NLRP3 inhibitors

Abstract

The present invention relates to a compound of formula (A) - NLRP3 inhibitor. The inhibitors described herein may be useful in treating NLRP3-related diseases or disorders, such as autoimmune diseases and inflammatory diseases. In particular, the present invention relates to compounds and pharmaceutical compositions that inhibit NLRP3, methods for treating NLRP3-related diseases or disorders, and methods for synthesizing these compounds. JPEG2026509095000501.jpg43170

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority and interest to U.S. Provisional Patent No. 63 / 441,687, entitled “NLRP3 Inhibitor,” filed on 27 January 2023, the disclosure thereof incorporated in its entirety by reference for all purposes.

[0002] (Field of Invention) This invention relates to inhibitors of NLRP3. The inhibitors described herein may be useful in treating NLRP3-related diseases or disorders, such as autoimmune diseases, Alzheimer's disease, and coronavirus infections, by inducing a sustained response. In particular, this invention relates to compounds and pharmaceutical compositions that inhibit NLRP3, methods for treating NLRP3-related diseases or disorders, and methods for synthesizing these compounds. [Background technology]

[0003] (background) 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 irritants, triggering the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome induces the release of caspase-1-dependent pro-inflammatory cytokines IL-1β and IL-18, as well as gasdelmin D-mediated pyroptotic cell death.

[0004] Inflammasomes play a crucial role in innate immunity by functioning as signaling platforms that process numerous pathogenic and cellular products associated with stress and injury. To date, the most well-studied and characterized inflammasome is the NLRP3 inflammasome, which consists of NLRP3 (receptor 3 containing a nucleotide-binding domain leucine-rich repeat (NLR) and pyrine domain), ASC (an apoptosis-associated speck-like protein containing a caspase-recruiting domain), and procaspase 1. Activation of the NLRP3 inflammasome is mediated by a wide variety of stimuli. Upon activation, the NLRP3 protein recruits the adapter ASC protein, which in turn recruits procaspase 1, leading to its cleavage and activation, and inducing the maturation and secretion of inflammatory cytokines and pyroptosis. However, abnormal activation of the NLRP3 inflammasome has been suggested to be associated with a variety of diseases, including diabetes, atherosclerosis, metabolic syndrome, cardiovascular disease, and neurodegenerative diseases, leading to considerable clinical interest in the search for potential inhibitors of the NLRP3 inflammasome. Recent studies have identified various inhibitors of the NLRP3 inflammasome pathway, which have been validated through in vitro and in vivo experiments in animal models of NLRP3-related diseases. 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 better option because it can prevent off-target immunosuppressive effects and thereby suppress tissue damage.

[0005] While numerous studies have been conducted on NLRP3 inhibitors, research to overcome NLRP3 inhibitor resistance and inhibitor specificity, which are major problems in patient treatment, is still ongoing.

[0006] (overview) A first aspect of the present invention relates to a compound of formula (A): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein R 1 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 cycloalkoxy, 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 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 is selected from H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 cycloalkyl, C3-C 10 cycloalkoxy, 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 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 they are attached and any intervening atoms form a 5- to 8-membered cycloalkane, 5- to 14-membered heterocycle, arene, or 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; R 3H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 4 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 3 and R 4 These atoms, together with the atoms to which they are bonded and any intervening atoms, form 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 halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 H, C1-C6 alkyl, C3-C 10Selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, and 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocyclyl is a halogen, oxo, OH, CN, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups; R 6 The substituent is selected from H, SO2R8, NH2, C1-C6 alkyl, C1-C6 alkyl-C(O)-, and aryl, and the alkyl or aryl substituent is optionally substituted with one or more substituents independently selected from halogen, CN, and OH; R 7 is H, C1-C6 alkyl, or NH2; or R 6 and R 7 These atoms, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 membered heterocycle or heteroarene; R 8 The alkyl group is selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and 5-6 membered heteroaryl groups, and the alkyl, cycloalkyl, or heteroaryl group is optionally substituted with one or more substituents independently selected from halogens, CN, and OH groups; Each R 9 is independently selected from halogens, OH, C1-C6 alkyl, and C1-C6 alkoxy, and the alkyl or alkoxy is optionally substituted with one or more halogens, OH; or Two R's 9 They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R 5 and R 9 These atoms, together with the atoms they are bonded to and any intervening atoms, form a 5-6 member heterocycle; n is an integer selected from 0, 1, and 2; However, R 5 When R is methyl, 6It is neither H nor CH3CO-.

[0007] Another aspect of the present invention relates to a compound of formula (I): [ka] Or relating to pharmaceutically acceptable salts, prodrugs, stereoisomers, solvates, or tautomers thereof, in the formula, R 1 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 2 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl; or R 1 and R 2These atoms, together with the atoms to which they are bonded and any intervening atoms, form 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 halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 4 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 3 and R 4These atoms, together with the atoms to which they are bonded and any intervening atoms, form 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 halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 H, C1-C6 alkyl, C3-C 10 Selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, and 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocyclyl is a halogen, oxo, OH, CN, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups; R 8 The alkyl group is selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and 5-6 membered heteroaryl groups, and the alkyl, cycloalkyl, or heteroaryl group is optionally substituted with one or more substituents independently selected from halogens, CN, and OH groups; Each R 9 is independently selected from halogens, OH, C1-C6 alkyl, and C1-C6 alkoxy, and the alkyl or alkoxy is optionally substituted with one or more halogens, OH; or Two R's 9 They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R 5 and R 9 These atoms, together with the atoms they are bonded to and any intervening atoms, form a 5-6 member heterocycle; n is an integer selected from 0, 1, and 2.

[0008] Another aspect of the present invention relates to a compound of formula (II): [ka] Or relating to pharmaceutically acceptable salts, prodrugs, stereoisomers, solvates, or tautomers thereof, in the formula, R 1 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 2 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl; or R 1 and R 2 These atoms, together with the atoms to which they are bonded and any intervening atoms, form 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 halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 4 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 3 and R 4 These atoms, together with the atoms to which they are bonded and any intervening atoms, form 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 halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 H, C1-C6 alkyl, C3-C 10 Selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, and 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocyclyl is a halogen, oxo, OH, CN, C1-C6 alkoxy, C3-C10 optionally substituted with one or more substituents independently selected from cycloalkyl and aryl; Each R 9 is independently selected from halogen, OH, C1-C6 alkyl, C1-C6 alkoxy, and the alkyl or alkoxy is optionally substituted with one or more halogen or OH; or Two Rs 9 together with the atoms to which they are attached and any intervening atoms form a 5- to 6-membered heterocycle; or R 5 and R 9 together with the atoms to which they are attached and any intervening atoms form a 5- to 6-membered heterocycle; n is an integer selected from 0, 1, and 2.

[0009] Another aspect of the present invention relates to a compound of formula (III):

Chemical formula

[0010] Another aspect of the present invention relates to a compound of formula (IV): [ka] Or relating to pharmaceutically acceptable salts, prodrugs, stereoisomers, solvates, or tautomers thereof, in the formula, R 1 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 2 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl; or R 1 and R 2These atoms, together with the atoms to which they are bonded and any intervening atoms, form 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 halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 4 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 3 and R 4These atoms, together with the atoms to which they are bonded and any intervening atoms, form 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 halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 H, C1-C6 alkyl, C3-C 10 Selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, and 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocyclyl is a halogen, oxo, OH, CN, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups; Each R 9 is independently selected from halogens, OH, C1-C6 alkyl, and C1-C6 alkoxy, and the alkyl or alkoxy is optionally substituted with one or more halogens, OH; or Two R's 9 They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R 5 and R 9 These atoms, together with the atoms they are bonded to and any intervening atoms, form a 5-6 member heterocycle; n is an integer selected from 0, 1, and 2.

[0011] Another aspect of the present invention relates to a compound of formula (V): [ka] Or relating to pharmaceutically acceptable salts, prodrugs, stereoisomers, solvates, or tautomers thereof, in the formula, R 1 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 2 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl; or R 1 and R 2 These atoms, together with the atoms to which they are bonded and any intervening atoms, form 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 halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 3 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 4 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 3 and R 4 These atoms, together with the atoms to which they are bonded and any intervening atoms, form 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 halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 5 H, C1-C6 alkyl, C3-C 10 Selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, and 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocyclyl is a halogen, oxo, OH, CN, C1-C6 alkoxy, C3-C 10Optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups; R 6 The substituent is selected from H, C1-C6 alkyl, C1-C6 alkyl-C(O)-, and aryl, and the alkyl or aryl substituent is optionally substituted with one or more substituents independently selected from halogen, CN, and OH; Each R 9 is independently selected from halogens, OH, C1-C6 alkyl, and C1-C6 alkoxy, and the alkyl or alkoxy is optionally substituted with one or more halogens, OH; or Two R's 9 They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R 5 and R 9 These atoms, together with the atoms they are bonded to and any intervening atoms, form a 5-6 member heterocycle; n is an integer selected from 0, 1, and 2; However, R 5 When R is methyl, 6 It is neither H nor 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 comprise excipients, diluents, or surfactants.

[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 comprise excipients, diluents, or surfactants.

[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 excipients, diluents, or surfactants.

[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 comprise excipients, diluents, or surfactants.

[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 excipients, diluents, or surfactants.

[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 excipients, diluents, or surfactants.

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

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

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

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

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

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

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

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

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

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

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

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

[0040] Another aspect of the present invention relates to the use of the compound of formula (IV), or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition in the treatment of 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 thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof, in the treatment of 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 thereof, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0060] The present invention further provides a method for treating a disease or disorder related to NLRP3, comprising administering to a patient suffering from at least one of the diseases or disorders 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the diseases or disorders 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the diseases or disorders 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the said disease or disorder 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the diseases or disorders 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the diseases or disorders a compound of formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0066] This invention provides an inhibitor of NLRP3, which is a therapeutic agent for the treatment of diseases and disorders.

[0067] The present invention further provides compounds and compositions having improved efficacy and safety profiles compared to known NLRP3 inhibitors. This disclosure also provides agents with 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the diseases or disorders 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the diseases or disorders 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the diseases or disorders 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the said disease or disorder 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the diseases or disorders 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 disorder related to NLRP3, comprising administering to a patient suffering from at least one of the diseases or disorders 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 disorders, bone disorders, cancers, cardiovascular disorders, ear disorders, endocrine disorders, eye disorders, fetal disorders, gastrointestinal disorders; genetic disorders, immune disorders, infectious diseases, liver disorders, mental disorders, metabolic disorders, muscle disorders, kidney disorders, neurological disorders, oral disorders, rare diseases, reproductive disorders, respiratory disorders, skin disorders, and olfactory / gustatory disorders, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders 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 disorders, bone disorders, cancers, cardiovascular disorders, ear disorders, endocrine disorders, eye disorders, fetal disorders, gastrointestinal disorders; genetic disorders, immune disorders, infectious diseases, liver disorders, mental disorders, metabolic disorders, muscle disorders, kidney disorders, neurological disorders, oral disorders, rare diseases, reproductive disorders, respiratory disorders, skin disorders, and olfactory / gustatory disorders, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders 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 disorders, bone disorders, cancers, cardiovascular disorders, ear disorders, endocrine disorders, eye disorders, fetal disorders, gastrointestinal disorders; genetic disorders, immune disorders, infectious diseases, liver disorders, mental disorders, metabolic disorders, muscle disorders, kidney disorders, neurological disorders, oral disorders, rare diseases, reproductive disorders, respiratory disorders, skin disorders, and olfactory / gustatory disorders, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders 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 disorders, bone disorders, cancers, cardiovascular disorders, ear disorders, endocrine disorders, eye disorders, fetal disorders, gastrointestinal disorders; genetic disorders, immune disorders, infectious diseases, liver disorders, mental disorders, metabolic disorders, muscle disorders, kidney disorders, neurological disorders, oral disorders, rare diseases, reproductive disorders, respiratory disorders, skin disorders, and olfactory / gustatory disorders, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders 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 disorders, bone disorders, cancers, cardiovascular disorders, ear disorders, endocrine disorders, eye disorders, fetal disorders, gastrointestinal disorders; genetic disorders, immune disorders, infectious diseases, liver disorders, mental disorders, metabolic disorders, muscle disorders, kidney disorders, neurological disorders, oral disorders, rare diseases, reproductive disorders, respiratory disorders, skin disorders, and olfactory / gustatory disorders, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders 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 disorders, bone disorders, cancers, cardiovascular disorders, ear disorders, endocrine disorders, eye disorders, fetal disorders, gastrointestinal disorders; genetic disorders, immune disorders, infectious diseases, liver disorders, mental disorders, metabolic disorders, muscle disorders, kidney disorders, neurological disorders, oral disorders, rare diseases, reproductive disorders, respiratory disorders, skin disorders, and olfactory / gustatory disorders, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders a compound of formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0080] The present invention further includes acne (ACNE); hereditary translucent papuloacrokeratosis; adult-onset Still's disease (AOSD); Eicardi-Goutier syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthraxosis; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); cardiovascular autoimmune diseases; gastrointestinal autoimmune diseases; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantifiable trait locus 11 (BMIQ11); osteoinflammatory diseases; cerebral edema; and Brussey's syndrome. Rhema; Candidiasis; Cervical lymphadenitis; Chondrocalcification; Chronic meningitis; Chronic relapsing polymyelitis (CRMO); Chronic urticaria; CINCA syndrome (CINCA); Conjunctival diseases; Conjunctivitis; Connective tissue diseases; Corneal diseases; Coronavirus infection; COVID-19; Crohn's disease; Cryopyrin-associated periodic syndromes (CAPS); Cystic fibrosis (CF); Autosomal dominant hearing loss type 34 (DFNA34) with or without inflammation; Dermatitis; Diabetes mellitus; Diabetic encephalopathy; Rash (RASH); Eye diseases; Familial cold autoinflammatory syndrome (FCU); Familial cold autoinflammatory syndrome type 1 (FCAS1); Home Familial cold autoinflammatory syndrome type 2 (FCAS2); Familial Mediterranean fever (FMF); Gout (GOUT); Hereditary periodic fever syndromes; Hidradenitis; Suppurative hidradenitis; Essential hypertension (EHT); Hyperuricemia; Autosomal dominant intellectual disability type 30 with speech delay and behavioral abnormalities (MRD30); Interstitial lung disease type 2 (ILD2); Hereditary keratitis (KERH); Hereditary transient keratoendotheliitis (KEFH); Lipoprotein quantitative trait locus (LPAQTL); Lymph node disorders; Age-related macular degeneration type 1 (ARMD1); Malaria (CM); Meningitis; Mevalonaciduria (MEVA); Mackle-Wells syndrome (MWS); Mycobacterium cansasi; Myocardial infarction (MCI1); Kidney stones; Nervous system disorders; Non-alcoholic steatohepatitis (NASH); Optic neuroplasty; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial diseases; Pharyngitis; Polyradiculopathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Septic arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid A amyloidosis;A method is provided for treating a disease, disorder, or symptom selected from the group consisting of silicosis; skin diseases; stomatitis; type 2 diabetes (T2D); ureteral disorders; urticaria (HIVES); vulvovaginal candidiasis; and Wells syndrome, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders a compound of formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0081] The present invention further includes acne (ACNE); hereditary translucent papuloacrokeratosis; adult-onset Still's disease (AOSD); Eicardi-Goutier syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthraxosis; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); cardiovascular autoimmune diseases; gastrointestinal autoimmune diseases; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantifiable trait locus 11 (BMIQ11); osteoinflammatory diseases; cerebral edema; and Brussey's syndrome. Rhema; Candidiasis; Cervical lymphadenitis; Chondrocalcification; Chronic meningitis; Chronic relapsing polymyelitis (CRMO); Chronic urticaria; CINCA syndrome (CINCA); Conjunctival diseases; Conjunctivitis; Connective tissue diseases; Corneal diseases; Coronavirus infection; COVID-19; Crohn's disease; Cryopyrin-associated periodic syndromes (CAPS); Cystic fibrosis (CF); Autosomal dominant hearing loss type 34 (DFNA34) with or without inflammation; Dermatitis; Diabetes mellitus; Diabetic encephalopathy; Rash (RASH); Eye diseases; Familial cold autoinflammatory syndrome (FCU); Familial cold autoinflammatory syndrome type 1 (FCAS1); Home Familial cold autoinflammatory syndrome type 2 (FCAS2); Familial Mediterranean fever (FMF); Gout (GOUT); Hereditary periodic fever syndromes; Hidradenitis; Suppurative hidradenitis; Essential hypertension (EHT); Hyperuricemia; Autosomal dominant intellectual disability type 30 with speech delay and behavioral abnormalities (MRD30); Interstitial lung disease type 2 (ILD2); Hereditary keratitis (KERH); Hereditary transient keratoendotheliitis (KEFH); Lipoprotein quantitative trait locus (LPAQTL); Lymph node disorders; Age-related macular degeneration type 1 (ARMD1); Malaria (CM); Meningitis; Mevalonaciduria (MEVA); Mackle-Wells syndrome (MWS); Mycobacterium cansasi; Myocardial infarction (MCI1); Kidney stones; Nervous system disorders; Non-alcoholic steatohepatitis (NASH); Optic neuroplasty; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial diseases; Pharyngitis; Polyradiculopathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Septic arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid A amyloidosis;A method is provided for treating a disease, disorder, or symptom selected from the group consisting of silicosis; skin diseases; stomatitis; type 2 diabetes (T2D); ureteral disorders; urticaria (HIVES); vulvovaginal candidiasis; and Wells syndrome, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0082] The present invention further includes acne (ACNE); hereditary translucent papuloacrokeratosis; adult-onset Still's disease (AOSD); Eicardi-Goutier syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthraxosis; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); cardiovascular autoimmune diseases; gastrointestinal autoimmune diseases; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantifiable trait locus 11 (BMIQ11); osteoinflammatory diseases; cerebral edema; and Brussey's syndrome. Rhema; Candidiasis; Cervical lymphadenitis; Chondrocalcification; Chronic meningitis; Chronic relapsing polymyelitis (CRMO); Chronic urticaria; CINCA syndrome (CINCA); Conjunctival diseases; Conjunctivitis; Connective tissue diseases; Corneal diseases; Coronavirus infection; COVID-19; Crohn's disease; Cryopyrin-associated periodic syndromes (CAPS); Cystic fibrosis (CF); Autosomal dominant hearing loss type 34 (DFNA34) with or without inflammation; Dermatitis; Diabetes mellitus; Diabetic encephalopathy; Rash (RASH); Eye diseases; Familial cold autoinflammatory syndrome (FCU); Familial cold autoinflammatory syndrome type 1 (FCAS1); Home Familial cold autoinflammatory syndrome type 2 (FCAS2); Familial Mediterranean fever (FMF); Gout (GOUT); Hereditary periodic fever syndromes; Hidradenitis; Suppurative hidradenitis; Essential hypertension (EHT); Hyperuricemia; Autosomal dominant intellectual disability type 30 with speech delay and behavioral abnormalities (MRD30); Interstitial lung disease type 2 (ILD2); Hereditary keratitis (KERH); Hereditary transient keratoendotheliitis (KEFH); Lipoprotein quantitative trait locus (LPAQTL); Lymph node disorders; Age-related macular degeneration type 1 (ARMD1); Malaria (CM); Meningitis; Mevalonaciduria (MEVA); Mackle-Wells syndrome (MWS); Mycobacterium cansasi; Myocardial infarction (MCI1); Kidney stones; Nervous system disorders; Non-alcoholic steatohepatitis (NASH); Optic neuroplasty; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial diseases; Pharyngitis; Polyradiculopathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Septic arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid A amyloidosis;A method is provided for treating a disease, disorder, or symptom selected from the group consisting of silicosis; skin diseases; stomatitis; type 2 diabetes (T2D); ureteral disorders; urticaria (HIVES); vulvovaginal candidiasis; and Wells syndrome, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders a compound of formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0083] The present invention further includes acne (ACNE); hereditary translucent papuloacrokeratosis; adult-onset Still's disease (AOSD); Eicardi-Goutier syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthraxosis; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); cardiovascular autoimmune diseases; gastrointestinal autoimmune diseases; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantifiable trait locus 11 (BMIQ11); osteoinflammatory diseases; cerebral edema; and Brussey's syndrome. Rhema; Candidiasis; Cervical lymphadenitis; Chondrocalcification; Chronic meningitis; Chronic relapsing polymyelitis (CRMO); Chronic urticaria; CINCA syndrome (CINCA); Conjunctival diseases; Conjunctivitis; Connective tissue diseases; Corneal diseases; Coronavirus infection; COVID-19; Crohn's disease; Cryopyrin-associated periodic syndromes (CAPS); Cystic fibrosis (CF); Autosomal dominant hearing loss type 34 (DFNA34) with or without inflammation; Dermatitis; Diabetes mellitus; Diabetic encephalopathy; Rash (RASH); Eye diseases; Familial cold autoinflammatory syndrome (FCU); Familial cold autoinflammatory syndrome type 1 (FCAS1); Home Familial cold autoinflammatory syndrome type 2 (FCAS2); Familial Mediterranean fever (FMF); Gout (GOUT); Hereditary periodic fever syndromes; Hidradenitis; Suppurative hidradenitis; Essential hypertension (EHT); Hyperuricemia; Autosomal dominant intellectual disability type 30 with speech delay and behavioral abnormalities (MRD30); Interstitial lung disease type 2 (ILD2); Hereditary keratitis (KERH); Hereditary transient keratoendotheliitis (KEFH); Lipoprotein quantitative trait locus (LPAQTL); Lymph node disorders; Age-related macular degeneration type 1 (ARMD1); Malaria (CM); Meningitis; Mevalonaciduria (MEVA); Mackle-Wells syndrome (MWS); Mycobacterium cansasi; Myocardial infarction (MCI1); Kidney stones; Nervous system disorders; Non-alcoholic steatohepatitis (NASH); Optic neuroplasty; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial diseases; Pharyngitis; Polyradiculopathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Septic arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid A amyloidosis;A method is provided for treating a disease, disorder, or symptom selected from the group consisting of silicosis; skin diseases; stomatitis; type 2 diabetes (T2D); ureteral disorders; urticaria (HIVES); vulvovaginal candidiasis; and Wells syndrome, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders a compound of formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0084] The present invention further includes acne (ACNE); hereditary translucent papuloacrokeratosis; adult-onset Still's disease (AOSD); Eicardi-Goutier syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthraxosis; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); cardiovascular autoimmune diseases; gastrointestinal autoimmune diseases; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantifiable trait locus 11 (BMIQ11); osteoinflammatory diseases; cerebral edema; and Brussey's syndrome. Rhema; Candidiasis; Cervical lymphadenitis; Chondrocalcification; Chronic meningitis; Chronic relapsing polymyelitis (CRMO); Chronic urticaria; CINCA syndrome (CINCA); Conjunctival diseases; Conjunctivitis; Connective tissue diseases; Corneal diseases; Coronavirus infection; COVID-19; Crohn's disease; Cryopyrin-associated periodic syndromes (CAPS); Cystic fibrosis (CF); Autosomal dominant hearing loss type 34 (DFNA34) with or without inflammation; Dermatitis; Diabetes mellitus; Diabetic encephalopathy; Rash (RASH); Eye diseases; Familial cold autoinflammatory syndrome (FCU); Familial cold autoinflammatory syndrome type 1 (FCAS1); Home Familial cold autoinflammatory syndrome type 2 (FCAS2); Familial Mediterranean fever (FMF); Gout (GOUT); Hereditary periodic fever syndromes; Hidradenitis; Suppurative hidradenitis; Essential hypertension (EHT); Hyperuricemia; Autosomal dominant intellectual disability type 30 with speech delay and behavioral abnormalities (MRD30); Interstitial lung disease type 2 (ILD2); Hereditary keratitis (KERH); Hereditary transient keratoendotheliitis (KEFH); Lipoprotein quantitative trait locus (LPAQTL); Lymph node disorders; Age-related macular degeneration type 1 (ARMD1); Malaria (CM); Meningitis; Mevalonaciduria (MEVA); Mackle-Wells syndrome (MWS); Mycobacterium cansasi; Myocardial infarction (MCI1); Kidney stones; Nervous system disorders; Non-alcoholic steatohepatitis (NASH); Optic neuroplasty; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial diseases; Pharyngitis; Polyradiculopathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Septic arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid A amyloidosis;A method is provided for treating a disease, disorder, or symptom selected from the group consisting of silicosis; skin diseases; stomatitis; type 2 diabetes mellitus (T2D); ureteral disorders; urticaria (HIVES); vulvovaginal candidiasis; and Wells syndrome, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders a compound of formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0085] The present invention further includes acne (ACNE); hereditary translucent papuloacrokeratosis; adult-onset Still's disease (AOSD); Eicardi-Goutier syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthraxosis; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); cardiovascular autoimmune diseases; gastrointestinal autoimmune diseases; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index quantifiable trait locus 11 (BMIQ11); osteoinflammatory diseases; cerebral edema; and Brussey's syndrome. Rhema; Candidiasis; Cervical lymphadenitis; Chondrocalcification; Chronic meningitis; Chronic relapsing polymyelitis (CRMO); Chronic urticaria; CINCA syndrome (CINCA); Conjunctival diseases; Conjunctivitis; Connective tissue diseases; Corneal diseases; Coronavirus infection; COVID-19; Crohn's disease; Cryopyrin-associated periodic syndromes (CAPS); Cystic fibrosis (CF); Autosomal dominant hearing loss type 34 (DFNA34) with or without inflammation; Dermatitis; Diabetes mellitus; Diabetic encephalopathy; Rash (RASH); Eye diseases; Familial cold autoinflammatory syndrome (FCU); Familial cold autoinflammatory syndrome type 1 (FCAS1); Home Familial cold autoinflammatory syndrome type 2 (FCAS2); Familial Mediterranean fever (FMF); Gout (GOUT); Hereditary periodic fever syndromes; Hidradenitis; Suppurative hidradenitis; Essential hypertension (EHT); Hyperuricemia; Autosomal dominant intellectual disability type 30 with speech delay and behavioral abnormalities (MRD30); Interstitial lung disease type 2 (ILD2); Hereditary keratitis (KERH); Hereditary transient keratoendotheliitis (KEFH); Lipoprotein quantitative trait locus (LPAQTL); Lymph node disorders; Age-related macular degeneration type 1 (ARMD1); Malaria (CM); Meningitis; Mevalonaciduria (MEVA); Mackle-Wells syndrome (MWS); Mycobacterium cansasi; Myocardial infarction (MCI1); Kidney stones; Nervous system disorders; Non-alcoholic steatohepatitis (NASH); Optic neuroplasty; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial diseases; Pharyngitis; Polyradiculopathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Septic arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland diseases; Sensorineural hearing loss; Serum amyloid A amyloidosis;A method is provided for treating a disease, disorder, or symptom selected from the group consisting of silicosis; skin diseases; stomatitis; type 2 diabetes (T2D); ureteral disorders; urticaria (HIVES); vulvovaginal candidiasis; and Wells syndrome, the method comprising administering to a patient suffering from at least one of the aforementioned diseases or disorders a compound of formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0086] In some embodiments, the present disclosure provides compounds that can be obtained by or obtained by methods for preparing the compounds described herein (e.g., methods comprising one or more steps described in the general procedure).

[0087] In some embodiments, the present disclosure provides compounds that can be obtained by methods for preparing the compounds described herein (e.g., synthesis of the compounds in the representative examples, methods comprising one or more steps described in Examples 1 to 9), or compounds obtained by such methods.

[0088] In some embodiments, the Disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein (for example, the intermediates are selected from the intermediates described in Preparation Part-Compounds P1-P16).

[0089] In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure.

[0090] In some embodiments, the Disclosure provides a method for preparing the compounds of the Disclosure, comprising one or more steps described herein.

[0091] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art in which this disclosure pertains. In this specification, singular nouns also include plural nouns unless the context clearly indicates otherwise. Similar or equivalent methods and materials to those described herein may be used in the practice or testing of this disclosure, but suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not considered prior art to the inventions described in the claims. In case of any conflict, this specification, including definitions, shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be limiting. In case of any conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure shall prevail.

[0092] Other features and advantages of this disclosure will become apparent from the following detailed description and claims. (Detailed explanation)

[0093] This disclosure provides a method for treating, preventing, or improving diseases or disorders related to NLRP3 by administering a therapeutically effective amount of the compounds disclosed herein to a subject in need.

[0094] Details of this disclosure are described in the attached description below. Similar or equivalent methods and materials may be used in the practice or testing of this disclosure, but only illustrative methods and materials are described here. Other features, purposes and advantages of this disclosure will become apparent from this specification and the claims. In this specification and the attached claims, singular nouns also include plural nouns unless the context makes otherwise clear. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as they would be generally understood by those skilled in the art to which this disclosure belongs. All patents and publications cited herein are incorporated herein by reference in their entirety. definition

[0095] In this disclosure, the articles “a” and “an” are used to refer to one or more (i.e., at least one) grammatical objects of the article. For example, “element” means one or more elements.

[0096] In this disclosure, the term "and / or" is used to mean either "and" or "or" unless otherwise specified.

[0097] The term "optionally substituted" is understood to mean that a particular chemical moiety (e.g., an alkyl group) can (but is not required to) bond with other substituents (e.g., heteroatoms). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have one or more substituents other than hydrogen. For example, at any point along the chain, it may bond to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term "optionally substituted" means that a given chemical moiety may contain other functional groups, but does not necessarily have any further functional groups. Preferred substituents used for any substitution of the listed groups are, but are not limited to, halogens, oxo, -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) This includes (OH)2, -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 means substituted or unsubstituted, the meaning of which is set out below.

[0098] As used herein, the term “substituted” means that a particular group or part has one or more suitable substituents, and that the substituents can be bonded to the particular group or part at one or more positions. For example, an aryl substituted with a cycloalkyl group indicates that the cycloalkyl group is bonded to one atom of the aryl group by bonding, or that it is condensed with the aryl group to share two or more common atoms.

[0099] In this specification, the term "unsubstituted" means that the specified group has no substituents.

[0100] Unless otherwise defined, the term "aryl" refers to a cyclic aromatic hydrocarbon group having one to three aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl, or naphthyl. If it contains two aromatic rings (e.g., bicyclic), the aromatic rings of the aryl group may be bonded at one point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be optionally substituted at any bonding site with one or more substituents, e.g., one to five substituents. Examples of substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, -OP(O)(OH)2, -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, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. The substituents themselves can be optionally substituted. Furthermore, if the group contains two fused rings, the aryl group as defined herein may have one or more saturated or partially unsaturated rings fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenantrenyl, indanyl, indenyl, tetrahydronaphthalenyl, and tetrahydrobenzoanurenyl.

[0101] Unless otherwise defined, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms, comprising one or more ring heteroatoms selected from N, O, S, P, or B, with the remaining ring atoms being C. A polycyclic aromatic radical may comprise two or more fused rings, and may further comprise two or more spiro-fused rings, such as bicyclic, tricyclic, tetracyclic, etc. Unless otherwise specified, “condensed” means two rings sharing two ring atoms. Unless otherwise specified, “spiro-condensed” means two rings sharing one ring atom. Heteroaryl as defined herein also means a bicyclic heteroaromatic group in which the heteroatom is selected from N, O, S, P, or B. Heteroaryl as defined herein also means a tricyclic heteroaromatic group comprising one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as defined herein also means a tetracyclic heteroaromatic group comprising one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical may be independently substituted with one or more substituents as described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranil, isothiazolyl, thiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrro [3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanil, thiochromanil, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthilidinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthilidinyl, thieno[2,[3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyridinyl, tetrahydropy Roro[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridine-2-one, flo[3,2-c]pyrimidinyl, flo[2,3-c]pyrimidinyl, 1H-pyrido[3,4-b][1,4]thiadinyl, benzoxazolyl, benzoisoxazolyl, flo[2,3-b]pyrimidinyl Lidinyl, benzothiophenyl, 1,5-naphthilidinyl, flo[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]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazole-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,This includes, but is not limited to, [3-b]pyrrolyl, 3H-indolyl, and their derivatives. Furthermore, if two or more fused rings are present, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated rings fused with 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 with the saturated or partially unsaturated rings described herein. Furthermore, if three or more fused rings are present, the heteroaryl groups defined herein may spirocondense one or more saturated or partially unsaturated rings. Any saturated or partially unsaturated ring described herein may be optionally substituted with one or more oxos. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxyindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridine-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, and 1,5,6,7-tetrahydrocyclopenta[b]pyrzo Contains lo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidine-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, benzo[c][1,2]oxabolol-1(3H)-olyl, 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrolo[1,2-d][1,4]oxazine-9-onyl, or 6a',7'-dihydro-6'H,9'H-spiro[cyclopropane-1,8'-pyrido[2,3-b]pyrolo[1,2-d][1,4]oxazine]-9'-onyl.

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

[0103] Alkyl refers to a linear or branched saturated hydrocarbon 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, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl.

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

[0105] An "alkenyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. An "alkenyl" group contains at least one double bond within its chain. The double bond of the alkenyl group may be unconjugated or conjugated with another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. The alkenyl group may be unsubstituted or substituted. Alkenyls as defined herein may be straight-chain or branched.

[0106] "Alkynyl" refers to a straight-chain or branched unsaturated hydrocarbon containing 2 to 12 carbon atoms. The "alkynyl" group contains at least one triple bond in the chain. Examples of alkynyl groups include ethynyl, propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. The alkynyl group may or may not be substituted.

[0107] The terms “alkylene,” “alkylenyl,” or “alkanediyl” refer to divalent alkyl radicals. Any of the monovalent alkyl groups described above may be alkylenes obtained by the extraction of a second hydrogen atom from the alkyl group. As defined herein, alkylenes may be C1-C6 alkylenes. Alkylenes may further be C1-C4 alkylenes. Typical alkylene groups include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, -CH2C(CH3)2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-, etc.

[0108] "Cycloalkyl" refers to a monocyclic or polycyclic saturated carbocyclic ring containing 3 to 18 carbon atoms. Polycyclic cycloalkyls may be condensed bicyclic cycloalkyls, cross-linked bicyclic cycloalkyls, or spiro-condensed bicyclic cycloalkyls. Polycyclic cycloalkyls contain at least one non-aromatic ring. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-indenyl, spiro[3.5]nonyl, spiro[5.5]undecyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0109] A "heterocyclyl," "heterocyclic," or "heterocycloalkyl" is a monocyclic or polycyclic ring containing 3 to 24 atoms, including carbon and one or more heteroatoms selected from N, O, S, P, or B, where the ring is not aromatic. The heterocycloalkyl ring structure may be substituted by 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, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinyl, and homotropanyl.

[0110] The term "aromatic" refers to a planar ring having 4n+2 electrons in a conjugated system. As used herein, "conjugated system" means a system in which p orbitals with delocalized electrons are linked, and this system may contain lone pairs of electrons.

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

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

[0113] As used herein, the term "cyano" refers to a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, i.e., C≡N.

[0114] "Spirocycloalkyl" or "spirocyclyl" refers to a carbon-source bicyclic system in which both rings are linked by a single atom. The rings may differ in size and properties, or they may be identical in size and properties. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, and spirodecane. One or both of the spiro rings may be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more carbon atoms in the spiro ring may be substituted with heteroatoms (e.g., O, N, S, or P). (C3-C 12 Spirocycloalkyls are spiro rings containing 3 to 12 carbon atoms. One or more carbon atoms may be substituted with heteroatoms.

[0115] The terms “spiroheterocycloalkyl,” “spiroheterocycle,” or “spiroheterocyclyl” are understood to mean a spirocycle in which at least one of the rings is a heterocycle (for example, at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0116] The term “solvate” refers to a variable stoichiometric complex formed by a solute and a solvent. For the purposes of this disclosure, such a solvent is not one that can impede 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 usually called hydrates. Hydrates include compositions containing a stoichiometric amount of water and compositions containing a variable amount of water.

[0117] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. Structural differences can be in their composition (geometric isomers) or their ability to rotate the plane of polarization (stereoisomers). With respect to stereoisomers, compounds of formula (A), particularly those of formulas (I), (II), (III), (IV), or (V), may have one or more chiral carbon atoms and can arise as racemates, racemic mixtures, and individual enantiomers or diastereomers.

[0118] This disclosure also relates to isotope-labeled compounds of formula I (e.g., 2 H and 14 The intention is to use a deuterated isotope (i.e., labeled with C). 2 H or D) and carbon-14 isotopes (i.e., 14 C) is particularly preferred because it is easy to prepare and detect. Furthermore, substitution with heavier isotopes such as deuterium may provide certain therapeutic benefits (such as an extended in vivo half-life or a reduced dose requirement) due to improved metabolic stability, and is therefore preferred in some situations. The isotope-labeled compounds of formula (A), particularly those of formulas (I), (II), (III), (IV), or (V), can generally be prepared by replacing the unisotope-labeled reagent with a suitable isotope-labeled reagent, following procedures similar to those disclosed in the following scheme and / or examples.

[0119] This disclosure also includes pharmaceutical compositions comprising therapeutically effective amounts of the disclosed compounds and pharmaceutically acceptable carriers. Typical “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, tartrate, borate, bromide, butyrate, calcium, calcium edetate, cansylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estrate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydravamin, hydrobromide, and hydrochloride. This includes hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucinate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picric acid, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, basic acetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate.

[0120] "Patient" or "subject" is a mammal, such as a human, mouse, rat, guinea pig, dog, cat, horse, cattle, pig, or a non-human primate, such as a monkey, chimpanzee, baboon, or rhesus macaque.

[0121] "Effective dose" is the amount that, when used in conjunction with the compound, is effective in treating or preventing a disease in the subject described herein.

[0122] As used in this disclosure, the term "carrier" includes carriers, excipients, and diluents, and means materials, compositions, or vehicles, such as liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials, that are involved in the transport or delivery of a pharmaceutical product from one organ or part of the body to another.

[0123] In relation to the subject, the term "treat" refers to improving at least one symptom of the disorder in the subject. Treatment includes curing, improving, or at least partially alleviating the disorder.

[0124] In this disclosure, unless otherwise specified, the term “disorder” is used to mean the terms “illness,” “symptom,” or “disease,” and is used interchangeably with these terms.

[0125] As used in this disclosure, the terms “administer,” “administering,” or “administration” refer to the direct administration of the disclosed compound or a pharmaceutically acceptable salt or composition of the disclosed compound to a subject, or to the administration of a prodrug derivative or analogue of the compound, or a pharmaceutically acceptable salt of the compound or composition, which can form an equivalent amount of the active compound in the subject’s body.

[0126] As used in this disclosure, the term "prodrug" means a compound that can be converted in vivo to the disclosed compound by a metabolic means (e.g., hydrolysis).

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

[0128] The term “pharmaceutically acceptable salt” also refers to a salt of a composition of this disclosure having 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 that inhibits NLRP3 kinase and / or a composition comprising a compound of formula A.

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

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

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

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

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

[0135] The amount of compounds in the compositions described herein required to achieve a therapeutic effect can be determined empirically by conventional procedures for a particular purpose. Generally, when a therapeutic agent (e.g., compounds or compositions of formulas A, I, II, III, IV, V described herein (and / or additional agents)) is administered for therapeutic purposes, the therapeutic agent is given in a pharmacologically effective dose. "Pharmacologically effective dose," "pharmacologically effective dose," "therapeutic effective dose," or "effective dose" means an amount sufficient to produce a desired physiological effect or to achieve a desired outcome, particularly for treating a disorder or disease. As used herein, an effective dose includes, for example, an amount sufficient to delay the onset of symptoms of a disorder or disease, alter the course of symptoms of a disorder or disease (e.g., slow the progression of symptoms of a disease), alleviate or eliminate one or more symptoms or signs of a disorder or disease, and reverse the symptoms of a disorder or disease. For example, administering a therapeutic agent to a patient with cancer provides a therapeutic benefit not only when the underlying condition is eradicated or improved, but also when the patient reports a reduction in the severity or duration of disease-related symptoms, such as a decrease in tumor burden, a decrease in circulating tumor cells, or an increase in progression-free survival. Therapeutic effects also include stopping or slowing the progression of the underlying disease or disability, regardless of whether improvement is achieved. Compounds of the Disclosure

[0136] In one embodiment, the present disclosure provides compounds of formula (A) and their salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers: [ka] Here, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and n are as described herein.

[0137] For the compound of formula (A), R 1 , R2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and n can be selected from the bases described herein, where applicable, and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 Any of the bases described herein for any of , and n, where applicable, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 9 It is understood that the remaining one or more of n can be combined with any of the groups described herein.

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

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

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

[0141] For the compound of formula (I), R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 , and n can be selected from the bases described herein, where applicable, and R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 Any of the bases described herein for any of , and n, where applicable, R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 9 It is understood that the remaining one or more of n can be combined with any of the groups described herein.

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

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

[0144] In some embodiments, the present disclosure provides compounds of formula (II) and their salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers: [ka] Here, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 And n are as described herein.

[0145] For the compound of formula (II), R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , and n can be selected from the bases described herein, where applicable, and R 1 , R 2 , R 3 , R 4 , R 5 , R 9 Any of the bases described herein for any of , and n, where applicable, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 It is understood that the remaining one or more of n can be combined with any of the groups described herein.

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

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

[0148] In some embodiments, the present disclosure provides compounds of formula (III) and their salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers: [ka] Here, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 W and n are as described herein.

[0149] For the compound of formula (III), R 1 , R 2 , R 3 , R 4 , R 5 , R 9 W and n may be selected from the bases described herein, where applicable, and R 1 , R 2 , R 3 , R 4 , R 5 , R 9 Any of the groups described herein for W and n, where applicable, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 It is understood that W and the remaining one or more n can be combined with any of the groups described herein.

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

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

[0152] In some embodiments, the present disclosure provides compounds of formula (IV) and their salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers: [ka] Here, R 1 , R 2 , R 3 , R 4 , R 5 , R 9 And n are as described herein.

[0153] For the compound of formula (IV), R 1 , R 2 , R 3 , R 4 , R 5 , R 9 , and n can be selected from the bases described herein, where applicable, and R 1 , R 2 , R 3 , R 4 , R 5 , R 9 Any of the bases described herein for any of , and n, where applicable, R 1 , R 2 , R 3 , R 4 , R 5 , R 9It is understood that the remaining one or more of n can be combined with any of the groups described herein.

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

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

[0156] In some embodiments, the present disclosure provides compounds of formula (V) and their salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers: [ka] Here, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 And n are as described herein.

[0157] For the compound of formula (V), R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and n can be selected from the bases described herein, where applicable, and R 1 , R 2 , R 3 , R 4 , R5 , R 6 , R 9 Any of the bases described herein for any of , and n, where applicable, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 It is understood that the remaining one or more of n can be combined with any of the groups described herein.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0221] In some embodiments, the compound is of formula (ID): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopic derivative, or tautomer thereof, where each R a is H, or two R a Together they form Arcanediyl (CH2) m - A crosslink is formed, and m is selected from 1 and 2.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0277] In some embodiments, the compound is of formula (III-B-1-II): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, isotopic derivative, or tautomer thereof, where each R a is H, or two R a Together they form Arcanediyl (CH2) m - A crosslink is formed, and m is selected from 1 and 2.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0337] In some embodiments, the compound is of formula (A-5): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof, where 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 is of formula (A-5-a): [ka] or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0354] In some embodiments, the compound is of formula (B): [ka] or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, in which, R 2 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 3 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 4 H, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Cycloalkyl, C3-C 10 Selected from cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is halogen, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C 10 Optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups; R 3 and R 4 These atoms, together with the atoms to which they are bonded and any intervening atoms, form 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 halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy; R 6The substituent is selected from H, SO2R8, NH2, C1-C6 alkyl, C1-C6 alkyl-C(O)-, and aryl, and the alkyl or aryl substituent is optionally substituted with one or more substituents independently selected from halogen, CN, and OH; R 7 is H, C1-C6 alkyl, or NH2; or R 6 and R 7 These atoms, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 membered heterocycle or heteroarene; R 8 The alkyl group is selected from C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and 5-6 member heteroaryl groups, and the alkyl, cycloalkyl, or heteroaryl group is optionally substituted with one or more substituents independently selected from halogens, CN, or OH groups; or Each R 9 is independently selected from halogens, OH, C1-C6 alkyl, and C1-C6 alkoxy, and the alkyl or alkoxy is optionally substituted with one or more halogens, OH; or Two R's 9 They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R 12 The group is selected from H, OH, C1-C6 alkyl, and C1-C6 alkoxy, and the alkyl group is optionally substituted with one or more groups selected from halogen, -OH, and C1-C6 alkoxy; R 12a It is selected from H, -CH3; R 12b It is selected from H, -CH3; R 13 It is selected from H, C1-C6 alkyl, Alternatively, R 12 and R 13These atoms, together with the atoms to which they are bonded and any intervening atoms, form a 3- to 8-membered cycloalkane or a 3- to 8-membered heterocycle, and the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy.

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

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

[0357] In some embodiments, R 1 These are halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 It is a C1-C6 alkyl group that is optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups.

[0358] In some embodiments, R 1 This is a C1-C6 alkyl group that is optionally substituted with one or more halogens.

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

[0360] In some embodiments, R 1 The methyl, ethyl, propyl, butyl, pentyl, and hexyl compounds are selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl compounds.

[0361] In some embodiments, R 1 The following are selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

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

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

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

[0365] In some embodiments, R 2 These are halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 It is a C1-C6 alkyl group that is optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups.

[0366] In some embodiments, R 2 This is a C1-C6 alkyl group that is optionally substituted with one or more halogens.

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

[0368] In some embodiments, R 2 The methyl, ethyl, propyl, butyl, pentyl, and hexyl compounds are selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl compounds.

[0369] In some embodiments, R 2 The following are selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

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

[0371] In some embodiments, R 1 and R 2 These atoms, together with the atoms to which they are bonded and any intervening atoms, form a 5- to 8-membered cycloalkane, a 5- to 14-membered heterocycle, an arene, or a heteroarene, and the cycloalkane, heterocycle, arene, or heteroarene is optionally substituted with one or more substituents independently selected from halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy.

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

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

[0374] In some embodiments, R 3 These are halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 It is a C1-C6 alkyl group that is optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups.

[0375] In some embodiments, R 3 This is a C1-C6 alkyl group that is optionally substituted with one or more halogens.

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

[0377] In some embodiments, R 3 The methyl, ethyl, propyl, butyl, pentyl, and hexyl compounds are selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl compounds.

[0378] In some embodiments, R 3 The following are selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

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

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

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

[0382] In some embodiments, R 3 These are halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 C3-C3 molecules are optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups. 10 It is a cycloalkyl group.

[0383] In some embodiments, R 3 C3-C 10 It is a cycloalkyl group.

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

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

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

[0387] In some embodiments, R 4 These are halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10It is a C1-C6 alkyl group that is optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups.

[0388] In some embodiments, R 4 This is a C1-C6 alkyl group that is optionally substituted with one or more halogens.

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

[0390] In some embodiments, R 4 The methyl, ethyl, propyl, butyl, pentyl, and hexyl compounds are selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl compounds.

[0391] In some embodiments, R 4 The following are selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

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

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

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

[0395] In some embodiments, R 4 These are halogens, OH, NH2, CN, C1-C6 alkyl, C1-C6 alkoxy, and C3-C 10 C3-C3 molecules are optionally substituted with one or more substituents independently selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocyclic, aryl, and heteroaryl groups. 10 It is a cycloalkyl group.

[0396] In some embodiments, R 4 C3-C 10 It is a cycloalkyl group.

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

[0398] In some embodiments, R 3 and R 4 These atoms, together with the atoms to which they are bonded and any intervening atoms, form a 5-8 membered cycloalkane or a 5-14 membered heterocycle, and the cycloalkane or heterocycle is optionally substituted with one or more substituents independently selected from halogens, OH, CN, C1-C6 alkyl, and C1-C6 alkoxy.

[0399] In some embodiments, R 3 and R 4 These atoms, together with the atoms to which they are bonded and any intervening atoms, form cyclopentane.

[0400] In some embodiments, R 3 and R 4 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0401] In some embodiments, R 3 and R 4 These atoms, together with the atoms to which they are bonded and any intervening atoms, form cyclohexane.

[0402] In some embodiments, R 3 and R 4 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0403] In some embodiments, R 3 and R 4 These atoms, together with the atoms to which they are bonded and any intervening atoms, form norbornanes.

[0404] In some embodiments, R 3 and R 4 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0405] In some embodiments, R 3 and R 4 These atoms, together with the atoms to which they are bonded and any intervening atoms, form bicyclo[2.2.2]octane.

[0406] In some embodiments, R 3 and R 4 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0407] In some embodiments, R 5 H, C1-C6 alkyl, C3-C 10 Selected from cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 acyl, SO2-C1-C6 alkyl, and 4-10 membered heterocyclyl, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocyclyl is a halogen, oxo, OH, CN, C1-C6 alkoxy, C3-C 10 It is optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups.

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

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

[0410] In some embodiments, R 5 The methyl, ethyl, propyl, butyl, pentyl, and hexyl compounds are selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl compounds.

[0411] In some embodiments, R 5 The following are selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl.

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

[0413] In some embodiments, R 5 It is ethyl.

[0414] In some embodiments, R 5 teeth, [ka] That is the case.

[0415] In some embodiments, R 5 teeth, [ka] That is the case.

[0416] In some embodiments, R 5 teeth, [ka] That is the case.

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

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

[0419] In some embodiments, R 5 teeth, [ka] That is the case.

[0420] In some embodiments, R 5 teeth, [ka] That is the case.

[0421] In some embodiments, R 5 teeth, [ka] That is the case.

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

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

[0424] In some embodiments, R 5 teeth, [ka] That is the case.

[0425] In some embodiments, R 5 teeth, [ka] That is the case.

[0426] In some embodiments, R 5 teeth, [ka] That is the case.

[0427] In some embodiments, R 5 C3-C 10 These are C1-C6 alkyl groups substituted with cycloalkyl groups.

[0428] In some embodiments, R 5 teeth, [ka] That is the case.

[0429] In some embodiments, R 5 These are C1-C6 alkyl groups substituted with aryl groups.

[0430] In some embodiments, R 5 teeth, [ka] That is the case.

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

[0432] In some embodiments, R 5 teeth, [ka] That is the case.

[0433] In some embodiments, R 5 C3-C 10 It is a cycloalkyl group.

[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 These are heterocyclines with 4 to 10 members.

[0440] In some embodiments, R 5 It is a 4-10 member heterocycline containing 1-3 heteroatoms independently selected from O, N, and S.

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

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

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

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

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

[0446] In some embodiments, R 5 teeth, [ka] That is the case.

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

[0448] In some embodiments, R 5 teeth, [ka] That is the case.

[0449] In some embodiments, R 6 The substituent is selected from H, SO2R8, NH2, C1-C6 alkyl, C1-C6 alkyl-C(O)-, and aryl, and the alkyl or aryl substituent is optionally substituted with one or more substituents independently selected from halogen, CN, and OH.

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

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

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

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

[0454] In some embodiments, R 6 teeth, [ka] That is the case.

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

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

[0457] In some embodiments, R 6 That is Ariel.

[0458] In some embodiments, R 6 teeth, [ka] That is the case.

[0459] In some embodiments, R 6 SO2R 8 That is the case.

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

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

[0462] In some embodiments, R 6 teeth, [ka] That is the case.

[0463] In some embodiments, R 6 teeth, [ka] That is the case.

[0464] In some embodiments, R 6 teeth, [ka] That is the case.

[0465] In some embodiments, R 6 The molecule is C1-C6 alkyl-C(O)-, and the alkyl group is optionally substituted with one or more substituents independently selected from halogens, 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 is H, C1-C6 alkyl, or -NH2.

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

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

[0475] In some embodiments, R 6 and R 7 These atoms, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 membered heterocycle or heteroarene.

[0476] In some embodiments, R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0477] In some embodiments, the ring [ka] It is optionally substituted with one or two substituents.

[0478] In some embodiments, R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0479] In some embodiments, the ring [ka] It is optionally substituted with one or two substituents.

[0480] In some embodiments, R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0481] In some embodiments, the ring [ka] It is replaced by an optional substitution.

[0482] In some embodiments, R 8 The substituent is selected from C1-C6 alkyl, C3-C8 cycloalkyl, and 5-6 membered heteroaryl groups, and the alkyl, cycloalkyl, or heteroaryl group is optionally substituted with one or more substituents independently selected from halogens, CN, and OH.

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

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

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

[0486] In some embodiments, R 8 teeth, [ka] That is the case.

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

[0488] In some embodiments, R 8 teeth, [ka] That is the case.

[0489] In some embodiments, R 8 It is a 5-6 member heteroaryl compound.

[0490] In some embodiments, R8 teeth, [ka] That is the case.

[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 The element is selected from halogens, OH groups, C1-C6 alkyl groups, and C1-C6 alkoxy groups, and the alkyl or alkoxy group is optionally substituted with one or more halogens or OH groups.

[0495] In some embodiments, n is 2.

[0496] Several embodiments, each R 9 The element is independently selected from halogens, OH groups, C1-C6 alkyl groups, and C1-C6 alkoxy groups, and the alkyl or alkoxy group is optionally substituted with one or more halogens or OH groups.

[0497] In some embodiments, R 9 It is OH.

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

[0499] In some embodiments, R 9 It is F.

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

[0501] In some embodiments, R9 It is methyl.

[0502] In some embodiments, R 9 This is a C1-C6 alkyl group that is optionally substituted with one or more halogens.

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

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

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

[0506] In some embodiments, two R 9 These atoms, together with the atoms they are bonded to and any intervening atoms, form a 5-6 member heterocycle.

[0507] In some embodiments, R 5 and R 9 These atoms, together with the atoms they are bonded to and any intervening atoms, form a 5-6 member heterocycle.

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

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

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

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

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

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

[0514] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 H is R 5 is methyl, and R 6 It is SO2CH3.7 H is H.

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

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

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

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

[0519] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is methyl, and R 5 It is 2-hydroxyethyl, and R6 It is SO2CH3. 7 H is H.

[0520] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 H is R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0521] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 H is R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0522] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 H is R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0523] In some embodiments, R 1 H is R2 H is R 3 is methyl, and R 4 is methyl, and R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0524] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 is methyl, and R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0525] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 is methyl, and R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0526] In some embodiments, R 1 H is R 2 H is R 3 is -CF3, R4 is H, and R 5 is methyl, and R 6 and R 7Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0527] In some embodiments, R 1 H is R 2 H is R 3 is -CF3, and R 4 H is R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0528] In some embodiments, R 1 H is R 2 H is R 3 is -CF3, and R 4 H is R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0529] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is methyl, and R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0530] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is methyl, and R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0531] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is methyl, and R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0532] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is -CF3, and R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0533] In some embodiments, R 1 H is R 2 H is R 3 H is R4 is -CF3, and R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0534] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is -CF3, and R 5 is methyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0535] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 H is R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0536] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 H is R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0537] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 H is R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0538] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 is methyl, and R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0539] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 is methyl, and R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0540] In some embodiments, R1 H is R 2 H is R 3 is methyl, and R 4 is methyl, and R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0541] In some embodiments, R 1 H is R 2 H is R 3 is -CF3, and R 4 H is R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0542] In some embodiments, R 1 H is R 2 H is R 3 is -CF3, R4 is H, and R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0543] In some embodiments, R 1 H is R 2 H is R 3 is -CF3, and R 4 H is R 5 is ethyl, and R 6 and R7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0544] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is methyl, and R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0545] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is methyl, and R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0546] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is methyl, and R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0547] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is -CF3, and R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0548] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is -CF3, and R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0549] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is -CF3, and R 5 is ethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0550] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R4 H is R 5 It is 2-hydroxyethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0551] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 H is R 5 It is 2-hydroxyethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0552] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 H is R 5 It is 2-hydroxyethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0553] In some embodiments, R 1 H is R 2 H is R 3 is methyl, and R 4 is methyl, and R 5 It is 2-hydroxyethyl, and R 6 and R 7together with the atoms to which they are attached and any intervening atoms,

Chem.

[0554] In some embodiments, R 1 is H, R 2 is 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 they are attached and any intervening atoms,

Chem.

[0555] In some embodiments, R 1 is H, R 2 is 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 they are attached and any intervening atoms,

Chem.

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

Chem.

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

Chemical formula

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

Chemical formula

[0559] <o004671>In some embodiments, R 1 is H, R 2 is H, R 3 is H, R 4 is methyl, R 5 is 2-hydroxyethyl, R 6 and R 7 together with the atoms to which they are attached and any intervening atoms form

Chemical formula

[0560] In some embodiments, R 1 is H, R2 H is R 3 H is R 4 is methyl, and R 5 It is 2-hydroxyethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0561] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is methyl, and R 5 It is 2-hydroxyethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0562] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is -CF3, and R 5 It is 2-hydroxyethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0563] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is -CF3, and R 5 It is 2-hydroxyethyl, and R6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

[0564] In some embodiments, R 1 H is R 2 H is R 3 H is R 4 is -CF3, and R 5 It is 2-hydroxyethyl, and R 6 and R 7 Together with the atoms to which they are bonded and any intervening atoms, [ka] It forms.

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

[0566] In some embodiments, the compound is selected from the compounds listed in Table 1, as well as their prodrugs and pharmaceutically acceptable salts.

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

[0568] In some embodiments, the compound is selected from the prodrugs of the compounds listed in Table 1 and their pharmaceutically acceptable salts.

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

[0570] JPEG2026509095000286.jpg210170JPEG2026509095000287.jpg190170JPEG2026509095000288.jpg221170JPEG20265090950002 89.jpg218170JPEG2026509095000290.jpg182170JPEG2026509095000291.jpg185170JPEG2026509095000292.jpg189170JPEG202 6509095000293.jpg177170JPEG2026509095000294.jpg184170JPEG2026509095000295.jpg196170JPEG2026509095000296.jpg20 9170JPEG2026509095000297.jpg219170JPEG2026509095000298.jpg198170JPEG2026509095000299.jpg211170JPEG20265090950 00300.jpg216170JPEG2026509095000301.jpg197170JPEG2026509095000302.jpg190170JPEG2026509095000303.jpg214170JPE G2026509095000304.jpg202170JPEG2026509095000305.jpg148170JPEG2026509095000306.jpg193170JPEG2026509095000307.j pg195170JPEG2026509095000308.jpg219170JPEG2026509095000309.jpg201170JPEG2026509095000310.jpg204170JPEG2026509 095000311.jpg209170JPEG2026509095000312.jpg182170JPEG2026509095000313.jpg209170JPEG2026509095000314.jpg192170

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

[0573] In some embodiments, the compound is a salt of any one of the acids listed in Table 2 and any one of the compounds listed in Table 1.

[0574] Table 2. Compounds of formulas (A), (I) to (V) and their pharmaceutically acceptable acid-forming salts. JPEG2026509095000315.jpg132170

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

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

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

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

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

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

[0581] In some embodiments, the compound is a salt of glutamic acid with one of the compounds listed in Table 1.

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

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

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

[0585] In some embodiments, the present disclosure provides compounds that are isotopic derivatives (e.g., isotope-labeled compounds) of any one of the compounds of the formulas disclosed herein.

[0586] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table 1, as well as its prodrug and pharmaceutically acceptable salt.

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

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

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

[0590] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using isotopic labeling reagents instead of non-isotopic labeling 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 formulas disclosed herein.

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

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

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

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

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

[0598] It is understood that a deuterium-labeled compound contains deuterium atoms having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

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

[0600] It is understood that deuterium-labeled compounds can be prepared using any of the various techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using a deuterium-labeled reagent instead of a non-deuterium-labeled reagent.

[0601] Compounds of the present disclosure containing the above-mentioned deuterium atom(s), or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. Furthermore, deuterium (i.e., 2 Substitution with H) can provide certain therapeutic benefits resulting from greater metabolic stability, such as an increased in vivo half-life or a reduced dose requirement.

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

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

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

[0605] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and / or 36 It is understood that S-labeled compounds can be prepared using any of the various techniques recognized in this art. For example, deuterium-labeled compounds can generally be prepared using non-isotope labeling reagents instead. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and 36 It can be prepared by using an S-labeled reagent and performing the procedures disclosed in the scheme and / or examples described herein.

[0606] the above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and 36 Compounds of the present disclosure containing one or more S atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present disclosure. Furthermore, isotopes (e.g., 18F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 33 S, 34 S, 35 S, and / or 36 Substitution with S) can provide certain therapeutic benefits resulting from greater metabolic stability, such as an increased in vivo half-life or a reduced dose requirement.

[0607] To avoid any doubt, in this specification, where a group is limited by "as described herein," it should be understood that such group encompasses the broadest definition that first appears, as well as each and all of the specific definitions relating to that group.

[0608] The various functional groups and substituents constituting the compound of formula (A) are typically selected so that the molecular weight of the compound does not exceed 1000 daltons. More commonly, the molecular weight of the compound is less than 900, e.g., less than 800, or less than 750, or less than 700, or less than 650 daltons. More conveniently, the molecular weight is less than 600, e.g., 550 daltons or less, e.g., 500 daltons or less, e.g., 450 daltons or less.

[0609] Suitable pharmaceutically acceptable salts of the compounds of this disclosure are, for example, acid addition salts of the compounds of this disclosure that are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, methanesulfonic citrate, or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of this disclosure that are sufficiently acidic are salts with alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or organic bases that give a pharmaceutically acceptable cation, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0610] It will be understood that any one compound of any of the formulas disclosed herein and any pharmaceutically acceptable salt thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the said compound.

[0611] As used herein, the term "isomerism" refers to compounds that have the same molecular formula but differ in the order of their atomic bonding or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereoisomers," and stereoisomers that cannot be superimposed on each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomer forms with opposite chiralities is called a "racemic mixture."

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

[0613] As used herein, the term “chiral isomer” means a compound having at least one chiral center. Compounds with multiple chiral centers may exist as individual diastereomers or as a mixture of diastereomers, called a “diastereomer mixture.” When there is one chiral center, the stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center were ranked according to the Cahn, Ingold, and Prelog ordering rules. (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 isomer” means a diastereomer that exists due to interfering rotations around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, and, according to the Cahn-Ingold-Prelog rule, indicate that the group is on the same side or opposite side of the double bond within the molecule.

[0615] It should be understood that the compounds disclosed herein may be represented as different chiral or geometric isomers. Furthermore, if a compound has chiral or geometric isomeric forms, all isomeric forms are intended to be included within the scope of this disclosure, and the naming of the compounds does not exclude any isomeric forms, nor should all isomers necessarily possess the same level of activity.

[0616] It should be understood that the structures and other compounds discussed in this disclosure include all of their atropic isomers. It should also be understood that not all atropic isomers have the same level of activity.

[0617] As used herein, the term “atropic isomer” refers to a type of stereoisomer in which the atoms of two isomers are spatially distinct. Atropic isomers exist because the rotation of a large group around a central bond is hindered and restricted. While such atropic isomers typically exist as a mixture, recent advances in chromatography techniques have made it possible to separate a mixture of two atropic isomers, if selected.

[0618] As used herein, the term “tautomer” refers to one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomeric form to another. This conversion results in a formal transfer of hydrogen atoms, involving the switching of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of tautomers. In solutions where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. Keto-enol tautomerism involves a simultaneous shift of electrons and hydrogen atoms. Ring chain tautomerism occurs as a result of an aldehyde group (-CHO) of a sugar chain molecule reacting with one of the hydroxyl groups (-OH) of the same molecule, giving it a cyclic (ring-shaped) form, as seen in glucose.

[0619] It should be understood that the compounds disclosed herein may be represented as different tautomers. Where a compound has tautomers, all tautomers are intended to be included within the scope of this disclosure, and the naming of the compounds does not exclude any tautomers. It should be understood that certain tautomers may have higher levels of activity than others.

[0620] Compounds with the same molecular formula but different bonding properties or order of their atoms, or different arrangements of their atoms in space, are called "isomers." Isomers with different arrangements of atoms in space are called "stereoisomers." Stereoiomers that are not mirror images of each other are called "diastereomers," and stereoisomers that cannot be superimposed as mirror images of each other are called "enantiomers." If a compound has a chiral center, for example, if it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers are characterized by the absolute configuration of their chiral center, described by Cahn and Prelog's R- and S-sequence rules, or by the way the molecule rotates its plane of polarization, and are called dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0621] The compounds of this disclosure may have one or more chiral centers; such compounds may be produced as individual (R)- or (S)-stereoisomers or mixtures thereof. Unless otherwise stated, the descriptions or nomenclature of specific compounds in this specification and claims are intended to include both individual enantiomers and mixtures thereof, racemates, or other mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001). Some of the compounds of this disclosure may have geometric isomer centers (E-isomers and Z-isomers). It should be understood that this disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers, as well as mixtures thereof, that have inflammasome inhibitory activity.

[0622] This disclosure also includes compounds of the disclosure as defined herein that involve one or more isotopic substitutions.

[0623] It should be understood that any compound of any of the formulas described herein includes, where applicable, the compound itself, as well as their salts and solvates. For example, salts can be formed between an anion on a substituted compound disclosed herein and a positively charged group (e.g., amino). Suitable anions include chlorides, bromides, iodides, sulfates, bisulfates, sulfamates, nitrates, phosphates, citrates, methanesulfons, trifluoroacetates, glutamates, glucuronates, glutarates, malates, maleates, succinates, fumarates, tartrates, tosylates, salicylates, lactates, naphthalenesulfons, 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 a cation on a substituted compound disclosed herein and a negatively charged group (e.g., a carboxylate). Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0625] It should be understood that the compounds of this disclosure, for example, salts of the compounds, may exist in hydrated or unhydrated (anhydrous) forms, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates, and non-limiting examples of solvates include ethanol solvate and acetone solvate.

[0626] As used herein, the term “solvate” means a solubilated form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to capture solvent molecules in a certain molar ratio in their crystalline solid state to form solvates. When the solvent is water, the solvate produced is a hydrate; when the solvent is an alcohol, the solvate produced is an alcoholate. Hydrates are formed by the bonding of one molecule of a substance in which water retains its molecular state as H2O with one or more molecules of water.

[0627] As used herein, the term “analog” refers to a compound that is structurally similar to another but has a slightly different composition (e.g., substitution of one atom with an atom of a different element, substitution of one atom in the presence of a particular functional group, or substitution of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance but different in structure or origin from the reference compound.

[0628] As used herein, the term “derivative” refers to a compound having a common core structure and being substituted with various groups as described herein.

[0629] As used herein, the term “biological equivalent” refers to a compound resulting from the exchange of one atom or group of atoms with another, broadly similar atom or group of atoms. The purpose of biological equivalent substitution is to produce a novel compound having similar biological properties to the parent compound. Biological equivalent substitution can be physicochemical or topological. Examples of carboxylic acid biological equivalents 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 should be understood that any particular compound of any of the formulas disclosed herein may exist in both solvated and unsolvated forms, such as hydrated forms. Suitable pharmaceutically acceptable solvates are hydrates, such as hemihydrate, monohydrate, dihydrate, or trihydrate. It should be understood that this disclosure encompasses all such solvated forms having inflammasome inhibitory activity.

[0631] Furthermore, it should be understood that any particular compound of any one of the formulas disclosed herein may exhibit polymorphism, and that this disclosure encompasses all such forms or mixtures thereof that have 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, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be measured by Karl Fischer analysis.

[0632] Any compound of any of the formulas disclosed herein may exist in many different tautomers, and references to compounds of formula (A), (I), (II), or (III) include all such forms. To avoid ambiguity, if a compound may exist in one of several tautomers and only one is specifically described or illustrated, nevertheless all others are encompassed by formula (A), (I), (II), or (III). Examples of tautomers include, for example, the following tautomer pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and nitro / acid-nitro, such as the keto-, enol-, and enolate- forms. [ka]

[0633] Compounds of any one of the formulas disclosed herein that contain an amine functional group may also form an N-oxide. In this specification, references to compounds of formula (I) or (II) containing an amine functional group also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms of nitrogen-containing heterocycles. N-oxides can be produced by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid), see, for example, Advanced Organic Chemistry by Jerry March, 4th Edition, Wiley Interscience, pages. More specifically, N-oxides can be prepared by the method of LWDeady (Syn. Comm. 1977, 7, 509-514), where the amine compound reacts with metachloroperoxybenzoic acid (m-CPBA) in an inert solvent such as dichloromethane.

[0634] Any compound of any of the formulas disclosed herein may be administered in the form of a prodrug, which is broken down in the body of a human or animal to release the compound disclosed. Prodrugs can be used to alter the physical and / or pharmacokinetic properties of the compounds disclosed herein. A prodrug can be formed if the compounds disclosed contain suitable groups or substituents to which characterizing groups can be attached. Examples of prodrugs include derivatives of any of the formulas disclosed herein, which contain an alkyl or acyl substituent on the ester or amide group that is cleavable in vivo.

[0635] Accordingly, this disclosure includes any of these compounds of the formulas defined above as disclosed herein, whether made available by organic synthesis or made available in the body of a human or animal by cleavage of its prodrug. Accordingly, this disclosure also includes any of these compounds of the formulas disclosed herein produced by organic synthesis means, and such compounds produced in the body of a human or animal by metabolism of precursor compounds, any of the compounds of the formulas disclosed herein may be compounds produced by synthesis or compounds produced by metabolism.

[0636] A suitable pharmaceutically acceptable prodrug of any compound of the formulas disclosed herein is based on reasonable medical judgment that it is suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity. Various forms of prodrugs are described in the following documents, for example: a) Methods in Enzymology, Vol. 42, p. 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”, by H. Bundgaard p. 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”, ACS Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0637] A suitable pharmaceutically acceptable prodrug of a compound having a hydroxyl group of any of the formulas disclosed herein is, for example, its ester or ether which is cleavable in vivo. A pharmaceutically acceptable ester or ether containing a hydroxyl group of any of the compounds of any of the formulas disclosed herein is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the body of a human or animal to produce a parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxyl group include C1-C groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 C1-C groups such as alkanoyl groups, ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. 10 Examples include alkoxycarbonyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxyl groups include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0638] A suitable pharmaceutically acceptable prodrug of any one compound of the formulas disclosed herein having a carboxyl group is, for example, an in vivo cleavable amide, such as an amine like ammonia, or a C2 amine like methylamine. 1-4 These are amides formed from alkylamines, dimethylamines, (C1-C4 alkyl)2-amines such as 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 or its esters.

[0639] A suitable pharmaceutically acceptable prodrug of any compound of the formulas disclosed herein having an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, acetyl, benzoyl, phenylacetyl, and C1-C such as substituted benzoyl and phenylacetyl groups. 10 Examples of amides formed by alkanoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

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

[0641] The compounds of the present invention can be prepared by various methods, including standard chemistry. A suitable synthetic route is shown in the following scheme.

[0642] Compounds of formula (A), particularly formulas (I), (II), (III), (IV), or (V), can be prepared by methods known in the art of organic synthesis, as partially defined by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are used as needed, according to general principles or chemistry. Protecting groups are handled according to standard methods of organic synthesis (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage in the synthesis of the compound using methods readily understood by those skilled in the art. Whether a stereocenter is present in compounds of formula (A), (I)-(III) can be recognized by those skilled in the art from the selection process, as well as the reaction conditions and sequence. Thus, the present invention includes both possible stereoisomers (unless specified in synthesis) and includes not only racemic compounds but also individual enantiomers and / or diastereomers. If a compound is required as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by the decomposition of the final product or any convenient intermediate. The decomposition of the final product, intermediate, or starting material can be carried out by any suitable method known in this art. See, for example, “Stereochemistry of Organic Compounds” by EL Eliel, SH Wilen, and LN Mander (Wiley-Interscience, 1994).

[0643] The compounds described herein 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 by many methods well known to those skilled in the art of organic synthesis. For example, the compounds of the present invention can be synthesized using the methods described below, along with synthetic methods known in the art of organic synthesis, or with modifications thereof that will be understood to those skilled in the art. Suitable methods include, but are not limited to, those described below. The compounds of the present invention can be synthesized according to steps outlined in general procedures, including aggregate intermediates or compounds of different sequences. Starting materials are commercially available or prepared by known procedures described in reported literature, or as shown below. General Procedure

[0645] Generally, compounds of formula (A) can be prepared according to a series of reactions shown in Scheme 1.

[0646] Scheme 1 [ka]

[0647] It should be understood that any of the compounds in Scheme 1, or any substituent in these compounds, can be further modified in any of the presented series of steps to provide modified derivatives of these compounds useful for the preparation of compounds of formula (A), particularly compounds of formula (I), formula (II), formula (III), formula (IV), or formula (V).

[0648] All reagents may be commercially available compounds themselves or synthetic products derived from commercially available reagents. One-step or multi-step synthetic methods, including but not limited to those described in the preparation section of this specification, may be used to prepare these reagents.

[0649] It will be obvious to experts in this field that any of the compounds of formula (A), (I), (II), (III), (IV), or (V) obtained by following the above procedure may be subject to further transformations and modifications that could lead to obtaining other compounds of formula (A), (I), (II), (III), (IV), or (V). Biological assays

[0650] Compounds designed, selected, and / or optimized by the methods described above can be characterized after production using a variety of assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they possess predicted activity, binding activity, and / or binding specificity.

[0651] Furthermore, high-throughput screening can accelerate analysis using such assays. As a result, it becomes possible to rapidly screen the activity of the molecules described herein using techniques known in this art. General methodologies 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 assays may utilize one or more different assay techniques, including but not limited to those described below.

[0652] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo biological assays include, but are not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein. Pharmaceutical composition

[0653] In some embodiments, the Disclosure provides pharmaceutical compositions comprising the compounds of the Disclosure as active ingredients. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the Disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

[0654] As used herein, the term “composition” is intended to encompass any product containing a specified amount of a specified component, as well as any product resulting directly or indirectly from a specified amount of a combination of specified components.

[0655] Solid preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that can also function as a diluent, flavoring agent, solubilizer, lubricant, suspending agent, binder, preservative, tablet disintegrant, or encapsulating material. In powders, the carrier is generally a finely divided solid, mixed with the finely divided active ingredient. In tablets, the active ingredient is generally mixed in appropriate proportions with a carrier having the required binding ability and compressed 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, methylcellulose, sodium carboxymethylcellulose, low-melting-point wax, and cocoa butter. In addition to the active ingredient, solid preparations may contain colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0656] Liquid preparations suitable for oral administration include emulsions, syrups, elixirs, aqueous solutions, and aqueous suspensions. These include solid preparations intended to be converted into liquid preparations immediately before use. Emulsions may be prepared with solutions such as aqueous propylene glycol, and may also contain emulsifiers such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions may be prepared by dissolving the active ingredient in water and adding appropriate colorants, flavorings, stabilizers, and thickeners. Aqueous suspensions may be prepared by dispersing finely divided active ingredients in water with viscous substances such as natural or synthetic rubber, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

[0657] The compounds of the present invention can be formulated for parenteral administration (e.g., injection, e.g., bolus injection or continuous infusion) and may be provided in unit dose forms in ampoules, pre-filled syringes, small-volume injectors, or multi-dose containers with added preservatives. The compositions may take the form of suspensions, solutions, or emulsions in oily or aqueous media, such as solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents, or media include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and organic esters for injection (e.g., ethyl oleate), and formulation agents such as preservatives, wetting agents, emulsifiers or suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be in powder form obtained by sterile isolation of a sterile solid or by freeze-drying from a solution consisting of a suitable medium, e.g., sterile, pyrogen-free water, before use.

[0658] The compounds of this disclosure can be formulated for oral administration in the form of tablets, capsules (including sustained-release or time-release formulations, respectively), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of this disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, in any form familiar to those skilled in the pharmaceutical art.

[0659] The formulations of this disclosure may be in the form of aqueous solutions 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, isotonic agents, viscosity / suspension agents, buffers, and pH adjusters, as well as mixtures thereof.

[0660] Any suitable dissolution accelerator can be used. Examples of dissolution accelerators include cyclodextrins selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly 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, randomly methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

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

[0662] Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts, such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, methylthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, as well as 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 halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercury nitrate, methylthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl p-hydroxybenzoate, as well as sorbic acid and mixtures thereof.

[0664] Furthermore, the aqueous vehicle may contain an isotonic agent to adjust its tonicity (osmotic pressure). The isotonic agent may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, and triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, as well as mixtures thereof. In some embodiments, the isotonic agent is selected from the group consisting of glycols (such as propylene glycol and triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, as well as mixtures thereof.

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

[0666] To adjust the formulation to an acceptable pH (typically about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjusters are typically mineral acids or metal hydroxide bases selected from potassium hydroxide, sodium hydroxide, hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Therefore, it is not necessary to use both an acid and a base; depending on the formulation, adding only one of the acid or 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. If used, the buffer is selected from the group consisting of phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffer (such as boric acid or its salts containing disodium tetraborate), citrate buffer (such as citric acid or its salts containing sodium citrate), and ε-aminocaproic acid, as well as mixtures thereof.

[0668] The formulation may further contain 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, polyoxyethylene-sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (tyloxapole), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, as well as mixtures thereof.

[0669] Oral compositions typically contain an inert diluent or a pharmaceutically acceptable food-grade carrier. They can also be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound can be mixed with an excipient and used in the form of tablets, lozenges, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which case the compound in the fluid carrier is applied to the mouth, the mouth is rinsed, and the mixture is spat out or swallowed. Pharmaceutically compatible binders and / or auxiliary substances may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring.

[0670] In a further aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of the disclosure as defined herein, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

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

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

[0673] The compositions of this disclosure can be obtained by conventional methods using conventional pharmaceutical excipients well known in the art. Accordingly, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings and / or preservatives.

[0674] A therapeutically effective dose of the compounds of this disclosure for use in treatment is sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the NLRP3-related conditions referred to herein.

[0675] A therapeutically effective dose of the compounds of this disclosure for use in treatment is sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with the NLRP3-related conditions referred to herein.

[0676] The size of the doses of compounds of formulas (A), (I), (II), (III), (IV), and (V) for therapeutic or prophylactic purposes naturally varies according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or subject, and the route of administration. How to use

[0677] In some embodiments, the Disclosure provides a method for inhibiting NLRP3 (e.g., in vitro or in vivo), comprising contacting cells with a therapeutically effective amount of the Compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0678] In some embodiments, the Disclosure provides a method for treating or preventing a disease or disorder disclosed herein in a subject requiring treatment or prevention of such disease or disorder, comprising administering a therapeutically effective amount of the Compounds Disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject.

[0679] In some embodiments, the Disclosure provides a method for treating a disease or disorder disclosed herein in a subject requiring treatment of such disease or disorder, comprising administering a therapeutically effective amount of the Compounds Disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject.

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

[0681] The compounds of the present invention are also useful in treating diseases related to NLRP3. For example, diseases and symptoms treatable by the method of the present invention include acne (ACNE); hereditary papulotranslucent acrokeratoderma; adult-onset Still's disease (AOSD); Eicardi-Goutier syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthraxosis; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); cardiovascular autoimmune diseases; gastrointestinal autoimmune diseases; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); and body mass index trait locus 11 (B MIQ11); osteoinflammatory disease; cerebral edema; brucellosis; candidiasis; cervical lymphadenitis; chondrocalcification; chronic meningitis; chronic relapsing polymyelitis (CRMO); chronic urticaria; CINCA syndrome (CINCA); conjunctival disease; conjunctivitis; connective tissue disease; corneal disease; coronavirus infection; COVID-19; Crohn's disease; cryopyrin-associated periodic syndromes (CAPS); cystic fibrosis (CF); autosomal dominant hearing loss type 34 (DFNA34), with or without inflammation; 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; suppurative hidradenitis; essential hypertension (EHT); hyperuricemia; autosomal dominant intellectual disability type 30 with speech delay and behavioral abnormalities (MRD30); interstitial lung disease type 2 (ILD2); hereditary keratitis (KERH); hereditary transient keratitis endotheliitis (KEFH); Lipoprotein quantitative trait locus (LPAQTL); lymph node disease; age-related macular degeneration type 1 (ARMD1); malaria (CM); meningitis; mevalonic aciduria (MEVA); Mackle-Wells syndrome (MWS); Mycobacterium cansasi; myocardial infarction (MCI1); nephrolithiasis; neurological disorders; non-alcoholic steatohepatitis (NASH); optic neuropapillitis; osteomyelitis; osteoporosis (OSTEOP); otitis media (OMS); papilledema; pericardial effusion; pericardial disease; pharyngitis; polyradiculopathy; primary bacterial infections;This includes proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); pyoderma; pyoderma gangrenosum; suppurative aseptic arthritis, pyoderma gangrenosum, and acne (PAPAS); respiratory failure; salmonellosis; Schnitzler syndrome; sebaceous gland disorders; sensorineural hearing loss; serum amyloid A amyloidosis; silicosis; skin diseases; stomatitis; type 2 diabetes mellitus (T2D); ureteral disorders; urticaria (HIVES); vulvovaginal candidiasis; and Wells syndrome.

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

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

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

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

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

[0687] In some embodiments, a method of treatment involves administering to a patient suffering from at least one of the aforementioned diseases or disorders 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 disorder is acne (ACNE).

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

[0691] In some embodiments, the disease or disorder is a hereditary papule translucent.

[0692] In some embodiments, the disease or disorder is adult-onset Still's disease (AOSD).

[0693] In some embodiments, the disease or disorder is Aicardi-Gutierre 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 disorder is anthraxosis.

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

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

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

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

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

[0703] In some embodiments, the disease or disorder is a cardiovascular autoimmune disease.

[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 disorder is the body mass index trait locus 11 (BMIQ11).

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

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

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

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

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

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

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

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

[0717] In some embodiments, the disease or disorder 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 disorder.

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

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

[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 disorder 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 autosomal dominant hearing loss type 34 (DFNA34), with or without inflammation.

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

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

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

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

[0733] In some embodiments, the disease or disorder is an eye 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.

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

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

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

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

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

[0744] In some embodiments, the disorder or disability is autosomal dominant intellectual disability type 30 (MRD30) with language 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 disorder is hereditary keratitis (KERH).

[0747] In some embodiments, the disease or disorder is hereditary transient keratitis 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 disorder.

[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 disorder is meningitis.

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

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

[0755] In some embodiments, the disease or disorder is Mycobacterium kansasi.

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

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

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

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

[0760] In some embodiments, the disease or disorder is optic neuritis.

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

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

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

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

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

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

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

[0768] In some embodiments, the disease or disorder is polyradiculopathy.

[0769] In some embodiments, the disease or disorder is a primary bacterial infection.

[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 disorder is pyoderma gangrenosum.

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

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

[0775] In some embodiments, the disease or disorder 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 disorder.

[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 disorder is silicosis.

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

[0782] In some embodiments, the disease or disorder 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 disorder.

[0785] In some embodiments, the disease or disorder is urticaria (HIVES).

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

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

[0788] In some embodiments, the Disclosure provides a method for treating or preventing an autoimmune disease in a subject requiring treatment or prevention of an autoimmune disease, comprising administering a therapeutically effective amount of a compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to a subject.

[0789] In some embodiments, the Disclosure provides a method for treating an autoimmune disease in a subject requiring treatment for an autoimmune disease, comprising administering a therapeutically effective amount of the Compounds of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject.

[0790] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in inhibiting NLRP3 (e.g., in vitro or in vivo).

[0791] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of diseases or disorders disclosed herein.

[0792] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment of diseases or disorders disclosed herein.

[0793] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of autoimmune diseases in subjects requiring treatment or prevention of autoimmune diseases.

[0794] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment or prevention of coronavirus infection in subjects requiring treatment or prevention of coronavirus infection.

[0795] In some embodiments, the present disclosure provides compounds of the present disclosure or pharmaceutically acceptable salts thereof for use in the treatment of autoimmune diseases in subjects requiring treatment for autoimmune diseases.

[0796] In some embodiments, the Disclosure provides compounds of the Disclosure or pharmaceutically acceptable salts thereof for use in the treatment of coronavirus infection in subjects requiring treatment for coronavirus infection.

[0797] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for inhibiting NLRP3 (e.g., in vitro or in vivo).

[0798] In some aspects, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating or preventing the diseases or disorders disclosed herein.

[0799] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating diseases or disorders disclosed herein.

[0800] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating or preventing autoimmune diseases in subjects requiring treatment or prevention of autoimmune diseases.

[0801] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating or preventing coronavirus infection in subjects requiring treatment or prevention of coronavirus infection.

[0802] In some embodiments, the Disclosure provides the use of the Compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating autoimmune diseases in subjects requiring treatment for autoimmune diseases.

[0803] In some embodiments, the Disclosure provides the use of the compounds of the Disclosure or pharmaceutically acceptable salts thereof in the manufacture of agents for treating coronavirus infection in subjects requiring treatment for coronavirus infection.

[0804] This disclosure provides compounds that function as inhibitors of NLRP3 (e.g., in vitro or in vivo). Accordingly, this disclosure provides a method for inhibiting NLRP3 in vitro or in vivo, the method comprising contacting cells with a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof as defined herein.

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

[0806] The efficacy of the compounds disclosed herein can be determined by industry-accepted assays / disease models, as described in the art and as can be found in current general knowledge.

[0807] This disclosure also provides a method for treating a disease or disorder involving a subject requiring such treatment, the method comprising administering a therapeutically effective amount of the compound, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein to the subject.

[0808] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. Route of administration

[0809] The compounds of this disclosure or pharmaceutical compositions containing these compounds can be administered to a subject by any convenient route of administration, regardless of whether it is systemic, peripheral, or topical (i.e., the desired site of action).

[0810] The routes of administration are not limited to, but include, oral (e.g., by oral ingestion); cheek; sublingual; transdermal (e.g., including by patches, bandages, etc.); transmucosal (e.g., including by patches, bandages, etc.); intranasal (e.g., nasal spray); ocular (e.g., by eye drops); lung (e.g., via mouth or nose, using aerosols, e.g., inhalation or inhalation therapy); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); parenteral administration by injection, such as subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, intradermal, intraarticular, subarachnoid, intrasternal; and, for example, by implanting a storage unit or reservoir subcutaneously or intramuscularly. Examples Examples of general synthesis procedures and compound preparation.

[0811] All reagents were commercially available and used without further purification. Yield refers to the purified and spectroscopically pure compound. Thin-layer chromatography (TLC) was performed using Merck TLC aluminum sheet silica gel 60°F. 254 The work was performed using plates and visualized by fluorescence quenching under ultraviolet light. Flash chromatography was performed using silica gel (Chromatorex, MB 70-40 / 75, 40-75 μm) purchased from Fuji Silysia Chemicals. NMR spectra were obtained. 1 The data was recorded using a Varian-400MR operating at 400 MHz in H. Chemical shifts are reported in ppm with solvent resonance as the internal standard. Data are reported as follows: s=singlet, br.=broad, d=doublet, t=triplet, q=quadruplet, m=multitate, dd=doublet of doublets, coupling constant (Hz), integral. Purity was recorded using a Waters e2695 Separations Module / 2998 PDA Detector HPLC system (column: XBridge C18, 5 μm, 4.6 mm (ID) x 150 mm (L), eluate: mixture of mobile phases A and B, mobile phase A: 100% acetonitrile, mobile phase B: pure water containing 0.1% formic acid and 10 mMNH4OAc, flow rate: 0.5 mL / min, detection: UV, 254 nm).

[0812] The following are abbreviations used in the following examples and elsewhere in this specification: JPEG2026509095000318.jpg235170JPEG2026509095000319.jpg2798 Building block composite Synthesis of (2-(methylsulfonamide)-4-(trifluoromethyl)phenyl)boronic acid (P2) [ka]

[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 equivalent) in pyridine (20 mL), MsCl (2.5 mL, 31.24 mmol, 1.5 equivalent) was added 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 LC-MS. After completion, the reaction mixture was concentrated under reduced pressure, 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), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was eluted by combiflash chromatography using a mixture of HCl (10 → 13%) and hexane to obtain 2.5 g (37%) of the title compound as an off-white solid. Analysis data: 1 H NMR (400 MHz, 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): Calculated value for C8H7BrF3NO2S [M+H] + 317.9, measured value 318.1.

[0814] Preparation 2. (2-(methylsulfonamide)-4-(trifluoromethyl)phenyl)boronic acid (P2). To a stirred solution of P2 (2.0 g, 6.28 mmol, 1.0 equivalent) in 1,4-dioxane (25.0 mL), KOAc (2.1 g, 22.00 mmol, 3.5 equivalents) and bis(pinacolato)diborone (2.3 g, 9.43 mmol, 1.5 equivalents) were added 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 equivalent) was added at ambient temperature. The mixture was stirred at 100 °C for 3 hours. The reaction was monitored by TLC and LC-MS. After completion of the starting materials, the reaction mixture was diluted with DCM (150 mL), filtered through a Celite bed, and the filtrate was concentrated under reduced pressure to obtain 2.0 g (crude product) of the title compound as a brown, rubbery liquid. Note: The crude product itself was not further purified before proceeding to the next step. Analytical data: LCMS (ESI): C 21 H 23 Calculated value for BFN3O3 [MH] + 282.1, measured value 282.1. Synthesis of (R)-6-chloro-N-(1-ethylpiperidine-3-yl)-5-methylpyridazine-3-amine (P5). [ka]

[0815] Preparation 3. tert-butyl (R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (P3) and tert-butyl (R)-3-((6-chloro-4-methylpyridazin-3-yl)amino)-piperidine-1-carboxylate (P3a). A stirred solution of 3,6-dichloro-4-methylpyridazine (5.0 g, 30.673 mmol, 1.0 equivalent) in DMSO (20 mL) was mixed with DIPEA (27.3 mL, 153.36 mmol, 5.0 equivalent), followed by the addition of tert-butyl (R)-3-aminopiperidine-1-carboxylate (7.97 g, 39.87 mmol, 1.3 equivalents). The resulting reaction mixture was stirred at 140°C to ambient temperature for 24 hours. The reaction was monitored by TLC and LC-MS. After the starter material was complete, the reaction mixture was quenched with water (100 mL) and extracted with RINKAN (3 × 100 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was eluted and subjected to flash chromatography using 15-20% EA in petroleum ether to obtain P3 and P3a. P3 analysis data: P3 yield was 2.5 g (24.2%) of the title compound as a light brown solid. 1 H NMR (400 MHz, DMSO-d6), δ: 6.88 (d, J = 7.2 Hz, 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, 11 H). LCMS (ESI): C 15 H 23 Calculated values ​​for ClN4O2 [M+H] + 327.1, measured value 327.3. Analysis data for P3a: Yield of P3a, title compound 1.14 (14%) as a light brown solid. 1 H NMR (400 MHz, 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, 11 H). LCMS (ESI): C 15 H23 Calculated values ​​for ClN4O2 [M+H] + 327.1, measured value 327.3.

[0816] Preparation 4. (R)-6-chloro-5-methyl-N-(piperidine-3-yl)pyridazine-3-amine (P4). To a stirred solution of tert-butyl (R)-3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (P3, 2.5 g, 7.669 mmol, 1.0 equivalent) in methanol (5.0 mL), 4N HCl in MeOH (10 mL) was added at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours, and the progress of the reaction was monitored by TLC and LC-MS. After the completion of the starting materials, the volatile substances were concentrated under reduced pressure. The residue was pulverized with diethyl ether and dried to obtain 1.7 g (97.7%) of the title compound as an off-white solid. Note: The crude product itself was not further purified before proceeding to the next step. Analysis data: 1 H NMR (400 MHz, 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 Calculated values ​​for ClN4 [M+H] + 227.1, measured value 227.3.

[0817] Preparation 5. (R)-6-chloro-N-(1-ethylpiperidine-3-yl)-5-methylpyridazine-3-amine (P5). To a stirred solution of (R)-6-chloro-5-methyl-N-(piperidine-3-yl)pyridazine-3-amine (P4, 500 mg, 2.212 mmol, 1.0 equivalent) in DCE (5.0 mL), AcOH (27 mg, 0.442 mmol, 0.2 equivalents) and a 30% acetaldehyde solution (5.0 mL) were added 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 LC-MS. After completion of the starting materials, the reaction mixture was quenched with saturated NaHCO3 (50 mL) and extracted with  (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography using a mixture of MeOH (5 → 10%) in DCM as the eluate to obtain 450 mg (95.7%) of the title compound as an off-white solid. Analysis data: 1 H NMR (400 MHz, DMSO-d6), δ: 6.80 (s, 1H), 6.77 (d, J = 8.0 Hz, 1H), 3.95-3.88 (m, 1H), 2.89-2.97 (m, 1H), 2.63-2.61 (m, 1H), 2.32 (q, J = 4.0 Hz, 2H), 2.17 (s, 3H), 1.99 (t, J = 9.6 Hz, 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 = 7.0 Hz, 3H).LCMS (ESI): C 12 H 19 Calculated value for ClN4 [M+H] + 255.1, measured value 255.3. Synthesis of (R)-2-(3-((6-chloro-5-methylpyridazin-3-yl)amino)piperidine-1-yl)ethane-1-ol (P6) [ka]

[0818] Preparation 6. (R)-2-(3-((6-chloro-5-methylpyridazine-3-yl)amino)piperidine-1-yl)ethane-1-ol (P6). To a stirred solution of (R)-6-chloro-5-methyl-N-(piperidine-3-yl)pyridazine-3-amine (P4, 500 mg, 2.212 mmol, 1.0 equivalent) in ACN (5.0 mL), potassium carbonate (612 mg, 4.425 mmol, 2.0 equivalents) and 2-bromoethane-1-ol (412 mg, 3.31 mmol, 1.5 equivalents) were added 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 LC-MS. After completion of the starting materials, 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 subjected to flash chromatography using a mixture of (5→25%) MeOH in DCM as the eluent, and 400 mg (66.0%) of the title compound was obtained as an off-white solid. Analysis data: 1 H NMR (400 MHz, DMSO-d6), δ: 6.80 (br. s, 1H), 6.77 (br. s, 1H), 4.34 (t, J = 5.2 Hz, 1H), 4.09 (dd, J = 10.4 Hz, 5.2 Hz, 1H), 3.93 (t, J = 4.0 Hz, 1H), 3.48 (dd, J = 11.2 Hz, 5.6 Hz, 2H), 3.15 (d, J = 4.8 Hz, 2H), 2.86 (d, J = 11.2 Hz, 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 Calculated values ​​for ClN4O [M+H] + 271.1, measured value 271.3. Synthesis of (R)-6-chloro-N-(1-ethylpiperidine-3-yl)-4-methylpyridazine-3-amine (P8) [ka]

[0819] Preparation 7. (R)-6-chloro-4-methyl-N-(piperidine-3-yl)pyridazine-3-amine (P7). To a stirred solution of tert-butyl (R)-3-((6-chloro-4-methylpyridazin-3-yl)amino)piperidine-1-carboxylate (P3a, 1.3 g, 3.988 mmol, 1.0 equivalent) in methanol (5.0 mL), 4N HCl in MeOH (5 mL) was added at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours, and the progress of the reaction was monitored by TLC and LC-MS. After the starter material was complete, the volatile substances were concentrated under reduced pressure. The residue was pulverized with diethyl ether and dried to obtain 900 mg of the crude title compound as an off-white solid. Note: The crude product itself was not further purified before proceeding to the next step. Analysis data: 1 H NMR (400 MHz, DMSO-d6), δ: 9.46 (br. s, 1H), 7.52 (s, 1H), 6.82 (br. s, 1H), 4.41 (br. s, 1H), 3.41-3.33 (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 Calculated values ​​for ClN4 [M+H] + 227.1, measured value 227.2.

[0820] Preparation 8. (R)-6-chloro-N-(1-ethylpiperidine-3-yl)-4-methylpyridazine-3-amine (P8). To a stirred solution of (R)-6-chloro-4-methyl-N-(piperidine-3-yl)pyridazine-3-amine (P7, 500 mg, 2.205 mmol, 1.0 equivalent) in DCE (5.0 mL), AcOH (27 mg, 0.442 mmol, 0.2 equivalents) and 30% aqueous acetaldehyde (5.0 mL) were added at ambient temperature. The resulting reaction mixture was stirred at ambient temperature for 16 hours, and the progress of the reaction was monitored by TLC and LC-MS. After completion of the starting materials, the reaction mixture was quenched with saturated NaHCO3 (20 mL) and extracted with  (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography using a mixture of MeOH (5 → 10%) in DCM as the eluate, yielding 450 mg (80%) of the title compound as an off-white solid. Analysis data: 1 H NMR (400 MHz, DMSO-d6), δ: 7.29 (s, 1H), 5.95 (d, J = 8.0 Hz, 1H), 4.16-4.09 (m, 1H), 2.96 (d, J = 8.4 Hz, 1H), 2.70 (d, J = 11.2 Hz, 1H), 2.34 (q, J = 7.2 Hz, 2H), 2.09 (s, 3H), 1.95-1.83 (m, 3H),1.56-1.33 (m, 3H), 0.97 (t, J = 9.6 Hz, 3H).LCMS (ESI): C 12 H 19 Calculated value for ClN4 [M+H] + 255.1, measured value 255.3. Synthesis of (R)-2-(3-((6-chloro-4-methylpyridazine-3-yl)amino)piperidine-1-yl)ethane-1-ol (P9) [ka]

[0821] Preparation 9. (R)-2-(3-((6-chloro-4-methylpyridazine-3-yl)amino)piperidine-1-yl)ethane-1-ol (P9). To a stirred solution of (R)-6-chloro-4-methyl-N-(piperidine-3-yl)pyridazine-3-amine (P3a, 500 mg, 2.212 mmol, 1.0 equivalent) in ACN (5.0 mL), potassium carbonate (612 mg, 4.425 mmol, 2.0 equivalents) and 2-bromoethane-1-ol (412 mg, 3.31 mmol, 1.5 equivalents) were added 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 LC-MS. After completion of the starting materials, 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 subjected to flash chromatography using a mixture of (5→25%) MeOH in DCM as the eluent, and 350 mg (58.0%) of the title compound was obtained as an off-white solid. Analysis data: 1 H NMR (400 MHz, DMSO-d6), δ: 7.29 (s, 1H), 5.95 (d, J = 7.6 Hz, 1H), 4.36 (br. s, 1H), 4.14-4.10 (m, 1H), 3.49 (br. s, 2H), 2.93 (d, J = 8.8 Hz, 1H), 2.70-2.68 (m, 1H), 2.40 (t, J = 6.4 Hz, 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 Calculated values ​​for ClN4O [M+H] + 271.1, measured value 271.2. Synthesis of (R)-6-chloro-5-methyl-N-(1-methylpiperidine-3-yl)pyridazin-3-amine (P10) and (R)-6-chloro-4-methyl-N-(1-methylpiperidine-3-yl)pyridazin-3-amine (P10a) [ka]

[0822] Preparation 10. (R)-2-(3-((6-chloro-4-methylpyridazine-3-yl)amino)piperidine-1-yl)ethane-1-ol (P10). To a stirred solution of 3,6-dichloro-4-methylpyridazine (1.0 g, 6.13 mmol, 1.0 equivalent) in DMSO (10.0 mL) in a sealed tube, DIPEA (15.8 g, 122.6 mmol, 20 equivalents) and (R)-1-methylpiperidine-3-amine (2.3 g, 12.26 mmol, 2.0 equivalents) were added 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 LC-MS. After completion of the starting materials, the reaction mixture was quenched with ice water (30 mL), the pH was adjusted to approximately 10-12 using NaHCO3, and then extracted with ELISA (3 × 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to combiflash chromatography using a 0-10% MeOH-DCM mixture as the eluent to obtain 700 mg (47%) of a mixture of positional isomers P10 and P10a. This mixture was further purified by SFC purification to obtain P10 (180 mg) (12.2%) and P10a (130 mg) (8.8%) as off-white solids. Analysis data: P10: 1 H NMR (400 MHz, 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 Calculated values ​​for ClN4 [M+H] + 241.11, measured value 241.35. P10a: 1H NMR (400 MHz, DMSO-d6), δ: 7.30 (d, J = 0.8 Hz, 1H), 5.95 (d, J = 8.0 Hz, 1H), 4.16-4.09 (m, 1H), 2.88 (d, J = 8.0 Hz, 1H), 2.60 (d, J = 10.4 Hz, 1H), 2.16 (s, 3H), 2.09 (s, 3H), 1.88-1.65 (m, 8H). LCMS (ESI): C 11 H 17 Calculated values ​​for ClN4 [M+H] + 241.11, measured value 241.36. Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1H-indazole (P13) [ka]

[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 equivalents) in 50 mL of dry THF, n-BuLi (1.6 M, 13.5 mL, 21.6 mmol, 1.0 equivalent) was added at 0°C. The resulting reaction mixture was stirred at 0°C for 30 minutes. Then, a solution of 1-bromo-2-fluoro-4-(difluoromethyl)benzene (5.0 g, 20.57 mmol, 1.0 equivalent) in 50 mL of THF was added at -78°C, and the mixture was stirred at -78°C for 1 hour. Subsequently, DMF (1.9 mL, 24.69 mmol, 1.2 equivalents) was added at -78°C, and the reaction mixture was stirred at 0°C for 30 minutes. The progress of the reaction was monitored by TLC and LC-MS. After the starting materials were fully prepared, the reaction mixture was quenched with AcOH (50 mL), followed by the addition of ice water (100 mL), and extracted with diethyl ether (2 × 100 mL). The combined organic layers were sequentially washed with dilute HCl solution (0.2 M, 100 mL), water (100 mL), and brine solution (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain (5.0 g crude product) (100%) as a pale yellow liquid. Note: The crude product itself does not require further purification before proceeding to the next step. Analysis data: 1 H NMR (400 MHz, CDCl3), δ: 10.38 (s, 1H), 7.92-7.88 (m, 1H), 7.5 (d, J = 8.4 Hz, 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 equivalent) in DME (50 mL), N-methylhydroxylamine hydrochloride (1.54 g, 18.4 mmol, 1.0 equivalent) and K2CO3 (2.8 g, 20.29 mmol, 1.1 equivalent) were added at ambient temperature. The reaction mixture was stirred at 40°C for 4-5 hours. The progress of the reaction was monitored by TLC and LC-MS. After the starting materials were complete, the reaction mixture was filtered and washed with DME (40 mL). The filtrate was concentrated under reduced pressure to obtain an intermediate. Hydrazine monohydrate (50 mL, 92.24 mmol, 5.0 equivalent) was added to the intermediate at ambient temperature. The resulting reaction mixture was refluxed at 100°C for 12 hours. The progress of the reaction was monitored by TLC and LC-MS. After the starting materials were removed, all volatile substances were evaporated under reduced pressure and extracted with HCl (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was eluted and subjected to combiflash chromatography using 10–20% HCl in petroleum ether to obtain 1.5 g of the title compound (P12, 31%) as a pale yellow solid. Analysis data: 1 ¹H NMR (400 MHz, DMSO-d6), δ: 14.11 (s, 1H), 8.34 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H). LCMS (ESI): Calculated values ​​for C8H4BrF3N2 [M+H] + 264.95, measured value 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 equivalent) in 1,4-dioxane (30.0 mL), bis(pinacolato)diborone (2.88 g, 11.36 mmol, 2.0 equivalents) and KOAc (2.78 g, 28.4 mmol, 5.0 equivalents) were added 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 equivalent) 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 LC-MS. After the starting materials were consumed, the reaction mixture was cooled to room temperature, filtered through a Celite pad, 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 ground over n-hexane at -78°C and filtered to obtain 1.2 g (P13, 79%) of the title compound as a pale yellow solid. Analysis data: 1 C 14 H 16 Calculated values ​​for BF3N2O2 [M+H] + 231.05, measured value 231.06. Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)-1H-indazole (P16) [ka]

[0826] Preparation 14. tert-butyl (R)-(1-(2-hydroxyethyl)piperidine-3-yl)carbamate (P14). To a stirred solution of tert-butyl-(R)-piperidine-3-ylcarbamate (10.0 g, 50.0 mmol, 1.0 equivalent) in ACN (150 mL), Na2CO3 (10.5 g, 100.0 mmol, 2.0 equivalents) and 2-bromoethanol (9.3 g, 75.0 mmol, 1.5 equivalents) were added 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 LC-MS. After completion of the starting materials, the reaction mixture was filtered through a Celite bed and washed with ELISA (100 mL). The filtrate was concentrated under reduced pressure. The residue was eluted by combiflash chromatography using a mixture of 1-2% MeOH in DCM to obtain 8.0 g (65%) of the title compound P14 as an off-white solid. Analysis data: 1 H NMR (400 MHz, DMSO-d6), δ: 6.68 (d, J = 8.0 Hz, 1H), 4.36 (bs, 1H), 4.09-4.08 (m, 1H), 3.44 (qt, J = 5.6 Hz, 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 = 5.6 Hz, 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 Calculated values ​​for N2O3 [M+H] + 245.18, measured value 245.38.

[0827] Preparation 15. (R)-2-(3-aminopiperidine-1-yl)ethane-1-ol, hydrochloride (P15). To a stirred solution of tert-butyl (R)-(1-(2-hydroxyethyl)piperidine-3-yl)carbamate (P14, 8.0 g, 32.62 mmol, 1.0 equivalent) in 1,4-dioxane (40 mL), 4N HCl in 1,4-dioxane (160 mL) was added 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 materials were complete, all volatile substances were evaporated under reduced pressure. The residue was pulverized with diethyl ether to obtain 4.0 g (85%) of the title compound P15 as an off-white solid. Analysis data: 1 H NMR (400 MHz, DMSO-d6), δ: 3.81-3.75 (m, 2H), 3.74-3.71 (m, 1H),3.56 (s, 3H), 3.39-3.34 (m, 2H),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 Calculated value for N2O [M+H] + 145.13, measured value 145.28.

[0828] Preparation 16. (R)-6-chloro-N-(1-ethylpiperidine-3-yl)-5-methylpyridazin-3-amine (P16) and (R)-6-chloro-N-(1-ethylpiperidine-3-yl)-4-methylpyridazin-3-amine (P16A). To a stirred solution of 3,6-dichloro-4-methylpyridazine (P15, 4.0 g, 24.5 mmol, 1.0 equivalent) in DMSO (40.0 mL), DIPEA (63.43 g, 490.76 mmol, 20 equivalents) and (R)-2-(3-aminopiperidine-1-yl)ethane-1-ol (6.3 g, 29.4 mmol, 1.2 equivalents) were added at ambient temperature in a sealed tube. The resulting reaction mixture was stirred at 165 °C for 48 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the starting materials, the reaction mixture was quenched with ice water (150 mL), the pH was adjusted to approximately 10-12 with NaHCO3 solution, and then extracted with siRNA (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using 0-10% MeOH in DCM as the eluent, yielding 1.5 g (40%) of the title compound as a mixture of positional isomers. Further SFC purification yielded P16 (200 mg, 3.0%) and P16A (180 mg, 2.7%) as off-white solids. Analysis data: P16: 1 H NMR (400 MHz, 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 Calculated values ​​for ClN4O [M+H] + 271.12, measured value 271.19. P16A: 1 H NMR (400 MHz, CDCl3), δ: 7.01 (s, 1H), 4.71 (br. s, 1H), 4.48 (br. s, 1H), 3.67-3.61 (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): C12 H 19 Calculated values ​​for ClN4O [M+H] + 271.12, measured 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) [ka]

[0829] Preparation of 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 equivalent) in DCM (25 mL) and MeOH (5 mL), BTMA·ICl2 (9.93 g, 28.54 mmol, 2.0 equivalent) and CaCO3 (3.57 g, 35.68 mmol, 2.5 equivalent) were added 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 LC-MS. After the reaction was complete, the reaction mixture was filtered and washed with DCM (80 mL). The filtrate was washed with saturated Na2S2O3 solution (2 × 60 mL) and water (40 mL), dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure at 45°C. The residue was subjected to flash chromatography on silica gel (230-400 mesh) using a mixture of butyl (10-20%) and hexane as the eluent, yielding 1.5 g (35%) of the title compound P17 as a yellow liquid. Analysis data: 1 ¹H NMR (400 MHz, 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): Calculated values ​​for C8H8F3IN [M+H] + 301.9, measured value 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 equivalent) in pyridine (20 mL), MsCl (2.3 mL, 29.89 mmol, 5.0 equivalent) was added at 0°C. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The progress of the reaction was monitored by TLC and LC-MS. After the reaction was complete, the reaction mixture was quenched with water (30 mL) and extracted with RINKAN (2 × 60 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na₂SO₄, filtered, and evaporated under reduced pressure at 45°C. The residue was eluted using a mixture of RINKAN (15 → ​​20%) and hexane and subjected to flash chromatography on silica gel (230-400 mesh) to obtain 1.7 g (75%) of the title compound P18 as an off-white solid. Analysis data: 1 H NMR (400 MHz, CDCl3), δ: 7.50 (br. s, 1H), 7.12 (br. s, 1H), 2.92 (s, 3H), 2.48 (s, 3H); LCMS (ESI): C9H 10 Calculated values ​​for F3INO2S [M+H] + 379.9, measured value 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 equivalent) and bis(pinacolato)diborone (670 mg, 2.63 mmol, 2.0 equivalents) in 1,4-dioxane (10 mL), KOAc (388 mg, 3.95 mmol, 3.0 equivalents) was added at ambient temperature. The reaction mixture was degassed under a nitrogen stream for 15 minutes. Then, Pd(dppf)Cl2·DCM (46 mg, 0.066 mmol, 0.05 equivalents) 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 LC-MS. The reaction mixture was cooled to ambient temperature, filtered through a Celite pad, and the pad was washed with 10% MeOH in DCM (40 mL). The filtrate was evaporated under reduced pressure at 40 °C. The residue was pulverized with hexane (2 × 30 mL) and decanted. The decanted hexane layer was concentrated under reduced pressure to obtain 0.8 g (crude product) of the title compound P19 as a yellow liquid. Analytical data: LCMS (ESI): C 15 H 21 Calculated values ​​for BF3NO4S [M+H] + 380.12, measured value 380.18. Synthesis of (R)-6-chloro-N-(1-methylpiperidine-3-yl)pyridazine-3-amine (P20) [ka]

[0832] Preparation 20. (R)-6-chloro-N-(1-methylpiperidine-3-yl)pyridazine-3-amine (P20). To a stirred solution of 3,6-dichloropyridazine (0.5 g, 3.35 mmol, 1.0 equivalent) in DMSO (10.0 mL), DIPEA (1.78 mL, 10.06 mmol, 3.0 equivalent) was added, followed by (R)-1-methylpiperidine-3-amine (0.38 g, 3.35 mmol, 1.0 equivalent) at ambient temperature. The resulting reaction mixture was stirred at 110 °C for 16 hours. The reaction was monitored by TLC and LC-MS. After completion of the starting materials, the reaction mixture was quenched with water (30 mL) and extracted with 10% MeOH (2 × 40 mL) in DCM. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure at 45 °C to obtain the residue. The residue was used as the eluent and subjected to flash chromatography on silica gel (230-400 mesh) using a mixture of 5% Et3N (10-20%) and DCM in MeOH to obtain 220 mg (28%) of the title compound P20 as an off-white solid. Analysis data: 1 H NMR (400 MHz, CD3OD), δ: 8.53 (s, 1H), 7.33 (d, J = 9.6 Hz, 1H), 6.93 (d, J = 9.6 Hz, 1H), 4.20-4.15 (m, 1H), 3.24-3.17 (m, 2H), 2.64 LCMS (ESI): C 10 H 15 Calculated values ​​for ClN4 [M+H] + 227.1, measured value 227.3. Synthesis of (R)-6-chloro-N-(1-ethylpiperidine-3-yl)pyridazine-3-amine (P23) [ka]

[0833] Preparation 21. tert-butyl (R)-(1-ethylpiperidine-3-yl)carbamate (P21). To a stirred solution of tert-butyl (R)-piperidine-3-ylcarbamate (5.0 g, 25.0 mmol, 1.0 equivalent) in ACN (75 mL), K2CO3 (4.14 g, 30.0 mmol, 1.2 equivalents) was added, followed by ethyl iodide (4.28 g, 27.5 mmol, 1.1 equivalents) 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 LC-MS. After completion of the starting materials, 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 the residue. The residue was eluted using a mixture of MeOH (1 → 2%) and DCM and subjected to flash chromatography on silica gel (230-400 mesh) to obtain 2.5 g (43%) of the title compound P21 as a pale yellow liquid. Analysis data: 1 H NMR (400 MHz, 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 = 6.8 Hz, 3H); LCMS (ELSD) (ESI): C 12 H 24 Calculated values ​​for N2O2 [M+H] + 229.18, measured value 229.25.

[0834] Preparation 22. (R)-1-ethylpiperidine-3-amine hydrochloride (P22). To a stirred solution of tert-butyl(R)-(1-ethylpiperidine-3-yl)carbamate (P21, 2.5 g, 10.95 mmol, 1.0 equivalent) in 1,4-dioxane (12.5 mL), 4 M HCl in 1,4-dioxane (25 mL) was added at 0°C. The resulting reaction mixture was stirred at ambient temperature for 16 hours. The progress of the reaction was monitored by TLC and LC-MS. After completion of the starting materials, the reaction mixture was concentrated under reduced pressure at 40°C to obtain the residue. The residue was pulverized with diethyl ether (20 mL) and dried to obtain 2.0 g (crude product) of the title compound P22 as a yellow solid. Analysis data:1 H NMR (400 MHz, 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 = 7.2 Hz, 3H); LCMS (ESI): C7H 17 Calculated value for ClN2 [M-HCl+H] + 129.13, measured value 129.18.

[0835] Preparation 23. (R)-6-chloro-N-(1-ethylpiperidine-3-yl)pyridazine-3-amine (P23). To a stirred solution of 3,6-dichloropyridazine (0.5 g, 3.35 mmol, 1.0 equivalent) in DMSO (5.0 mL), DIPEA (1.75 mL, 10.06 mmol, 3.0 equivalent), followed by P22 (607 mg, 3.69 mmol, 1.1 equivalent), was added at ambient temperature. The resulting reaction mixture was stirred at 120 °C for 16 hours. The reaction was monitored by TLC and LC-MS. After completion of the starting materials, the reaction mixture was quenched with water (30 mL) and extracted with 10% MeOH (2 × 40 mL) in DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 45 °C to obtain the residue. The residue was used as the eluent and subjected to flash chromatography on silica gel (230-400 mesh) using a mixture of 5% Et3N (10-20%) and DCM in MeOH, yielding 300 mg (37%) of the title compound P23 as a light brown solid. Analysis data: 1H NMR (400 MHz, CD3OD), δ: 7.37 (d, J = 9.6 Hz, 1H), 6.96 (d, J = 9.6 Hz, 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 = 7.6 Hz, 4H).LCMS (ESI): C 11 H 17 Calculated values ​​for ClN4 [M+H] + 241.1, measured value 241.36. Synthesis of (R)-6-chloro-N-(1-ethylpiperidine-3-yl)-5-methylpyridazin-3-amine and (R)-6-chloro-N-(1-ethylpiperidine-3-yl)-4-methylpyridazin-3-amine (P24 and P24A) [ka]

[0836] Preparation 24. (R)-6-chloro-N-(1-ethylpiperidine-3-yl)-5-methylpyridazin-3-amine and (R)-6-chloro-N-(1-ethylpiperidine-3-yl)-4-methylpyridazin-3-amine (P24 and P24A). To a stirred solution of 3,6-dichloro-4-methylpyridazine (2.5 g, 15.33 mmol, 1.0 equivalent) in DMSO (25.0 mL), DIPEA (39.5 g, 306.7 mmol, 20 equivalents) and P22 (3.6 g, 18.0 mmol, 1.2 equivalents) were added 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 LC-MS. After completion of the starting materials, the reaction mixture was quenched with ice water (30 mL), the pH was adjusted to 10-12 with NaHCO3 solution, and extracted with siRNA (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was eluted and subjected to combiflash chromatography using 0-10% MeOH in DCM to obtain 1.5 g (40%) of the title compound as a mixture of positional isomers. This mixture was further purified by SFC to obtain peak 1 (P24, 500 mg, 8.0%) and peak 2 (P24A, 400 mg, 6.4%) as off-white solids. [ka] NOE experimental data shows that irradiation with 2.18 ppm of H1 protons increases the amount of H17 protons to 6.81 ppm. Analysis data: 1 H NMR (400 MHz, DMSO-d6), δ: 6.81 (s, 1H), 6.78 (d, J = 8.0 Hz, 1H), 3.95-3.89 (m, 1H), 2.89-2.83 (m, 1H), 2.67-2.61 (m, 1H), 2.35 (qt, J = 6.4 Hz, 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 = 8.0 Hz, 3H).LCMS (ESI): C 12 H 19 Calculated values ​​for ClN4 [M+H] + 255.13, measured value 255.32. [ka] NOE experimental data shows that irradiation with 5.95 ppm of H19 protons increases H2O protons to 4.11 ppm and H1 protons to 2.96 ppm. Analysis data: 1 H NMR (400 MHz, DMSO-d6), δ: 7.29 (s, 1H), 5.95 (d, J = 7.6 Hz, 1H), 4.16-4.09 (m, 1H), 2.97-2.91 (m, 1H), 2.72-2.54 (m, 2H), 2.35 (qt, J = 7.2 Hz, 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 = 7.2 Hz, 3H).LCMS (ESI): C 12 H 19 Calculated values ​​for ClN4 [M+H] + 255.13, measured value 255.28. Synthesis of (R)-3-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P25) [ka]

[0837] Preparation 25. (R)-3-(4-methyl-6-((1-methylpiperidine-3-yl)amino)pyridazin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P25). 1. 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 equivalent) and P10 (0.54 g, 2.27 mmol, 1.0 equivalent) in 1,4-dioxane (6.0 mL) and water (2.0 mL), sodium carbonate (0.48 g, 4.54 mmol, 2.0 equivalent) was added at ambient temperature. The reaction mixture was degassed under a nitrogen stream for 15 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.114 mmol, 0.05 equivalent) 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 LC-MS. After the starting materials were removed, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was eluted using reverse-phase column chromatography with a mixture of ACN (0-70%) and water to obtain 0.210 g (24%) of the title compound as a brown solid. Analysis data: 1 H NMR (400 MHz, DMSO-d6), δ: 8.42 (s, 2H), 7.82 (br. s, 1H), 7.04 (d, J =8.4 Hz, 1H), 6.98-6.92 (m, 1H), 6.68 (d, J =8.4 Hz, 1H), 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 Calculated values ​​for F3N6 [M+H] + 381.19, measured value 381.54. Synthesis of 7-(6-chloro-4,5-dimethylpyridazin-3-yl)-4-(trifluoromethyl)-1H-benzo[d][1,2,3]triazole (P27) [ka]

[0838] Preparation 26.3-(6-chloro-4,5-dimethylpyridazin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P26). To a stirred solution of 3,6-dichloro-4,5-dimethylpyridazine (0.58 g, 1.0 equivalent, 3.31 mmol) in a mixture of 1,4-dioxane (3.0 mL) and water (1.0 mL), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)benzene-1,2-diamine (1.0 g, 1.0 equivalent, 3.31 mmol) and sodium carbonate (0.70 g, 2.0 equivalent, 6.62 mmol) were added at room temperature. The resulting mixture was purged with argon for 10 minutes. Then, at room temperature, the [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex was added together with dichloromethane (0.121 g, 0.05 equivalent, 0.16 mmol). The resulting reaction mixture was stirred at 100°C for 3 hours. The reaction was monitored by TLC. The reaction mixture was diluted with 10% MeOH (20 mL) in DCM and filtered through a Celite pad. The Celite pad was washed with 10% MeOH in DCM (10 mL), and the combined filtrate was concentrated under reduced pressure. The crude compound was purified using reverse-phase column chromatography on a C18 column with a mixture of ACN (0→60%) and water as the eluent, yielding 0.3 g (28%) of the title compound 3 as a brown solid. Analytical data: LCMS (ESI): C 13 H 12 Calculated values ​​for ClF3N4 [M+H] + 317.07, Measured value 317.07.

[0839] Preparation 27.7-(6-chloro-4,5-dimethylpyridazin-3-yl)-4-(trifluoromethyl)-1Hbenzo[d][1,2,3]triazole (P27). To a stirred solution of P26 (0.30 g, 1.0 equivalent, 0.949 mmol) in AA (0.11 mL, 2.0 equivalents, 1.89 mmol), a solution of sodium nitrite (0.131 g, 2.0 eq, 1.899 mmol) in water (1.5 mL) was added at 0°C, and the resulting reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, diluted with water (20 mL), and extracted with EA (2 × 30 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain 310 mg (crude product) of the title compound P27 as a brown solid. Analytical data: LCMS (ESI): C 13 H 10 Calculated values ​​for ClF3N5 [M+H] + 328.05, measured value 328.14. Synthesis of (R)-3-(6-((1-methylpiperidine-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P29) [ka]

[0840] Preparation 28. (R)-6-chloro-N-(1-methylpiperidine-3-yl)-5-(trifluoromethyl)pyridazine-3-amine (P28). To a stirred solution of 3,6-dichloro-4-(trifluoromethyl)pyridazine (0.50 g, 2.30 mmol, 1.0 equivalent) in DMSO (3.0 mL), (R)-1-methylpiperidine-3-amine (0.211 g, 1.84 mmol, 0.8 equivalent) and N,N-diisopropylethylamine (2.0 mL, 11.52 mmol, 5.0 equivalent) were added at ambient temperature and the mixture was stirred at 130 °C for 16 hours. The reaction was monitored by TLC and LC-MS. After completion of the starting materials, the reaction mixture was concentrated under reduced pressure. Following the above procedure, an additional 0.50 g of 3,6-dichloro-4-(trifluoromethyl)pyridazine was treated with (R)-1-methylpiperidine-3-amine, and both batches were mixed. The combined residue was subjected to reverse-phase column purification using a mixture of water (0-90%) and ACN (10%) as the eluent, yielding 0.43 g (32%) of the title compound P28 and 0.42 g (31%) of compound P28A as brown solids. Analytical data for compound P28: 1 H NMR (400 MHz, DMSO-d6), δ: 7.55 (d, J = 7.6 Hz, 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 [M+H] for ClF3N4: 295.09, Measured value: 295.23. [ka] The structure of compound P28 was confirmed by NOE: Irradiation with H17 (7.39 ppm) protons resulted in an increase in H19 (-NH, double line, 7.55 ppm) protons. Analysis data for P28A: LCMS (ESI): C 11 H 14Calculated values ​​for ClF3N4 [M+H] + 295.09, measured value 295.23.

[0841] Preparation 29. (R)-3-(6-((1-methylpiperidine-3-yl)amino)-4-(trifluoromethyl)pyridazin-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 equivalent) and P28 (0.39 g, 1.32 mmol, 1.0 equivalent) in a mixture of 1,4-dioxane (3.0 mL) and water (1.0 mL), sodium carbonate (0.28 g, 2.64 mmol, 2.0 equivalent) was added at ambient temperature. The reaction mixture was degassed under a nitrogen stream for 15 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (76 mg, 0.06 mmol, 0.05 equivalent) 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 LC-MS. After the starting materials were removed, the reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was eluted using reverse-phase column chromatography with a mixture of ACN (0-70%) and water to obtain 0.270 g (47%) of the title compound as a brown solid. Analytical data: LCMS (ESI): C 18 H 20 Calculated values ​​for F6N6 [M+H] + 435.17, measured value 435.66. Synthesis of (R)-3-(6-((1-methylpiperidine-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P30) [ka]

[0842] Preparation 30. (S)-3-(6-((1-methylpiperidine-3-yl)amino)-4-(trifluoromethyl)pyridazin-3-yl)-6-(trifluoromethyl)benzene-1,2-diamine (P30). To a stirred solution of P28A (0.35 g, 1.18 mmol, 1.0 equivalent) in a mixture of 1,4-dioxane (6 mL) and water (0.5 mL), sodium carbonate (0.25 g, 2.36 mmol, 2.0 equivalents) 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 equivalents) were added at ambient temperature. The reaction mixture was degassed under a nitrogen stream for 10 minutes. Then, tetrakis(triphenylphosphine)palladium(0) (0.127 g, 0.11 mmol, 0.1 equivalent) 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, filtered through a Celite bed, and washed with 1,4-dioxane (2 × 25 mL). The combined filtrate was concentrated under reduced pressure. The crude product was subjected to flash chromatography on silica gel (230-400 mesh) using a mixture of MeOH (0-10%) and DCM as the eluent, yielding 0.20 g (39%) of the title compound P30 as a brown solid. Analytical data: LCMS (ESI): C 18 H 20 Calculated values ​​for F6N6 [M+H] + 435.17, measured value 435.59. Synthesis of (R)-4-chloro-N-(1-methylpiperidine-3-yl)-5,6,7,8-tetrahydrophthalazine-1-amine (P33) [ka]

[0843] Preparation 31.2,3,5,6,7,8-Hexahydrophthalazine-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 equivalent) in AA (270 mL), sodium acetate (38.85 g, 473.68 mmol, 8.0 equivalents) and hydrazine monohydrate (5.5 mL, 177.63 mmol, 3.0 equivalents) were added 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 LC-MS. After completion of the starting materials, the reaction mixture was quenched in cold water (200 mL), the precipitated solid was collected by filtration, washed with cold water, and dried under vacuum. This solid was pulverized with n-hexane and dried to obtain 6.3 g (64%) of the title compound as a colorless solid. Analysis data: 1 H NMR (400 MHz, 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 Calculated values ​​for N2O2 [M+H] + 167.07, measured value 167.09.

[0844] Preparation 32,1,4-dichloro-5,6,7,8-tetrahydrophthalazine (P32). POCl3 (31.5 mL) was added to P31 (6.3 g, 37.91 mmol, 1.0 equivalent) at ambient temperature. The resulting reaction mixture was stirred at 110 °C for 12 hours. The reaction was monitored by TLC and LC-MS. After the starting materials were complete, the reaction mixture was concentrated under reduced pressure. The residue was quenched in cold water (100 mL), the precipitated solid was collected by filtration, washed with cold water, and dried under vacuum. This solid was pulverized with n-hexane and dried to obtain 5.0 g (65%) of the title compound P32 as a brown solid. Analysis data: 1 ¹H NMR (400 MHz, DMSO-d6), δ: 2.76–2.73 (m, 4H), 1.89–1.85 (m, 4H). LC-MS (ESI): Calculated values ​​for C8H8Cl2N2 [M+H] + 203.01, measured value 203.10.

[0845] Preparation 33. (R)-4-chloro-N-(1-methylpiperidine-3-yl)-5,6,7,8-tetrahydrophthalazine-1-amine (P33). To a stirred solution of P32 (1.0 g, 4.92 mmol, 1.0 equivalent) in DMSO (10 mL), DIPEA (6.35 g, 49.24 mmol, 10 equivalents) and (R)-1-methylpiperidine-3-amine (1.12 g, 9.84 mmol, 2.0 equivalents) were added 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 LC-MS. After completion of the starting materials, the reaction mixture was quenched with saturated NaHCO3 solution (10 mL) and extracted with SiO2 (3 × 25 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash column chromatography using a mixture of MeOH (0 → 10%) and DCM as the eluate to obtain 0.30 g (23%) of the title compound as a brown liquid. Analytical data: LCMS (ESI): C 14 H 21 Calculated values ​​for ClN4 [M+H] + 281.15, measured value 281.17. Synthesis of (R)-4-chloro-N-(1-ethylpiperidine-3-yl)-5,6,7,8-tetrahydrophthalazine-1-amine (P34) [ka]

[0846] Preparation 34. (R)-4-chloro-N-(1-ethylpiperidine-3-yl)-5,6,7,8-tetrahydrophthalazine-1-amine (P34). To a stirred solution of 1,4-dichloro-5,6,7,8-tetrahydrophthalazine (P-32, 1.0 g, 4.924 mmol, 1.0 equivalent) in DMSO (10 mL), DIPEA (6.352 g, 49.244 mmol, 10 equivalents) and (R)-1-ethylpiperidine-3-amine (1.25 g, 9.849 mmol, 2.0 equivalents) were added at ambient temperature. The resulting reaction mixture was stirred in a sealed tube at 160 °C for 6 hours. The progress of the reaction was monitored by TLC and LC-MS. After the completion of the starting materials, all volatile substances were removed under vacuum. The residue was purified by reverse-phase column chromatography using a mixture of ACN (0 → 30%) in water and 0.1% FA to obtain 0.5 g (34%) of the title compound P34 as a brown liquid. Analysis data: 1 H NMR (400 MHz, CDCl3), δ: 8.37 (br. s, exch. with D2O, 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 (fused with water, 3H), 1.36 (t, J = 7.2 Hz, 2H).LCMS (ESI): C 15 H 23 Calculated values ​​for ClN4 [M+H] + 295.16, measured value 295.32. Synthesis of N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)methanesulfonamide (P37) [ka]

[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 equivalent) and pyridine (16.81 mL, 208.316 mmol, 5.0 equivalents) in DCM (200 mL), methanesulfonyl chloride (16.12 mL, 208.31 mmol, 5.0 equivalents) was added 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 LC-MS. After completion of the starting materials, the reaction mixture was quenched with water (250 mL) and extracted with Â(3 × 150 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain 10 g (crude product) of the title compound P37 as a brown liquid. The crude product itself was not purified and proceeded to the next step. Analysis data: LCMS (ESI): Calculated values ​​for C9H9BrF3NO4S2 [M+H] + 366.19, measured 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 equivalent) in a THF / MeOH (1:1, 200 mL) mixture, a solution of LiOH monohydrate (31.94 g, 761.42 mmol, 30 equivalents) in water (100 mL) was added 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 LC-MS. After completion of the starting materials, the reaction mixture was concentrated under reduced pressure. The residue was quenched with cold water (50 mL) and extracted with SiO2SO4 (3 × 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (230-400 mesh) using a mixture of SiO2SO4 (0 → 20%) and hexane to obtain 7.0 g (87%) of the title compound P36 as a colorless solid. Analysis data: 1¹H NMR (400 MHz, 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): Calculated values ​​for C8H7BrF3NO2S [MH] - 315.93, measured value 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 equivalent) and bis(pinacolato)diborone (5.98 g, 23.577 mmol, 1.5 equivalents) in 1,4-dioxane (75 mL), KOAc (4.628 g, 47.154 mmol, 3.0 equivalents) was added at ambient temperature. The reaction mixture was degassed under a nitrogen stream for 15 minutes, and then PdCl2(dppf)·DCM (0.552 g, 0.786 mmol, 0.05 equivalents) was added 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 LC-MS. After completion of the starting materials, the reaction mixture was filtered through a Celite pad, and the Celite pad was washed with SiO2 (50 mL). The filtrate was concentrated under reduced pressure at 40 °C. The residue was eluted using a mixture of butyl (0-10%) and hexane and subjected to flash chromatography on silica gel (230-400 mesh) to obtain 5.0 g (crude product) of the title compound P37 as a brown solid. The crude product itself proceeded to the next step. Analysis data: LCMS (ESI): Calculated value of corresponding boronic acid C8H9BF3NO4S [MH] - 282.03, measured value 282.01. Synthesis of (R)-4-chloro-N-(1-ethylpiperidine-3-yl)-5,6,7,8-tetrahydro-5,8-ethanophthalazine-1-amine (P38) [ka]

[0850] Preparation 38. (R)-4-chloro-N-(1-ethylpiperidine-3-yl)-5,6,7,8-tetrahydro-5,8-ethanophthalazine-1-amine (P38). To a stirred solution of 1,4-dichloro-5,6,7,8-tetrahydro-5,8-ethanophthalazine (0.6 g, 2.619 mmol, 1.0 equivalent) in DMSO (10.0 mL), N,N-diisopropylethylamine (2.346 mL, 13.094 mmol, 5.0 equivalents) and (R)-1-ethylpiperidine-3-amine (1.0 g, 7.86 mmol, 3.0 equivalents) were added at ambient temperature, and the mixture was stirred at 160 °C for 6 hours. The reaction was monitored by TLC and LC-MS. After the completion of the starting materials, all volatile substances were removed under vacuum. The residue was purified by reverse-phase column chromatography using ACN in water and 0.1% FA to obtain 0.4 g (47%) of the title compound P38 as a brown liquid. Analytical data: LCMS (ESI): C 17 H 25 Calculated values ​​for ClN4 [M+H] + 321.18, measured value 321.34. Synthesis of N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)phenyl)ethanesulfonamide (P40) [ka]

[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 equivalent) and bis(pinacorato)diborone (7.93 g, 31.24 mmol, 1.5 equivalent) in 1,4-dioxane (150 mL), KOAc (6.1 g, 62.49 mmol, 3.0 equivalent) was added at ambient temperature. The mixture was degassed with an argon stream for 10 minutes. Then, Pd(PPh3)2Cl2 (0.73 g, 1.04 mmol, 0.05 equivalent) was added. The resulting reaction mixture was stirred at 100 °C for 2 hours. The progress of the reaction was monitored by TLC and LC-MS. The reaction mixture was filtered through a Celite pad, and the pad was washed with 1,4-dioxane (50 mL). The filtrate was completely concentrated under reduced pressure to obtain the residue. The residue was subjected to flash chromatography on silica gel (80 g, 230-400 mesh) using a mixture of SiO(0-20%) and hexane as the eluent, yielding 4.1 g (69%) of the title compound P39 as an off-white solid. Analysis data: 1 1H NMR (400 MHz, CDCl3) , δ: 7.68 (d, J = 7.6 Hz, 1H), 6.86 (dd, J = 7.6 Hz, 0.8 Hz, 1H), 6.79 (d, J = 0.8 Hz, 1H), 4.91 (br. s, 2H), 1.34 (s, 12H); LCMS (ESI): C 13 H 18 Calculated values ​​for BF3NO2 [M+H] + 288.13, measured 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 equivalent) in DCM (8 mL), TEA (2.1 g, 20.90 mmol, 6.0 equivalents) was added, followed by ethanesulfonyl chloride (0.67 g, 5.22 mmol, 1.5 equivalents) at 0°C. The resulting reaction mixture was stirred at ambient temperature for 4 hours. The reaction was monitored by TLC and LC-MS. 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...

Claims

1. Compound of formula (A): 【Chemistry 1】 or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof. [In the formula, R １ is selected from H, C １ -C ６ alkyl, C １ -C ６ alkoxy, C ３ -C １０ cycloalkyl, C ３ -C １０ cycloalkoxy, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, heterocycle, aryl, heteroaryl, and the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH ２ , CN, C １ -C ６ alkyl, C １ -C ６ alkoxy, C ３ -C １０ cycloalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, heterocycle, aryl, and heteroaryl, and is optionally substituted with one or more substituents independently selected therefrom; R ２ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; or R １ and R ２ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes, 5-14 membered heterocycles, arenes, or heteroarenes, and the cycloalkanes, heterocycles, arenes, or heteroarenes contain halogens, OH, CN, and C １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ３ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ４ is selected from H, C １ -C ６ alkyl, C １ -C ６ alkoxy, C ３ -C １０ cycloalkyl, C ３ -C １０ cycloalkoxy, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, heterocycle, aryl, heteroaryl, and the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH ２ , CN, C １ -C ６ alkyl, C[[ID=3%]] １ -C ６ alkoxy, C ３ -C １０ cycloalkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, heterocycle, aryl, and heteroaryl; R ３ and R ４ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes and 5-14 membered heterocycles, and the cycloalkanes and heterocycles are composed of halogens, OH, CN, and C. １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ５ H, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Achille, SO ２ -C １ -C ６ Selected from alkyls and 4- to 10-membered heterocyclines, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocycline is a halogen, oxo, OH, CN, or C １ -C ６ Alkoxy, C ３ -C １０ Optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups; R ６ H, SO ２ R ８ NH ２ , C １ -C ６ Alkyl, C １ -C ６ Selected from alkyl-C(O)- and aryl, the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, and OH; R ７ H, C １ -C ６ Alkyl, or NH ２ is; or R ６ and R ７ These atoms, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 membered heterocycle or heteroarene; R ８ C １ -C ６ Alkyl, C ３ -C ８ Selected from cycloalkyls and 5-6 membered heteroaryls, the alkyl, cycloalkyl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogens, CN, and OH; Each R ９ is halogen, OH, C １ -C ６ Alkyl, C １ -C ６ Independently selected from alkoxy, the alkyl or alkoxy is optionally substituted with one or more halogens, OH groups; or Two R's ９ They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R ５ and R ９ These, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; n is an integer selected from 0, 1, and 2; However, R ５ When R is methyl, ６ is H or CH ３ It's not CO- either.

2. The aforementioned compound is of formula (I): 【Chemistry 2】 The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof. [In the formula, R １ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ２ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; or R １ and R ２ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes, 5-14 membered heterocycles, arenes, or heteroarenes, and the cycloalkanes, heterocycles, arenes, or heteroarenes contain halogens, OH, CN, and C １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ３ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ４ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ３ and R ４ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes and 5-14 membered heterocycles, and the cycloalkanes and heterocycles are composed of halogens, OH, CN, and C. １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ５ H, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Achille, SO ２ -C １ -C ６ Selected from alkyls and 4- to 10-membered heterocyclines, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocycline is a halogen, oxo, OH, CN, or C １ -C ６ Alkoxy, C ３ -C １０ Optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups; R ８ C １ -C ６ Alkyl, C ３ -C ８ Selected from cycloalkyls and 5-6 membered heteroaryls, the alkyl, cycloalkyl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogens, CN, and OH; Each R ９ is halogen, OH, C １ -C ６ Alkyl, C １ -C ６ Independently selected from alkoxy, the alkyl or alkoxy is optionally substituted with one or more halogens, OH groups; or Two R's ９ They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R ５ and R ９ These, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; n is an integer selected from 0, 1, and 2.

3. The aforementioned compound is of formula (II): 【Transformation 3】 The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof. [In the formula, R １ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ２ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; or R １ and R ２ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes, 5-14 membered heterocycles, arenes, or heteroarenes, and the cycloalkanes, heterocycles, arenes, or heteroarenes contain halogens, OH, CN, and C １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ３ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ４ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ３ and R ４ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes and 5-14 membered heterocycles, and the cycloalkanes and heterocycles are composed of halogens, OH, CN, and C. １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ５ H, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Achille, SO ２ -C １ -C ６ Selected from alkyls and 4- to 10-membered heterocyclines, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocycline is a halogen, oxo, OH, CN, or C １ -C ６ Alkoxy, C ３ -C １０ Optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups; Each R ９ is halogen, OH, C １ -C ６ Alkyl, C １ -C ６ Independently selected from alkoxy, the alkyl or alkoxy is optionally substituted with one or more halogens, OH groups; or Two R's ９ They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R ５ and R ９ These, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; n is an integer selected from 0, 1, and 2.

4. The aforementioned compound is of formula (III): 【Chemistry 4】 The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof. [In the formula, W is selected from CH and N; R １ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ２ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; or R １ and R ２ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes, 5-14 membered heterocycles, arenes, or heteroarenes, and the cycloalkanes, heterocycles, arenes, or heteroarenes contain halogens, OH, CN, and C １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ３ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ４ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ３ and R ４ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes and 5-14 membered heterocycles, and the cycloalkanes and heterocycles are composed of halogens, OH, CN, and C. １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ５ H, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Achille, SO ２ -C １ -C ６ Selected from alkyls and 4- to 10-membered heterocyclines, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocycline is a halogen, oxo, OH, CN, or C １ -C ６ Alkoxy, C ３ -C １０ Optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups; Each R ９ is halogen, OH, C １ -C ６ Alkyl, C １ -C ６ Independently selected from alkoxy, the alkyl or alkoxy is optionally substituted with one or more halogens, OH groups; or Two R's ９ They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R ５ and R ９ These, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; n is an integer selected from 0, 1, and 2.

5. The aforementioned compound is of formula (III-A): 【Transformation 5】 The compound according to claim 4, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

6. The aforementioned compound is of formula (III-B): 【Transformation 6】 The compound according to claim 4, or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

7. The aforementioned compound is of formula (IV): 【Transformation 7】 The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof. [In the formula, R １ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ２ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; or R １ and R ２ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes, 5-14 membered heterocycles, arenes, or heteroarenes, and the cycloalkanes, heterocycles, arenes, or heteroarenes contain halogens, OH, CN, and C １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ３ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ４ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ３ and R ４ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes and 5-14 membered heterocycles, and the cycloalkanes and heterocycles are composed of halogens, OH, CN, and C. １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ５ H, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Achille, SO ２ -C １ -C ６ Selected from alkyls and 4- to 10-membered heterocyclines, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocycline is a halogen, oxo, OH, CN, or C １ -C ６ Alkoxy, C ３ -C １０ Optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups; Each R ９ is halogen, OH, C １ -C ６ Alkyl, C １ -C ６ Independently selected from alkoxy, the alkyl or alkoxy is optionally substituted with one or more halogens, OH groups; or Two R's ９ They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R ５ and R ９ These, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; n is an integer selected from 0, 1, and 2.

8. The aforementioned compound is of formula (V): 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof. [In the formula, R １ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ２ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; or R １ and R ２ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes, 5-14 membered heterocycles, arenes, or heteroarenes, and the cycloalkanes, heterocycles, arenes, or heteroarenes contain halogens, OH, CN, and C １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ３ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ４ H, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ３ -C １０ Cycloalkoxy, C ２ -C ６ Alkenil, C ２ -C ６ Selected from alkynyl, heterocyclic, aryl, and heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocyclic, cycloalkyl, aryl, or heteroaryl is a halogen, OH, or NH ２ , CN, C １ -C ６ Alkyl, C １ -C ６ Alkoxy, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Optionally substituted with one or more substituents independently selected from alkynyl, heterocyclic, aryl, and heteroaryl groups; R ３ and R ４ These atoms, together with the atoms to which they are bonded and any intervening atoms, form 5-8 membered cycloalkanes and 5-14 membered heterocycles, and the cycloalkanes and heterocycles are composed of halogens, OH, CN, and C. １ -C ６ Alkyl, C １ -C ６ Optionally substituted with one or more substituents independently selected from the alkoxy; R ５ H, C １ -C ６ Alkyl, C ３ -C １０ Cycloalkyl, C ２ -C ６ Alkenil, C ２ -C ６ Alkinyl, C １ -C ６ Achille, SO ２ -C １ -C ６ Selected from alkyls and 4- to 10-membered heterocyclines, wherein the alkyl, cycloalkyl, alkenyl, alkynyl, acyl, or heterocycline is a halogen, oxo, OH, CN, or C １ -C ６ Alkoxy, C ３ -C １０ Optionally substituted with one or more substituents independently selected from cycloalkyl and aryl groups; R ６ H, C １ -C ６ Alkyl, C １ -C ６ Selected from alkyl-C(O)- and aryl, the alkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, CN, and OH; Each R ９ is halogen, OH, C １ -C ６ Alkyl, C １ -C ６ Independently selected from alkoxy, the alkyl or alkoxy is optionally substituted with one or more halogens, OH groups; or Two R's ９ They, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; or R ５ and R ９ These, together with the atoms to which they are bonded and any intervening atoms, form a 5-6 member heterocycle; n is an integer selected from 0, 1, and 2; However, R ５ When R is methyl, ６ is H or CH ３ It's not CO- either.

9. The following compounds are selected: or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

10. A pharmaceutical composition comprising a 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 according to claim 10, further comprising one or more additional pharmaceutically active agents.

12. A method for inhibiting intracellular NLRP3, comprising contacting the cells 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, wherein the contact is in vitro or in vivo.

14. A method for treating or preventing a disease or disorder related to NLRP3, comprising administering a compound according to any one of claims 1 to 9, or a pharmaceutical composition according to claim 10 or 11, to a subject in need thereof.

15. The aforementioned diseases or disorders include acne (ACNE); hereditary translucent papulacarkeratosis; adult-onset Still's disease (AOSD); Eicardi-Goutier syndrome (AGS); familial Alzheimer's disease type 1 (AD1); amyloidosis; amyotrophic lateral sclerosis type 1 (ALS1); anthraxosis; aphthous stomatitis; arthritis; arthropathy; aseptic meningitis; asthma (ASTHMA); cardiovascular autoimmune diseases; gastrointestinal autoimmune diseases; autoinflammatory syndromes; Behçet's syndrome (BD); Blau syndrome (BLAUS); body mass index trait locus 11 (BMIQ11); bone inflammatory diseases; Cerebral edema; brucellosis; candidiasis; cervical lymphadenitis; chondrocalcification; chronic meningitis; chronic relapsing polymyelitis (CRMO); chronic urticaria; CINCA syndrome (CINCA); conjunctival diseases; conjunctivitis; connective tissue diseases; corneal diseases; coronavirus infection; COVID-19; Crohn's disease; cryopyrin-associated periodic syndromes (CAPS); cystic fibrosis (CF); autosomal dominant hearing loss type 34 (DFNA34) with or without inflammation; dermatitis; diabetes mellitus; diabetic encephalopathy; rash; eye diseases; familial cold autoinflammatory syndrome (FCU); familial cold autoinflammatory syndrome 1 FCAS type 1; Familial cold autoinflammatory syndrome type 2 (FCAS 2); Familial Mediterranean fever (FMF); Gout (GOUT); Hereditary periodic fever syndromes; Hidradenitis; Suppurative hidradenitis; Essential hypertension (EHT); Hyperuricemia; Autosomal dominant intellectual disability type 30 with speech delay and behavioral abnormalities (MRD 30); Interstitial lung disease type 2 (ILD 2); Hereditary keratitis (KERH); Hereditary transient corneal endotheliitis (KEFH); Lipoprotein quantitative trait locus (LPAQTL); Lymph node disorders; Age-related macular degeneration type 1 (ARMD 1); Malaria (CM); Meningitis; Mevalonic aciduria (MEVA) Mackle-Wells syndrome (MWS); Mycobacterium cansasi; Myocardial infarction (MCI1); Kidney stones; Neurological disorders; Non-alcoholic steatohepatitis (NASH); Optic neuropapillitis; Osteomyelitis; Osteoporosis (OSTEOP); Otitis media (OMS); Papilledema; Pericardial effusion; Pericardial disease; Pharyngitis; Polyradiculopathy; Primary bacterial infections; Proteasome-associated autoinflammatory syndrome type 1 (PRAAS1); Pyoderma; Pyoderma gangrenosum; Septic arthritis, pyoderma gangrenosum, and acne (PAPAS); Respiratory failure; Salmonellosis; Schnitzler syndrome; Sebaceous gland disorders; Sensorineural hearing loss;The method according to claim 14, selected from the group consisting of serum amyloid A amyloidosis; silicosis; skin diseases; stomatitis; type 2 diabetes (T2D); ureteral diseases; urticaria (HIVES); vulvovaginal candidiasis; and Wells syndrome.

16. The method according to claim 14, wherein the disease or disorder is an autoimmune disease.

17. The method according to claim 14, wherein the disease or disorder is an inflammatory disease.

18. The method according to claim 14, wherein the disease or disorder is coronavirus infection.

19. The method according to any one of claims 12 to 18, wherein the subject is a mammal.

20. The method according to claim 19, wherein the subject is a human.

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