amine and (R)-6-chloro-N-(1-ethylpiperidin-3-yl)-4-methylpiperidin-3-amine (P24 and P24A). To a stirred solution of 3,6-dichloro-4-methylpyrrolidone (2.5 g, 15.33 mmol, 1.0 eq) in DMSO (25.0 mL) was added DIPEA (39.5 g, 306.7 mmol, 20 eq) and P22 (3.6 g, 18.0 mmol, 1.2 eq) at ambient temperature. The resulting reaction mixture was stirred at 165 ° C for 48 hours. The progress of the reaction was monitored by TLC and LCMS. After the starting material was completed, the reaction mixture was quenched with ice water (30 mL), the pH was adjusted to about 10 to 12 with NaHCO 3 solution, and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was subjected to combined flash chromatography using 0-10% MeOH / DCM as eluent to afford 1.5 g of the title compound (40%) as a mixture of regioisomers, which was further purified by SFC to afford Peak 1 (P24, 500 mg, 8.0%), Peak 2 (P24A, 400 mg, 6.4%) as an off-white solid. In the NOE experimental data, when the H1 proton at 2.18 ppm is irradiated, the H17 proton at 6.81 ppm is enhanced. Analytical data: 1 H NMR (400MHz, DMSO-d6), δ: 6.81 (s, 1H), 6.78 (d, J = 8.0Hz, 1H), 3.95-3.89 (m, 1H), 2.89-2.83 (m, 1H), 2.67-2.61 (m, 1H), 2.35 ( qt,J=6.4Hz,2H),2.18(s,3H),2.07-1.80(m,3H),1.70-1.66(m,1H),1.55-1.44(1H),1.32-1.10(m,1H),1.0(t,J=8.0Hz,3H). LCMS(ESI):C 12 H 19 ClN4[M+H]+ Calculated value: 255.13, experimental value 255.32. In the NOE experimental data, when irradiating H19 protons at 5.95 ppm, H20 protons at 4.11 ppm and H1 protons at 2.96 ppm enhanced the analytical data: 1 H NMR (400MHz, DMSO-d6), δ: 7.29 (s, 1H), 5.95 (d, J = 7.6Hz, 1H), 4.16-4.09 (m, 1H), 2.97-2.91 (m, 1H), 2.72-2.54 (m, 2H), 2.35 (q t,J=7.2Hz,2H),2.09(s,3H),1.95-1.75(m,3H),1.65-1.55(1H),1.52-1.49(m,1H),1.45-1.35(m,1H),1.02(t,J=7.2Hz,3H). LCMS(ESI):C 12 H 19 ClN4[M+H] + The calculated value is 255.13, and the experimental value is 255.28. Synthesis of (R)-3-(4-methyl-6-((1-methylpiperidin-3-yl)amino)piperidin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P25)

[0837] Preparation 25. (R)-3-(4-Methyl-6-((1-methylpiperidin-3-yl)amino)piperidin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P25). To a stirred solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzene-1,2-diamine (0.50 g, 2.27 mmol, 1.0 eq), P10 (0.54 g, 2.27 mmol, 1.0 eq) in 1,4-dioxane (6.0 mL) and water (2.0 mL) was added sodium carbonate (0.48 g, 4.54 mmol, 2.0 eq) at ambient temperature. The reaction mixture was degassed with a stream of nitrogen for 15 minutes. Subsequently, tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.114 mmol, 0.05 eq) was added at this temperature. The mixture was stirred at 100 ° C for 4 hours. The progress of the reaction was monitored by TLC and LCMS. After the starting material was completed, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography using a mixture of ACN (0 to 70%) and water as eluent to afford 0.210 g of the title compound as a brown solid (24%). Analytical data: 1 H NMR (400MHz, DMSO-d6), δ: 8.42 (s, 2H), 7.82 (br.s, 1H), 7.04 (d, J = 8.4Hz, 1H), 6.98-6.92 (m, 1H), 6.68 (d, J = 8.4Hz, 1 H),4.79-4.57(m,1H),3.10-2.95(m,2H),2.80-2.62(m,5H),2.45-2.30(m,1H),2.20-2.02(m,4H),1.89-1.80(m,2H). LCMS(ESI):C 18 H 23 F3N6[M+H] + The calculated value is 381.19, and the experimental value is 381.54. Synthesis of 7-(6-chloro-4,5-dimethyl-3-yl)-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole (P27)

[0838] Preparation 26. 3-(6-Chloro-4,5-dimethylthiazolin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P26). To a stirred solution of 3,6-dichloro-4,5-dimethylthiazolidine (0.58 g, 1.0 eq, 3.31 mmol) in a mixture of 1,4-dioxane (3.0 mL) and water (1.0 mL) at room temperature were added 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzene-1,2-diamine (1.0 g, 1.0 eq, 3.31 mmol) and sodium carbonate (0.70 g, 2.0 eq, 6.62 mmol). The resulting mixture was purged with argon for 10 minutes. Subsequently, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (0.121 g, 0.05 eq, 0.16 mmol) was added at room temperature. The resulting reaction mixture was stirred at 100°C for 3 hours. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with 10% MeOH in DCM (20 mL) and filtered through a pad of Celite. The Celite pad was washed with 10% MeOH in DCM (10 mL), and the combined filtrates were concentrated under reduced pressure. The crude compound was subjected to reverse phase column chromatography on a C18 column using a mixture of ACN (0→60%) and water as the eluent to afford 0.3 g of the title compound 3 as a brown solid (28%). Analytical data: LCMS (ESI): C 13 H 12ClF3N4[M+H] + The calculated value is 317.07, and the experimental value is 317.07.

[0839] Preparation 27. 7-(6-Chloro-4,5-dimethylthiazol-3-yl)-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole (P27). To a stirred solution of P26 (0.30 g, 1.0 eq, 0.949 mmol) in AA (0.11 mL, 2.0 eq, 1.89 mmol) was added a solution of sodium nitrite (0.131 g, 2.0 eq, 1.899 mmol) in water (1.5 mL) at 0 ° C., and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction progress was monitored by TLC. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, diluted with water (20 ml) and extracted with EA (2 × 30 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 310 mg of the title compound P27 (crude material) as a brown solid. Analytical data: LCMS (ESI): C 13 H 10 ClF3N5[M+H] + The calculated value is 328.05, and the experimental value is 328.14. Synthesis of (R)-3-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)piperidin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P29)

[0840] Preparation 28. (R)-6-Chloro-N-(1-methylpiperidin-3-yl)-5-(trifluoromethyl)piperidin-3-amine (P28). To a stirred solution of 3,6-dichloro-4-(trifluoromethyl)piperidin (0.50 g, 2.30 mmol, 1.0 eq) in DMSO (3.0 mL) was added (R)-1-methylpiperidin-3-amine (0.211 g, 1.84 mmol, 0.8 eq) and N,N-diisopropylethylamine (2.0 mL, 11.52 mmol, 5.0 eq) at ambient temperature and stirred at 130 ° C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the starting material was completed, the reaction mixture was concentrated under reduced pressure. Following the above procedure, another 0.50 g of 3,6-dichloro-4-(trifluoromethyl)piperidin was treated with (R)-1-methylpiperidin-3-amine and the two batches were mixed. The combined residues were purified by reverse phase column using a mixture of water (0-90%) and ACN (10%) as eluent to afford 0.43 g of the title compound P28 (32%) and 0.42 g of compound P28A (31%) as a brown solid. Analytical data of compound P28: 1 H NMR (400MHz, DMSO-d6), δ: 7.55 (d, J = 7.6Hz, 1H), 7.39 (s, 1H), 4.15-4.05 (m, 1H), 2.85-2.80 (m, 1H), 2.52-2.50 (m ,1H),2.35-2.30(m,1H),2.25(s,3H),2.20-2.15(m,1H),1.80-1.70(m,2H),1.60-1.50(m,1H),1.45-1.35(m,1H). LCMS(ESI):C 11 H 14 Calculated value of ClF3N4[M+H] is 295.09, found value is 295.23. The structure of compound P28 was confirmed by NOE: upon irradiation of H17 (7.39 ppm) protons, an enhancement of H19 (-NH, doublet, 7.55 ppm) protons was observed. Analytical data of P28A: LCMS (ESI): C 11 H 14 ClF3N4[M+H] + The calculated value is 295.09, and the experimental value is 295.23.

[0841] Preparation 29. (R)-3-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)piperidin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P29). To a stirred solution of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzene-1,2-diamine (0.40 g, 1.32 mmol, 1.0 eq), P28 (0.39 g, 1.32 mmol, 1.0 eq) in a mixture of 1,4-dioxane (3.0 mL) and water (1.0 mL) was added sodium carbonate (0.28 g, 2.64 mmol, 2.0 eq) at ambient temperature. The reaction mixture was degassed with a stream of nitrogen for 15 minutes. Subsequently, tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.06 mmol, 0.05 eq) was added at this temperature. The mixture was heated to 100° C. and stirred for 6 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was subjected to reverse phase column chromatography using a mixture of ACN (0 to 70%) and water as eluent to afford 0.270 g of the title compound as a brown solid (47%). Analytical data: LCMS (ESI): C 18 H 20 F6N6[M+H] + The calculated value is 435.17, and the experimental value is 435.66. Synthesis of (R)-3-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)piperidin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P30)

[0842] Preparation 30. (S)-3-(6-((1-methylpiperidin-3-yl)amino)-4-(trifluoromethyl)piperidin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P30). To a stirred solution of P28A (0.35 g, 1.18 mmol, 1.0 eq) in a mixture of 1,4-dioxane (6 mL) and water (0.5 mL) was added sodium carbonate (0.25 g, 2.36 mmol, 2.0 eq) and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzene-1,2-diamine (0.53 g, 1.77 mmol, 1.5 eq) at ambient temperature. The reaction mixture was degassed with a stream of nitrogen for 10 minutes. Subsequently, tetrakis(triphenylphosphine)palladium(0) (0.127 g, 0.11 mmol, 0.1 eq) was added at ambient temperature. The reaction mixture was heated to 100° C. and stirred at 100° C. for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was cooled to ambient temperature and filtered through a bed of celite, which was washed with 1,4-dioxane (2 x 25 mL). The combined filtrates were concentrated under reduced pressure. The crude compound was flash chromatographed on silica gel (230-400 mesh) using a mixture of MeOH (0-10%) and DCM as eluent to afford 0.20 g of the title compound P30 as a brown solid (39%). Analytical data: LCMS (ESI): C 18 H 20 F6N6[M+H] + The calculated value is 435.17, and the experimental value is 435.59. Synthesis of (R)-4-chloro-N-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydro-1-piperidin-1-amine (P33)

[0843] Preparation 31. 2,3,5,6,7,8-Hexahydro-1,4-dione (P31). To a stirred solution of 4,5,6,7-tetrahydroisobenzofuran-1,3-dione (9.0 g, 59.21 mmol, 1.0 eq) in AA (270 mL) was added sodium acetate (38.85 g, 473.68 mmol, 8.0 eq) and hydrazine monohydrate (5.5 mL, 177.63 mmol, 3.0 eq) at ambient temperature. The resulting reaction mixture was stirred at 100 ° C for 12 hours. The progress of the reaction mixture was monitored by TLC and LCMS. After the completion of the starting material, the reaction mixture was quenched into cold water (200 mL), and the precipitated solid was collected by filtration, washed with cold water and dried in vacuo. This solid was triturated with n-hexane and dried to give 6.3 g of the title compound as a colorless solid (64%). Analytical data: 1H NMR (400MHz, DMSO-d6), δ: 11.34-11.30(m,2H), 2.38-2.30(m,4H), 1.68-1.61(m,4H). LCMS(ESI):C8H 10 N2O2[M+H] + Calculated value: 167.07, experimental value: 167.09.

[0844] Preparation 32. 1,4-Dichloro-5,6,7,8-tetrahydrofuran (P32). POCl3 (31.5 mL) was added to P31 (6.3 g, 37.91 mmol, 1.0 eq) at ambient temperature. The resulting reaction mixture was stirred at 110 ° C for 12 hours. The progress of the reaction mixture was monitored by TLC and LCMS. After the completion of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was quenched into cold water (100 mL), and the precipitated solid was collected by filtration, washed with cold water and dried in vacuo. This solid was triturated with n-hexane and dried to give 5.0 g of the title compound P32 (65%) as a brown solid. Analytical data: 1 H NMR (400MHz, DMSO-d6), δ: 2.76-2.73 (m, 4H), 1.89-1.85 (m, 4H). LCMS(ESI): C8H8Cl2N2[M+H] + Calculated value: 203.01, experimental value 203.10.

[0845] Preparation 33. (R)-4-Chloro-N-(1-methylpiperidin-3-yl)-5,6,7,8-tetrahydropiperidin-1-amine (P33). To a stirred solution of P32 (1.0 g, 4.92 mmol, 1.0 eq) in DMSO (10 mL) was added DIPEA (6.35 g, 49.24 mmol, 10 eq) and (R)-1-methylpiperidin-3-amine (1.12 g, 9.84 mmol, 2.0 eq) in a sealed tube at ambient temperature. The resulting reaction mixture was stirred at 160 ° C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. After the completion of the starting material, the reaction mixture was quenched with saturated NaHCO solution (10 mL) and extracted with EtOAc (3×25 mL). The combined organic layers were dried over anhydrous NaSO, filtered and concentrated under reduced pressure. The residue was subjected to flash column chromatography using a mixture of MeOH (0→10%) and DCM as eluent to give 0.30 g of the title compound as a brown liquid (23%). Analytical data: LCMS (ESI): C 14 H 21ClN4[M+H] + Calculated value: 281.15, experimental value 281.17. Synthesis of (R)-4-chloro-N-(1-ethylpiperidin-3-yl)-5,6,7,8-tetrahydropiperidin-1-amine (P34)

[0846] Preparation 34. (R)-4-Chloro-N-(1-ethylpiperidin-3-yl)-5,6,7,8-tetrahydropiperidin-1-amine (P34). To a stirred solution of 1,4-dichloro-5,6,7,8-tetrahydropyridine (P-32, 1.0 g, 4.924 mmol, 1.0 eq) in DMSO (10 mL) was added DIPEA (6.352 g, 49.244 mmol, 10 eq) and (R)-1-ethylpiperidin-3-amine (1.25 g, 9.849 mmol, 2.0 eq) at ambient temperature. The resulting reaction mixture was stirred in a sealed tube at 160 ° C for 6 hours. The reaction progress was monitored by TLC and LCMS. After the starting material was completed, all volatiles were removed in vacuo. The residue was purified by reverse phase column chromatography using a mixture of ACN (0→30%) and water containing 0.1% FA to give 0.5 g of the title compound P34 as a brown liquid (34%). Analytical data: 1 H NMR (400 MHz, CDCl 3 ), δ: 8.37 (br.s, exchanged with D 2 O, 1H), 6.23 (br.s, 1H), 4.85 (s, 1H), 3.74-3.55 (m, 1H), 3.10-2.95 (m, 2H), 2.63 (s, 8H), 2.32-2.18 (m, 1H), 1.93-1.68 (m, 3H), 1.56 (combined with water, 3H), 1.36 (t, J=7.2 Hz, 2H). LCMS (ESI): C 15 H 23 ClN4[M+H] + Calculated value: 295.16, experimental value 295.32. Synthesis of N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide (P37)

[0847] Preparation 35. N-(2-Bromo-5-(trifluoromethyl)phenyl)-N-(methylsulfonyl)methanesulfonamide (P35). To a stirred solution of 2-bromo-5-(trifluoromethyl)aniline (10.0 g, 41.60 mmol, 1.0 eq) and pyridine (16.81 mL, 208.316 mmol, 5.0 eq) in DCM (200 mL) was added methanesulfonyl chloride (16.12 mL, 208.31 mmol, 5.0 eq) at 0 ° C. The resulting reaction mixture was stirred at ambient temperature for 12 hours. The progress of the reaction was monitored by TLC and LCMS. After completion of the starting material, the reaction mixture was quenched with water (250 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 10 g of the title compound P37 (crude material) as a brown liquid. The crude material itself was carried on to the next step without any purification. Analytical data: LCMS (ESI): C9H9BrF3NO4S2[M+H] + Calculated value: 366.19, experimental value 366.85.

[0848] Preparation 36. N-(2-Bromo-5-(trifluoromethyl)phenyl)methanesulfonamide (P36). To a stirred solution of P35 (10.0 g, 25.38 mmol, 1 eq) in a mixture of THF / MeOH (1: 1, 200 mL) was added a solution of monohydrated LiOH (31.94 g, 761.42 mmol, 30 eq) in water (100 mL) at 0 ° C. The resulting reaction mixture was stirred at ambient temperature for 12 hours. The reaction progress was monitored by TLC and LCMS. After the completion of the starting material, the reaction mixture was concentrated under reduced pressure. The residue was quenched with cold water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was flash chromatographed on silica gel (230 to 400 mesh) using a mixture of EtOAc (0→20%) and hexane to give 7.0 g of the title compound P36 (87%) as a colorless solid. Analytical data: 1 H NMR (400MHz, CDCl3), δ: 7.92 (d, J = 1.6 Hz, 1H), 7.73, 7.72 (dd, J = 0.4 Hz, 1H), 7.34-7.33 (m, 1H), 6.94 (br.s, 1H), 3.06 (s, 3H). LCMS(ESI): C8H7BrF3NO2S[MH] - The calculated value is 315.93, and the experimental value is 315.99.

[0849] Preparation 37. N-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide (P37). To a stirred solution of P36 (5.0 g, 15.718 mmol, 1 eq) and bis(pinacolato)diboron (5.98 g, 23.577 mmol, 1.5 eq) in 1,4-dioxane (75 mL) was added KOAc (4.628 g, 47.154 mmol, 3.0 eq) at ambient temperature. The reaction mixture was degassed with a stream of nitrogen for 15 minutes, followed by the addition of PdCl2(dppf)·DCM (0.552 g, 0.786 mmol, 0.05 eq) at room temperature. The resulting reaction mixture was stirred at 100 ° C for 6 hours. The progress of the reaction was monitored by TLC and LCMS. After the starting material was complete, the reaction mixture was filtered through a celite pad and the celite pad was washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure at 40 ° C. The residue was flash chromatographed over silica gel (230-400 mesh) using a mixture of EtOAc (0→10%) and hexanes as eluent to afford 5.0 g of the title compound P37 as a brown solid (crude material). The crude material was carried forward to the next step. Analytical data: LCMS (ESI): corresponding to benzoic acid C8H9BF3NO4S[MH] - The calculated value is 282.03, and the experimental value is 282.01. Synthesis of (R)-4-chloro-N-(1-ethylpiperidin-3-yl)-5,6,7,8-tetrahydro-5,8-ethylpiperidin-1-amine (P38)

[0850] Preparation 38. (R)-4-Chloro-N-(1-ethylpiperidin-3-yl)-5,6,7,8-tetrahydro-5,8-ethoxypiperidin-1-amine (P38). To a stirred solution of 1,4-dichloro-5,6,7,8-tetrahydro-5,8-ethylpiperidin-3-ol (0.6 g, 2.619 mmol, 1.0 eq) in DMSO (10.0 mL) was added N,N-diisopropylethylamine (2.346 mL, 13.094 mmol, 5.0 eq) and (R)-1-ethylpiperidin-3-amine (1.0 g, 7.86 mmol, 3.0 eq) at ambient temperature and stirred at 160 ° C for 6 hours. The progress of the reaction was monitored by TLC and LCMS. After the starting material was completed, all volatiles were removed in vacuo. The residue was purified by reverse phase column chromatography using ACN and water containing 0.1% FA to give 0.4 g of the title compound P38 as a brown liquid (47%). Analytical data: LCMS (ESI): C 17 H 25 ClN4[M+H] + Calculated value: 321.18, experimental value 321.34. Synthesis of N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)ethanesulfonamide (P40)

[0851] Preparation 39. 2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)aniline (P39). To a stirred solution of 2-bromo-5-(trifluoromethyl)aniline (5 g, 20.83 mmol, 1.0 eq) and bis(pinacolato)diboron (7.93 g, 31.24 mmol, 1.5 eq) in 1,4-dioxane (150 mL) was added KOAc (6.1 g, 62.49 mmol, 3.0 eq) at ambient temperature. The mixture was degassed with an argon stream for 10 minutes. Subsequently, Pd(PPh3)2Cl2 (0.73 g, 1.04 mmol, 0.05 eq) was added. The resulting reaction mixture was stirred at 100°C for 2 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a pad of celite and the pad was washed with 1,4-dioxane (50 mL). The filtrate was concentrated under reduced pressure to obtain a residue. The residue was flash chromatographed over silica gel (80 g, 230-400 mesh) using a mixture of EtOAc (0→20%) and hexanes as eluent to afford 4.1 g of the title compound P39 as an off-white solid (69%). Analytical data: 1 H NMR (400MHz, CDCl3), δ: 7.68 (d, J = 7.6Hz, 1H), 6.86 (dd, J = 7.6Hz, 0.8Hz, 1H), 6.79 (d, J = 0.8Hz, 1H), 4.91 (br.s, 2H), 1.34 (s, 12H); LCMS (ESI): C 13 H 18 BF3NO2[M+H] + Calculated value: 288.13, experimental value 288.27.

[0852] Preparation 40. N-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)ethanesulfonamide (P40). To a stirred solution of P39 (1.0 g, 3.48 mmol, 1.0 eq) in DCM (8 mL) was added TEA (2.1 g, 20.90 mmol, 6.0 eq) at 0 ° C., followed by the addition of ethanesulfonyl chloride (0.67 g, 5.22 mmol, 1.5 eq). The resulting reaction mixture was stirred at ambient temperature for 4 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was washed with water (2×10 mL) and brine (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure at 40 ° C to obtain a residue. The residue was flash chromatographed over silica gel (40 g, 230 to 400 mesh) using a mixture of EtOAc (0→30%) and hexane as an eluent to give 0.8 g of the title compound P40 (60%) as a light brown gum. Analytical data: 1 H NMR (400MHz, CDCl3), δ: 8.63 (s, 1H), 7.89-7.88 (m, 2H), 7.33-7.31 (m, 1H), 3.14 (q, J = 7.2Hz, 2H), 1.38-1.32 (m, 15H); LCMS (ESI): C 15 H 22 BF3NO4S[M+H] + Calculated value: 380.12, experimental value 380.48. Synthesis of N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)propane-2-sulfonamide (P43)

[0853] Preparation 41. N-(2-Bromo-5-(trifluoromethyl)phenyl)propane-2-sulfenamide (P41). To a stirred solution of 2-bromo-5-(trifluoromethyl)aniline (2.0 g, 8.33 mmol, 1.0 eq) in toluene (40.0 mL) was added SOCl2 (0.8 mL, 10.83 mmol, 1.3 eq) at ambient temperature. The resulting reaction mixture was stirred at 110 ° C for 2 hours. The reaction progress was monitored by TLC. The reaction mixture was concentrated under reduced pressure at 45 ° C to obtain a residue. The residue was dissolved in anhydrous THF (40.0 mL) and cooled to 0 ° C. Subsequently, THF (6.24 mL, 12.49 mmol, 1.5 eq) containing 2M isopropylmagnesium chloride was added at 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 1 hour. The reaction progress was monitored by TLC and LCMS. The reaction mixture was quenched with NH4Cl solution (40 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure at 45° C. to give a residue. The residue was subjected to silica gel (40 g, 230-400 mesh) flash chromatography using a mixture of EtOAc (0→10%) / hexane as the eluent to give 2.1 g (76%) of the title compound P41 as a brown gum. Analytical data: 1 H NMR (400MHz, CDCl3), δ: 6.86 (dd, J = 7.64Hz, 0.8Hz, 1H), 7.55 (d, J = 1.6Hz, 1H), 7. 15-7.13(m,1H),6.41(s,1H),3.11-3.08(m,1H),1.43-1.41(m,6H); LCMS(ESI): C 10 H 11 BrF3NOS[M+H] + Calculated value: 329.97, experimental value 330.14.

[0854] Preparation 42. N-(2-Bromo-5-(trifluoromethyl)phenyl)propane-2-sulfonamide (P42). To a stirred solution of P41 (1.6 g, 4.84 mmol, 1.0 eq) in DCM (48.0 mL) was added m-CPBA (65% moisture) (1.92 g, 7.26 mmol, 1.5 eq) at 0 ° C. The resulting reaction mixture was stirred at 0 ° C for 4 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was washed with saturated NaHCO solution (2×60 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure at 45 ° C to obtain a residue. The residue was flash chromatographed on silica gel (230 to 400 mesh) using a mixture of EtOAc (0→20%) and hexane as an eluent to give 1.25 g of the title compound P42 (75%) as an off-white solid. Analytical data: 1 H NMR (400MHz, CDCl3), δ: 8.00 (d, J = 1.6Hz, 1H), 7.69 (d, J = 8.4Hz, 1H), 7.25 (dd, J = 8.4Hz ,1.6Hz,1H),6.82(s,1H),3.31(sep,J=6.8Hz,1H),1.42(d,J=6.8Hz,1H); LCMS(ESI):C 10 H 11 BrF3NO2S[M+H] + Calculated value: 345.96, experimental value 346.28.

[0855] Preparation 43. N-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)propane-2-sulfonamide (P43). In a microwave vial, KOAc (510 mg, 5.20 mmol, 3.0 eq) was added to a stirred solution of P42 (600 mg, 1.73 mmol, 1.0 eq) and bis(pinacolato)diboron (660 mg, 2.60 mmol, 1.5 eq) in 1,4-dioxane (12 mL) at ambient temperature. The mixture was degassed with a stream of argon for 10 minutes. Subsequently, Pd(PPh3)2Cl2 (61 mg, 0.087 mmol, 0.05 eq) was added. The mixture was stirred at 150 ° C in a microwave synthesizer for 1 hour. The reaction mixture was filtered through a pad of celite and the pad was washed with 1,4-dioxane (10 mL). The filtrate was concentrated under reduced pressure at 45 ° C to give the title compound P43 (850 mg, crude material) as a brown gummy compound. Analytical data: LCMS (ESI): C 16 H 23 BF3NO4S[MH] -Calculated value: 392.14, experimental value 392.26. Synthesis of (R)-6-(2-amino-4-(trifluoromethyl)phenyl)-N-(1-ethylpiperidin-3-yl)-4-methylpiperidin-3-amine (P44)

[0856] Preparation 44. (R)-6-(2-Amino-4-(trifluoromethyl)phenyl)-N-(1-ethylpiperidin-3-yl)-4-methylpiperidin-3-amine (P44). To a stirred solution of P24A (300 mg, 1.17 mmol, 1.0 eq) and P39 (1.0 g, 3.53 mmol, 3.0 eq) in a mixture of 1,4-dioxane (24.0 mL) and H2O (6.0 mL) was added Na2CO3 (374 mg, 3.53 mmol, 3.0 eq) at ambient temperature. The reaction mixture was degassed with a stream of nitrogen for 5 minutes. Subsequently, Pd(PPh3)4 (68 mg, 0.059 mmol, 0.05 eq) was added. The reaction mixture was stirred at 100°C for 16 hours. The progress of the reaction was monitored by TLC and LCMS. The reaction mixture was filtered through a pad of celite and the pad was washed with 1,4-dioxane (10 mL). The filtrate was concentrated under reduced pressure to obtain a residue. The residue was flash chromatographed over silica gel (40 g, 230-400 mesh) using a mixture of MeOH (0→20%) and DCM as eluent to afford 360 mg of the title compound P44 as a brown gum (81%). Analytical data: LCMS (ESI): C 19 H 24 F3N5[M+H] + Calculated value: 380.20, experimental value 380.41. Synthesis of (R)-3-((4-methyl-6-(2-(methylsulfonamido)-4-(trifluoromethyl)phenyl)tetrafluoroethylene-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (P45)

[0857] Preparation 45. (R)-tert-butyl 3-((4-methyl-6-(2-(methylsulfonamido)-4-(trifluoromethyl)phe...

Claims

1. A compound comprising formula (A): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, characterized in that R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; R 6 Selected from H, SO2R 8 , NH2, C1-C6 alkyl, C1-C6 alkyl-C(O)-, aryl, wherein the alkyl or aryl group is optionally substituted with one or more substituents independently selected from halogen, CN, OH; R 7 is H, C1-C6 alkyl or NH2; or R 6 and R 7 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring or heteroaromatic ring; R 8 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkyl, cycloalkyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, and OH; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2; The restriction condition is that when R 5 When it is methyl, R 6 Not H or CH3CO-.

2. The compound according to claim 1, characterized in that The compound comprises formula (I): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; R 8 is selected from C1-C6 alkyl, C3-C8 cycloalkyl, 5- to 6-membered heteroaryl, wherein the alkyl, cycloalkyl or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, CN, and OH; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2.

3. The compound according to claim 1, characterized in that The compound comprises formula (II): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2.

4. The compound according to claim 1, characterized in that The compound comprises formula (III): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: W is selected from CH, N; R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2.

5. The compound according to claim 4, characterized in that The compounds include formula (III-A): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

6. The compound according to claim 4, characterized in that The compounds include formula (III-B): or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

7. The compound according to claim 1, characterized in that The compound comprises formula (IV): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2.

8. The compound according to claim 1, characterized in that The compounds include formula (V): or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate or tautomer thereof, wherein: R 1 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 2 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; or R 1 and R 2 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an aromatic hydrocarbon, or a heteroaromatic hydrocarbon, wherein the cycloalkane, heterocycle, aromatic hydrocarbon, or heteroaromatic hydrocarbon is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 4 Selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyloxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl and heteroaryl; R 3 and R 4 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 8-membered cycloalkane or a 5- to 14-membered heterocycle, wherein the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 Selected from H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, 4 to 10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, pendant oxygen, OH, CN, C1-C6 alkoxy, C3-C 10 Cycloalkyl, aryl; R 6 is selected from H, C1-C6 alkyl, C1-C6 alkyl-C(O)-, aryl, wherein the alkyl or aryl group is optionally substituted with one or more substituents independently selected from halogen, CN, OH; Each R 9 Independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, wherein the alkyl or alkoxy is optionally substituted with one or more halogen, OH; or Two R's 9 together with the atoms to which it is attached and any intervening atoms, form a 5- to 6-membered heterocyclic ring; or R 5 and R 9 Together with the atoms to which it is attached and any intervening atoms, it forms a 5- to 6-membered heterocyclic ring; n is an integer selected from 0, 1 and 2; The restriction condition is that when R 5 When it is methyl, R 6 Not H or CH3CO-.

9. A compound, characterized in that Selected from: or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof.

10. A pharmaceutical composition, characterized in that Comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, stereoisomer, solvate or tautomer thereof and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10, further comprising one or more additional pharmaceutically active agents.

12. A method for inhibiting NLRP3 in a cell, characterized in that: The method comprises contacting the cell with a compound according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 or 11.

13. The method according to claim 12, characterized in that The contacting is performed in vitro or in vivo.

14. A method for treating or preventing a disease or condition associated with NLRP3, characterized in that: The method comprises administering the compound according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 10 or 11 to a subject in need thereof.

15. The method according to claim 14, characterized in that The disease or condition is selected from the group consisting of: acne vulgaris (ACNE); hereditary acral keratoderma hyaline papularis; adult-onset Still's disease (AOSD); Aicardi-Goutieres Syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthracene; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); autoimmune diseases of the cardiovascular system; autoimmune diseases of the gastrointestinal tract; autoinflammatory syndrome; Behcet's syndrome Syndrome; Blau syndrome (BLAUS); body mass index quantitative trait locus 11 (BMIQ11); bone inflammatory diseases; cerebral edema; brucellosis; candidiasis; cervical lymphadenitis; chondrocalcinosis; chronic meningitis; Chronic recurrent multifocal osteomyelitis (CRMO); chronic urticaria; Cinca syndrome (CINCA); conjunctival diseases; conjunctivitis; connective tissue diseases; corneal diseases; coronavirus infections; Covid-19; Crohn's disease; cryptopyrin-associated periodic syndrome (CAPS); cystic fibrosis (CF); autosomal dominant hearing loss type 34 with or without inflammation (DFNA34); dermatitis; diabetes; diabetic encephalopathy; rash (RASH); eye diseases; familial cold autoinflammatory syndrome (FCU); familial cold autoinflammatory syndrome type 1 (FCAS1); familial cold autoinflammatory syndrome type 2 (FCAS2); familial Mediterranean fever (FMF); gout (GOUT); hereditary periodic fever syndromes; hidradenitis; Hidradenitis suppurativa; essential hypertension (EHT); hyperuricemia; autosomal dominant intellectual developmental disorder type 30 (MRD30) with speech delay and behavioral abnormalities; interstitial lung disease type 2 (ILD2); hereditary keratitis (KERH); hereditary transient corneal endotheliitis (KEFH); lipoprotein quantitative trait locus (LPAQTL); lymphadenopathy; age-related macular degeneration type 1 (ARMD1); malaria (CM); meningitis; mevalonic aciduria (MEVA); Muckle-Wells syndrome (MWS); Mycobacterium kansasii Kansasii); myocardial infarction (MCI1); kidney stones; neurologic diseases; nonalcoholic steatohepatitis (NASH); papillitis; osteomyelitis; osteoporosis (OSTEOP); otitis media (OMS); papilledema; pericardial effusion; pericardial disease; pharyngitis; polyradiculoneuropathy; primary bacterial infections; proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); pyoderma; Pyoderma gangrenosum; Pyogenic aseptic arthritis, pyoderma gangrenosum, and acne (PAPAS); respiratory failure; Salmonellosis; Schnitzler syndrome; sebaceous gland disorders; sensorineural hearing loss; serum amyloid a-type amyloidosis; silicosis; skin disorders; stomatitis; type 2 diabetes mellitus (T2D); ureteral disorders; urticaria (HIVES); vulvovaginal candidiasis; and Wells syndrome.

16. The method according to claim 14, characterized in that The disease or disorder is an autoimmune disease.

17. The method according to claim 14, characterized in that The disease or disorder is an inflammatory disease.

18. The method according to claim 14, characterized in that The disease or condition is a coronavirus infectious disease.

19. The method according to any one of claims 12 to 18, characterized in that The individual is a mammal.

20. The method according to claim 19, characterized in that The individual is a human.

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