Pyridazine compounds for inhibiting NLRP3

Abstract

To develop small molecules for modulating NLRP3 activity to treat various diseases and disorders because it is preclinically demonstrated that NLRP3 hyperactivation plays a critical role in many inflammatory and degenerative diseases including NASH, atherosclerosis and other cardiovascular diseases, Alzheimer's disease, Parkinson's disease, diabetes, gout, and numerous other autoinflammatory diseases.SOLUTION: The present disclosure relates to inhibitors of NLRP3 useful in the treatment of diseases and disorders inhibited by the protein and having the formula (I).SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 171,932, filed April 7, 2021, and U.S. Provisional Patent Application No. 17 / 528,928, filed November 17, 2021, the entire contents of each of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to inhibitors of NLR family pyrin domain-containing 3 (NLRP3) protein. The inhibitors described herein are useful for treating diseases and disorders associated with the regulation of NLRP3 protein. Specifically, the present invention relates to compounds and pharmaceutical compositions that inhibit NLRP3, methods of treating diseases and disorders associated with NLRP3 using the compounds and pharmaceutical compositions, and methods of synthesizing the compounds and compositions. [Background technology]

[0003] The innate immune response is mediated by different types of receptors called pattern recognition receptors (PRRs). PRRs recognize the presence of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Engagement of these receptors triggers the activation of downstream inflammatory pathways that help resolve damage. However, in many cases, this activation can become uncontrollable, leading to disease.

[0004] Inflammasomes represent a class of PRRs that are critical components of the innate immune response. Inflammasome activation triggers a cascade of events that release IL-1β, IL-18, and promote an inflammatory form of cell death called pyroptosis, which is induced by activation of gasdermins. Pyroptosis is a unique form of inflammatory cell death that leads to the release of not only cytokines but also other intracellular components that promote broader immune responses of both the innate and adaptive immune systems. Thus, inflammasome activation is a key regulator of the inflammatory cascade. Summary of the Invention [Problem to be solved by the invention]

[0005] NLRP3 is the best-characterized inflammasome and has been shown to be important in innate immune and inflammatory responses. While some other NLR complexes, such as NLRC4, are activated under very specific circumstances, NLRP3 can be activated by numerous stimuli and should be considered a sensor of intracellular homeostatic imbalance. Therefore, its precise function is essential. In addition to its role in host immune defense, dysregulation of NLRP3 has been implicated in the pathogenesis of many inflammatory disorders. These include genetic disorders such as cryopyrin-associated periodic syndromes (CAPS), which are caused by gain-of-function mutations in the NLRP3 gene, as well as many common neurological and systemic diseases. Importantly, preclinical evidence has demonstrated that overactivation of NLRP3 plays a key role in numerous inflammatory and degenerative diseases, including NASH, atherosclerosis and other cardiovascular diseases, Alzheimer's disease, Parkinson's disease, diabetes, gout, and many other autoinflammatory diseases. Thus, there is an unmet need in the art to develop small molecules to modulate NLRP3 activity to treat various diseases and disorders. [Means for solving the problem]

[0006] In a first aspect, the present disclosure provides, inter alia, a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ), O, S, or C(R b )(R c ) and R ais hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R a But R 1 cyclization to form a 3- to 8-membered heterocycloalkyl; R b is hydrogen or C1-C6 alkyl; R c is hydrogen or C1-C6 alkyl, or R b and R c together with the atom to which they are attached form a C3-C8 cycloalkyl; Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O)t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(3-8 membered heterocycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(5- to 9-membered heteroaryl), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of halo, CN, C1-C6 alkyl, -R 4 OR 5 , -NR 5 R 6 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; or R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a is hydrogen, deuterium, C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; t is 1 or 2, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0007] Another aspect of the present disclosure is a compound of formula I': [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ), O, S, or C(R b )(R c ) and R a is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R a But R 1 cyclization to form a 3- to 8-membered heterocycloalkyl; R bis hydrogen or C1-C6 alkyl; R c is hydrogen or C1-C6 alkyl, or R b and R c together with the atom to which they are attached form a C3-C8 cycloalkyl; Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) n -(C3-C10 cycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(3- to 8-membered heterocycloalkyl), or -(CH2) n -(5- to 9-membered heteroaryl), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of halo, CN, C1-C6 alkyl, -NR 5 R 6 , -R 4 OR 5 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a is hydrogen, deuterium, C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; t is 1 or 2, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0008] Another aspect of the present disclosure is a compound of formula I″: [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ), O, S, or C(R b )(R c ) and R a is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R a But R 1 cyclization to form a 3- to 8-membered heterocycloalkyl; R b is hydrogen or C1-C6 alkyl; R c is hydrogen or C1-C6 alkyl, or R b and R c together with the atom to which they are attached form a C3-C8 cycloalkyl; Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(3- to 8-membered heterocycloalkyl), or -(CH2) n -(5- to 9-membered heteroaryl), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5)2, and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of halo, CN, C1-C6 alkyl, -NR 5 R 6 , -R 4 OR 5 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where R 4 Only, -R 4 OR 5 and R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; t is 1 or 2, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0009] Another aspect of the present disclosure is a compound of formula II: [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(3- to 8-membered heterocycloalkyl), or -(CH2) n -(5- to 9-membered heteroaryl), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of halo, CN, C1-C6 alkyl, -NR 5 R 6 , -R 4 OR 5 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; or R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R2a is hydrogen, deuterium, C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; t is 1 or 2, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0010] In some aspects, the disclosure provides compounds obtained by or obtained by a method for preparing a compound described herein (e.g., a method comprising one or more steps described in Schemes 1, 2, and 3).

[0011] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

[0012] In some aspects, the present disclosure provides intermediates described herein that are suitable for use in the methods for preparing the compounds described herein (e.g., the intermediates are selected from the intermediates described in Examples 1 and 2).

[0013] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0014] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0015] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[0016] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0017] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0018] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0019] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychological disorder, graft-versus-host disease, allodynia, or an NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3.

[0020] In some embodiments, the disease or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0021] In some embodiments, the kidney disease is an acute kidney disease, a chronic kidney disease, or a rare kidney disease.

[0022] In some embodiments, the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0023] In some embodiments, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0024] In some embodiments, the NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0025] In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease.

[0026] In some aspects, the disclosure provides methods of preparing the compounds of the disclosure.

[0027] In some aspects, the disclosure provides methods of preparing compounds comprising one or more of the steps described herein.

[0028] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular also includes the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, 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 admitted to be prior art to the claimed invention. In case of conflict, the present specification, including definitions, will control. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. In the event of a conflict between the chemical structure and the name of a compound disclosed herein, the chemical structure will control.

[0029] Other features and advantages of the present disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION OF THE INVENTION

[0030] The present disclosure relates to pyridazine and phthalazine derivatives, pharmaceutically acceptable salts, solvates, clathrates, hydrates, single stereoisomers, mixtures of stereoisomers, or racemic mixtures of stereoisomers thereof, which can inhibit NLRP3 activity and are therefore useful in methods of treating the human or animal body. The disclosure also relates to processes for the preparation of these compounds, pharmaceutical compositions containing them, and their use in treating diseases in which NLRP3 is involved, such as inflammation, autoimmune diseases, cancer, infectious diseases, diseases or disorders of the central nervous system, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic system diseases, rheumatic diseases, psychological diseases, graft-versus-host disease, allodynia, or NLRP3-associated diseases in subjects determined to have a germline or somatic non-silent mutation in NLRP3.

[0031] definition Unless otherwise stated, the following terms used in the specification and claims have the following meanings, as set forth below.

[0032] As used herein, "alkyl," "C1, C2, C3, C4, C5, or C6 alkyl," or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (straight-chain) saturated aliphatic hydrocarbon groups and C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl include moieties having 1 to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl. In some embodiments, a straight-chain or branched alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight chain, C3-C6 for branched chain), and in other embodiments, a straight-chain or branched alkyl has 4 or fewer carbon atoms.

[0033] As used herein, the term "optionally substituted alkyl" refers to an unsubstituted alkyl or an alkyl having specified substituents replacing one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moiety.

[0034] As used herein, the term "alkenyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched-chain alkenyl groups. In certain embodiments, a straight-chain or branched-chain alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkenyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkenyl groups containing 3 to 6 carbon atoms.

[0035] As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

[0036] As used herein, the term "alkynyl" includes unsaturated aliphatic groups similar in length and possible substitution to the alkyl groups described above, but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl) and branched-chain alkynyl groups. In certain embodiments, a straight-chain or branched-chain alkynyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight chain, C3-C6 for branched chain). The term "C2-C6" includes alkynyl groups containing 2 to 6 carbon atoms. The term "C3-C6" includes alkynyl groups containing 3 to 6 carbon atoms. As used herein, a "C2-C6 alkenylene linker" or "C2-C6 alkynylene linker" is intended to include a C2, C3, C4, C5, or C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon group. For example, a C2-C6 alkenylene linker is intended to include C2, C3, C4, C5, and C6 alkenylene linker groups.

[0037] As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moiety.

[0038] Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include both unsubstituted moieties and moieties with one or more of the specified substituents. For example, substituted heterocycloalkyls include those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

[0039] As used herein, the term "cyano" refers to a nitrile radical (eg, --CN).

[0040] As used herein, the term "cycloalkyl" refers to a group having 3 to 30 carbon atoms (e.g., C3-C 12 , C3-C10 , or C3-C8), a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyl, only one of the rings in the cycloalkyl need be non-aromatic.

[0041] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated 3- to 8-membered monocyclic or bicyclic, 7- to 12-membered bicyclic (fused, bridged, or spiro) or 11- to 14-membered tricyclic system (fused, bridged, or spiro) having, unless otherwise specified, one or more heteroatoms (such as O, N, S, P, or Se), e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or e.g., 1, 2, 3, 4, 5, or 6 heteroatoms, independently selected from the group consisting of nitrogen, oxygen, and sulfur.Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazetanyl, and the like. Panyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexa 1,5'-furo[3,4-b]pyridin]-yl, 3'H-spiro[cyclohexane-1,1'-furo[3,4-c]pyridin]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, 5,6,7,8-tetrahydropyrido[4 ,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, 5,6-dihydro-4H-cyclopenta[b]thiophenyl, and the like.For polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl need be non-aromatic (eg, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0042] As used herein, the term "optionally substituted heterocycloalkyl" refers to an unsubstituted heterocycloalkyl having specified substituents replacing one or more hydrogen atoms on one or more carbon or heteroatoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moiety.

[0043] Unless otherwise specifically 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. When containing two aromatic rings (such as bicyclic), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl) or may be fused (e.g., naphthyl). An aryl group may be optionally substituted at any point of attachment with one or more substituents, e.g., one to five substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C-C)alkyl, (C-C)alkyl, -O-(C-C)alkenyl, -O-(C-C)alkynyl, (C-C)alkenyl, (C-C)alkynyl, -OH, -O-P(O)(OH), -OC(O)(C-C)alkyl, -C(O)(C-C)alkyl, -OC(O)O(C-C)alkyl, -NH, NH((C-C)alkyl), N((C-C)alkyl), -S(O)-(C-C)alkyl, -S(O)NH(C-C)alkyl, and -S(O)N((C-C)alkyl). Substituents may themselves be optionally substituted. Additionally, when containing two or more fused rings, aryl groups as defined herein can have a saturated or partially unsaturated ring fused to a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, 10,11-dihydro-5H-dibenzo[a,d][7]annulenyl, and the like.

[0044] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or polycyclic aromatic radical of 5 to 24 ring atoms containing one or more ring heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being C. Heteroaryl, as defined herein, also means a bicyclic heteroaromatic group in which the heteroatoms are selected from N, O, S, P, Se, or B. Heteroaryl, as defined herein, also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, Se, or B. The aromatic radicals are optionally substituted independently with one or more substituents described herein. Examples include furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolinyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triphenylmethane, and the like. Azinyl, imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indole benzo[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, benzo[de]isoquinolinyl, benzo ...quinazolinyl, benzo[de]isoquinolinyl, benzo[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, benzo[de]isoquinolinyl, benzo[de]isoquinolinyl, benzo[4,3-b][1,6]naphthyridinyl, benzo[de]isoquinolinyl, benzo[4,3-b]pyrazinyl, quinazolinyl, benzo[de]isoquinolinyl, benzo[de]isoquinolinyl, benzo[4,3-b][1,6]naphthyridinyl, benzo[de]isoquinolinyl, benzo[de]isoquinolinyl, benzo[4,3-b][1,6]naphthyridinyl, benzo[de]isoquinolinyl, benzo[de]isoquinolinyl, benzo[4,3-b][1,6]naphthyridinyl, benzo[de]iso yl, 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]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ 2-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazolyl, benzisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4, 3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, heteroaryl groups as defined herein can have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring, for example, a 5-membered heteroaromatic ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaromatic ring containing 1 to 3 nitrogen atoms, wherein the saturated or partially unsaturated ring contains 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is optionally substituted with one or more oxo. In heteroaryl ring systems containing more than two fused rings, the saturated or partially unsaturated ring may be further fused to a saturated or partially unsaturated ring as described herein.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, oxindolyl, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydrobenzofuranyl, and the like. dro-6H-pyrido[3,2-b]pyrrolidinyl, 8H-pyrido[3,2-b]pyrrolidinyl, 1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolidine, pyrazolo[1,5-a]pyrimidin-7(4H)-onyl, 3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl, or benzo[c][1,2]oxaborol-1(3H)-olyl.

[0045] A cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may have at one or more ring positions (e.g., a ring carbon or a heteroatom such as N) a substituent as described above, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, amino The aryl and heteroaryl groups may be substituted with carbonyl, alkylthiocarbonyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. The aryl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic to form polycyclic systems (e.g., tetralin, methylenedioxyphenyl such as benzo[d][1,3]dioxol-5-yl).

[0046] As used herein, the term "substituted" means that any one or more hydrogen atoms on the specified atom are replaced with a selection from the described group, provided that the replacement does not exceed the normal valence of the specified atom and provides a stable compound. When the substituent is oxo or keto (i.e., =0), two hydrogen atoms on the atom are replaced. Keto substituents are not present in aromatic moieties. As used herein, a ring double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation from RM to a useful degree of purity and formulation into an effective therapeutic agent.

[0047] When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, such substituent may be bonded to any atom in the ring. When a substituent is listed without indicating the atom to which such substituent is bonded to the remainder of the compound of a given formula, such substituent may be bonded through any atom of such formula. Combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0048] When any variable (e.g., R) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0 to 2 R moieties, that group may also be optionally substituted with up to 2 R moieties, and R at each occurrence is selected independently of the definition of R. Also, combinations of substituents and / or variables are permissible, but only if such combinations result in stable compounds.

[0049] As used herein, the term "hydroxy" or "hydroxyl" includes groups with an --OH or --O-- group.

[0050] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0051] The terms "haloalkyl" or "haloalkoxyl" refer to an alkyl or alkoxyl substituted with one or more halogen atoms.

[0052] As used herein, the term "optionally substituted haloalkyl" refers to an unsubstituted haloalkyl having specified substituents replacing one or more hydrogen atoms on one or more hydrocarbon backbone carbon atoms. Such substituents can include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moiety.

[0053] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy groups or radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonate, phosphinate, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0054] It is understood that the present disclosure provides methods for the synthesis of compounds of any of the formulas described herein. The present disclosure also provides detailed methods for the synthesis of various disclosed compounds of the present disclosure according to the following schemes, as well as those shown in the Examples.

[0055] It should be understood that throughout this specification, when a composition is described as having, including, or comprising particular components, it is contemplated that the composition also consists essentially of or consists of the recited components. Similarly, when a method or process is described as having, including, or comprising particular process steps, the process also consists essentially of or consists of the recited processing steps. Furthermore, it should be understood that the order of steps or sequence for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be performed simultaneously.

[0056] It should be understood that the synthetic processes of the present disclosure can tolerate a wide variety of functional groups and, therefore, can employ a variety of substituted starting materials. Although the processes generally provide the desired final compound at or near the end of the entire process, in certain cases it may be desirable to further convert the compound to its pharmaceutically acceptable salt.

[0057] It will be understood that the compounds of the present disclosure can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or readily preparable intermediates by employing standard synthetic methods and procedures that are known to those skilled in the art, or that will be apparent to those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Without being limited to any one or several sources, classic texts such as Smith, M.B., March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley & Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons (1995) (incorporated herein by reference) are useful and recognized reference texts of organic synthesis known to those skilled in the art.

[0058] Those skilled in the art will note that the order of certain steps, such as the introduction and removal of protecting groups, may be varied during the reaction sequences and synthetic schemes described herein. Those skilled in the art will recognize that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups may also be used to distinguish between similar functional groups in a molecule. Lists of protecting groups and methods for introducing and removing these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0059] Unless otherwise specified, any reference to a method of treatment or prevention should be understood to include the use of the compounds to provide treatment or prevention as described herein. Unless otherwise specified, any reference to a method of treatment or prevention should further be understood to include the use of the compounds for the preparation of a medicament for treating or preventing such a condition. Treatment or prevention includes treatment or prevention in humans or non-human animals, including rodents and other disease models.

[0060] Unless otherwise specified, any description of a method of treatment should be understood to include the use of a compound to provide treatment as described herein. Unless otherwise specified, any description of a method of treatment should further be understood to include the use of a compound to prepare a medicament for treating such a condition. Treatment includes the treatment of humans or non-human animals, including rodents and other disease models. As used herein, the term "subject" is interchangeable with the term "subject in need thereof," and both refer to a subject having a disease or at risk of developing a disease. "Subject" includes mammals. A mammal can be, for example, a human or a suitable non-human mammal, such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep, or pig. In one embodiment, the mammal is a human. A subject in need thereof can be a subject that has previously been diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof can also be a subject suffering from a disease or disorder disclosed herein. Alternatively, the subject in need thereof may be a subject at increased risk of developing such a disease or disorder compared to the general population (i.e., a subject who is more likely to develop such a disorder compared to the general population). The subject in need thereof may have a refractory or resistant disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need of treatment has tried and failed all known effective treatments for the disease or disorder disclosed herein. In some embodiments, the subject in need of treatment has received at least one prior treatment.

[0061] As used herein, the term "treating" or "treat" describes the management and care of a patient for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the present disclosure, or a pharmaceutically acceptable salt, polymorph, or solvate thereof, to alleviate the symptoms or complications of the disease, condition, or disorder, or to eliminate the disease, condition, or disorder. The term "treating" can also include treatment of cells in vitro or in an animal model. It should be understood that reference to "treating" or "treat" includes the alleviation of established symptoms of a condition. Thus, "treating" or "treatment" of a disease state, disorder, or condition includes: (1) preventing or delaying the appearance of clinical symptoms of the disease state, disorder, or condition that develop in a human who is or may be affected by the disease state, disorder, or condition but who has not yet experienced or exhibited clinical or non-clinical symptoms of the disease state, disorder, or condition; (2) inhibiting the disease state, disorder, or condition, i.e., arresting, alleviating, or delaying the onset of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or non-clinical symptom thereof; or (3) alleviating or attenuating the disease, i.e., causing regression of the disease state, disorder, or condition or at least one clinical or non-clinical symptom thereof.

[0062] It is to be understood that the compounds of the present disclosure, or pharmaceutically acceptable salts, polymorphs, or solvates thereof, can be or may be used to prevent the associated disease, condition, or disorder, or to identify suitable candidates for such purposes.

[0063] As used herein, the terms "preventing," "prevent," or "protecting against" describe reducing or eliminating the onset of symptoms or complications of such disease, condition, or disorder.

[0064] It should be understood that those skilled in the art may refer to general reference texts for detailed descriptions of known techniques discussed herein or equivalent techniques. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, NY; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, NY; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition (1990). These texts may, of course, also be referenced when making or using embodiments of the present disclosure.

[0065] It should be understood that the present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

[0066] As used herein, the term "pharmaceutical composition" refers to a formulation containing a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. The unit dosage form may be in any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salt, hydrate, solvate, or isomer) in a unit dose composition is an effective amount and varies according to the specific treatment involved. Those skilled in the art will understand that routine modifications to dosage may be necessary depending on the age and condition of the patient. The dosage also depends on the route of administration. Various routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and any required preservatives, buffers, or propellants.

[0067] As used herein, the term "pharmaceutically acceptable" refers to compounds, anions, cations, materials, compositions, carriers, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0068] As used herein, the term "pharmaceutically acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable, useful in the preparation of pharmaceutical compositions, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. As used in the specification and claims, "pharmaceutically acceptable excipient" includes both one and more than one such excipient.

[0069] It should be understood that the pharmaceutical compositions of the present disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may contain the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; an antibacterial agent such as benzyl alcohol or methylparaben; an antioxidant such as ascorbic acid or sodium bisulfite; a chelating agent such as ethylenediaminetetraacetic acid; a buffer such as acetate, citrate, or phosphate, and an agent for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted using acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic.

[0070] It should be understood that the compound or pharmaceutical composition of the present disclosure can be administered to a subject by many of the well-known methods currently used for chemotherapy treatment.For example, the compound of the present disclosure can be injected into the bloodstream or body cavity, or orally administered, or applied through the skin using a patch.The selected dose should be sufficient to be effective treatment, but not so high as to cause unacceptable side effects.The condition (for example, the disease or disorder disclosed herein) and the state of the patient's health should preferably be closely monitored during and after treatment for a considerable period of time.

[0071] As used herein, the term "therapeutically effective amount" refers to an amount of a pharmaceutical agent to treat, alleviate, or prevent a specified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The precise effective amount for a subject will vary depending on the subject's weight, size, and health; the nature and extent of the condition; and the therapeutic or combination therapy selected for administration. The therapeutically effective amount for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.

[0072] It is understood that for any compound, the therapeutically effective amount can be estimated initially, for example, in cell culture assays of neoplastic cells or in animal models, usually rats, mice, rabbits, dogs, or pigs. Animal models can also be used to determine appropriate concentration ranges and routes of administration. Such information can then be used to determine useful doses and routes for administration in humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED 50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 / ED 50 It can be expressed as a ratio. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage can vary within this range depending on the dosage form used, sensitivity of the patient, and the route of administration.

[0073] Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's general health, the subject's age, weight, and sex, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance / response to therapy.

[0074] Pharmaceutical compositions containing the active compounds of the present disclosure can be prepared by a generally known method, for example, by conventional mixing, dissolving, granulating, dragee-making, suspending, emulsifying, encapsulating, encapsulating or lyophilizing process. Pharmaceutical compositions can be formulated by a conventional method using one or more pharmaceutically acceptable carriers, including excipients and / or adjuvants that facilitate the processing of active compounds into pharmaceutical preparations that can be used.Of course, the appropriate formulation depends on the selected route of administration.

[0075] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble), or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. The composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

[0076] Sterile injection solution can be prepared by incorporating the required amount of active compound in suitable solvent, and optionally with one or combination of the above-mentioned components, and then sterile filtered.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains basic dispersion medium and other components that are required from the above-listed ones.For the sterile powder that is used to prepare sterile injection solution, the preparation method is vacuum drying and freeze drying, and obtain the powder of active compound plus any additional desired components from the solution that has been previously sterile filtered.

[0077] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is orally applied, swished, expectorated, or swallowed. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, primogel, or corn starch; a lubricant such as magnesium stearate or sterote; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0078] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, eg, a gas such as carbon dioxide, or a nebulizer.

[0079] Systemic administration can also be via transmucosal or transdermal means. For transmucosal or transdermal administration, a penetrant appropriate to the barrier to be permeated is used in the formulation. Such penetrants are generally known in the art, and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated into ointments, salves, gels, or creams as generally known in the art.

[0080] The active compounds can be prepared with pharmaceutically acceptable carriers that protect the compound against rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparing such formulations will be apparent to those skilled in the art. Materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies against viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0081] It is particularly advantageous to formulate oral or parenteral compositions into dosage unit form for ease of administration and uniformity of dosage.As used herein, dosage unit refers to a physically discrete unit suitable as a single dose for the subject to be treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect together with necessary pharmacological carrier.The specification of dosage unit form of the present disclosure is determined and directly depends on the unique properties of active compound and the specific therapeutic effect to be achieved.

[0082] In therapeutic applications, dosages of pharmaceutical compositions used in accordance with the present disclosure will vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or attending physician administering the treatment, among other factors that will affect the selected dosage. Generally, dosages should be sufficient to cause a delay, preferably regression, of symptoms of the diseases or disorders disclosed herein, and preferably complete regression of the disease or disorder. Dosages can range from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of a pharmaceutical agent is an amount that provides an objectively identifiable improvement as noted by a clinician or other qualified observer. Improved survival and growth indicate regression. As used herein, the term "dose-effective manner" refers to the amount of active compound that produces the desired biological effect in a subject or cell.

[0083] It will be appreciated that the pharmaceutical compositions may be included in a container, pack, or dispenser together with instructions for administration.

[0084] For compounds of the present disclosure that are capable of further forming salts, it should be understood that all of these forms are also contemplated within the scope of the claimed disclosure.

[0085] As used herein, the term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present disclosure, in which the parent compound is modified by making its acid or base salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, etc. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, glycolariolsanilic acid, hexylresorcylic acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, hydroxymaleic acid, hydroxynaphthoic acid, isethionic acid, lactic acid, lactobionic acid, laurylsulfonic acid, These include, but are not limited to, those derived from inorganic and organic acids selected from maleic acid, malic acid, mandelic acid, methanesulfonic acid, napsylic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, sulfamic acid, sulfanilic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and commonly occurring amino acids such as glycine, alanine, phenylalanine, arginine, and the like.

[0086] In some embodiments, the pharmaceutically acceptable salt is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a diethylamine salt, a choline salt, a meglumine salt, a benzathine salt, a tromethamine salt, an ammonia salt, an arginine salt, or a lysine salt.

[0087] Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, muconic acid, etc. The present disclosure also encompasses salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., either an alkali metal ion, alkaline earth ion, or aluminum ion, or when an organic base, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like, is coordinated. It is understood that in the salt form, the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, for example, 3:1, 2:1, 1:2, or 1:3.

[0088] It should be understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) or crystal forms (polymorphs) defined herein of the same salt.

[0089] The compound, or a pharmaceutically acceptable salt thereof, may be administered orally, nasally, transdermally, pulmonary, inhalation, buccal, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, and parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain administration routes.

[0090] The dosage regimen utilizing the compound is selected according to various factors, including the type, species, age, weight, sex, and medical condition of the patient, the severity of the condition to be treated, the route of administration, the patient's renal and hepatic function, and the particular compound or salt thereof used. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progression of the condition. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to counter or arrest the progression of the condition.

[0091] Techniques for formulating and administering the disclosed compounds of the present disclosure can be found in Remington: the Science and Practice of Pharmacy, 19th edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein and their pharmaceutically acceptable salts are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents, and sterile aqueous or organic solutions. The compound will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

[0092] Unless otherwise indicated, all percentages and ratios used herein are by weight. Other features and advantages of the present disclosure will be apparent from the different examples. The examples provided illustrate different components and methodologies useful for implementing the present disclosure. These examples do not limit the claimed disclosure. Based on the present disclosure, one skilled in the art will be able to identify and employ other components and methodologies useful for implementing the present disclosure.

[0093] In the synthetic schemes described herein, compounds may be shown in one particular configuration for simplicity. Such a particular configuration should not be construed as limiting the disclosure to one or another isomer, tautomer, positional isomer, or stereoisomer, and does not exclude mixtures of isomers, tautomers, positional isomers, or stereoisomers, but it should be understood that a given isomer, tautomer, positional isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, positional isomer, or stereoisomer.

[0094] All publications and patent documents cited herein are incorporated by reference as if each such publication or document was specifically and individually indicated to be incorporated herein by reference. Citation of publications and patent documents is not intended as an admission that any is pertinent prior art, nor is it any admission as to the contents or date thereof. While the invention has now been described by way of written description, those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and examples which follow are for purposes of illustration and not limiting the scope of the claims which follow.

[0095] As used herein, the phrase "compounds of the present disclosure" refers generically and specifically to compounds disclosed herein.

[0096] Compounds of the Disclosure In one aspect, the present disclosure provides, inter alia, a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ), O, S, or C(R b )(R c ) and R ais hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R a But R 1 cyclization to form a 3- to 8-membered heterocycloalkyl; R b is hydrogen or C1-C6 alkyl; R c is hydrogen or C1-C6 alkyl, or R b and R c together with the atom to which they are attached form a C3-C8 cycloalkyl; Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O)t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(3-8 membered heterocycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(5- to 9-membered heteroaryl), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, and is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of halo, CN, C1-C6 alkyl, -R 4 OR 5 , -NR 5 R 6 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; or R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a is hydrogen, deuterium, C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; t is 1 or 2, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0097] In some embodiments, the compound is a compound of formula (I), or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ) or O, R a is hydrogen or C1-C6 alkyl; Y is a 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, -R 4 OR 5 , -R 4 SR 6 , or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, -(CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(3-8 membered heterocycloalkyl), -(CH2) n -(C6-C 10 aryl), or -(CH2) n -(5-9 membered heteroaryl), including C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from one or more of halo, CN, C1-C6 alkyl, or -R 4 OR 5 is replaced by R 2 is hydrogen or C1-C6 alkyl optionally substituted with one or more halo; R 3 is hydrogen or C1-C6 alkyl optionally substituted with one or more halo, or R 2 and R 3 together with the atoms to which they are attached, C3-C8 cycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, C3-C8 cycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a But it's a halo, R 4 is a bond or C1-C6 alkyl; R 5 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, wherein alkyl is optionally substituted with one or more D; n is 0, 1, 2, 3, or 4, but However, R 1is a compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, with the proviso that: is not a C2 alkyl or C4 alkyl substituted with morpholinyl.

[0098] In some embodiments, the compound is a compound of formula (I'): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X, Y, and R 1 is described herein as shown in formula I', R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a is hydrogen, deuterium, C1-C6 alkyl, halo, or C1-C6 haloalkyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0099] In some embodiments, the compound is a compound of formula (I″): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X, Y, and R 1 is described herein as shown in formula I″; R 2is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 P(O)(R 5 )2, or -R 4SF5, wherein C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0100] In some embodiments, the compound of formula (I) is a compound of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R 1 , R 2 , and R 3 is a compound described herein as shown in Formula II, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0101] In some embodiments, the compound of formula (II) is a compound of formula (II-a): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R 2a , R 4 , and R 5 is described herein as shown in Formula II, R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10aryl, or 5- to 9-membered heteroaryl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein:

[0102] In some embodiments, the compound of formula (II) is a compound of formula (II-b): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R 2a , R 4 , and R 5 is described herein as shown in Formula II, R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atoms to which they are attached, optionally one or more R 2a or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, which forms a C3-C8 cycloalkyl substituted with

[0103] In some embodiments, the compound of Formula (II) is a compound of Formula (II-c): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R 2a , R 4 , and R5 is described herein as shown in Formula II, R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atoms to which they are attached, optionally one or more R 2a or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, which forms a 3- to 8-membered heterocycloalkyl substituted with

[0104] In some embodiments, the compound of Formula (II) is a compound of Formula (II-d): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R 2a , R 4 , and R 5 is described herein as shown in Formula II, R 1 But there are more than one halo, -R 4 OR 5 , a C1-C6 alkyl substituted with a 3- to 8-membered heterocycloalkyl, or a 5- to 9-membered heteroaryl; R 2 and R 3 together with the atoms to which they are attached, optionally one or more R 2a C6-C substituted with 10 aryl-forming compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0105] In some embodiments, the compound of Formula (II) is a compound of Formula (II-d-1): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R 2a , R 4 , and R 5 is described herein as shown in Formula II, R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atoms to which they are attached, optionally one or more R 2a or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, which forms a 5-9 membered heteroaryl substituted with

[0106] In some embodiments, the compound of Formula (II) is a compound of Formula (II-e): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 2a , R 4 , and R 5 is described herein as shown in Formula II, R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 However, along with the atoms to which they are attached, C6-C 10aryl or 5-9 membered heteroaryl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by Y is a 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound is substituted with one, two, or three of any of:

[0107] In some embodiments, the compound of formula (II) is a compound of formula (II-f): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 2a , R 4 , and R 5 is described herein as shown in Formula II, R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; Y is a 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR5 or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound is substituted with one, two, or three of any of:

[0108] In some embodiments, the compound of formula (II) is a compound of formula (II-g): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 2a , R 4 , and R 5 is described herein as shown in Formula II, R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; Y is a 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound is substituted with one, two, or three of any of:

[0109] In some embodiments, the compound of Formula (II) is a compound of Formula (II-h): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Each R2a is hydrogen or deuterium, R 1 is C1-C6 alkyl, -(CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(3- to 8-membered heterocycloalkyl), or -(CH2) n -(5-9 membered heteroaryl), wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally selected from one or more of halo, CN, C1-C6 alkyl, C6-C 10 Aryl, -NR 5 R 6 , or -R 4 OR 5 is replaced by Y is C6-C 10 aryl, optionally selected from one or more of halo, C1-C6 alkyl, C1-C6 haloalkyl, or -R 4 OR 5 is replaced by R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 and R 6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; n is 0, 1, 2, 3, or 4, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0110] In some embodiments, the compound of formula (II) is a compound of formula (II-i): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 2a , R 4 , and R 5 is described herein as shown in Formula II, R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; Y is a 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound is substituted with one, two, or three of any of:

[0111] In some embodiments, the compound of formula (II) is a compound of formula (II-j): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 2a , R 4 , and R 5 is described herein as shown in Formula II, R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; Y is a 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound is substituted with one, two, or three of any of:

[0112] For compounds of formula (I), (I'), (I"), or (II), X, R a , R b , R c , Y, R 1 , R 2 , R 3 , R 2a , R 4 , R 5 , R 6 , R 7 , R 8 , n, or t may each be selected from groups described herein, where applicable; X, R a , R b , R c , Y, R 1 , R 2 , R 3 , R 2a , R 4 , R 5 , R 6 , R 7 , R 8 Any group described herein for any of X, R, n, or t, as applicable, may be a , R b , R c , Y, R 1 , R 2 , R 3 , R 2a , R 4 , R 5 , R 6 , R 7 , R 8 It is understood that one or more of the remaining moieties of , n, or t may be combined with any group described herein.

[0113] Variable X, Y, R a , R b , and R c In some embodiments, X is N(R a ), O, S, or C(R b )(R c )

[0114] In some embodiments, X is N(R a )

[0115] In some embodiments, X is O.

[0116] In some embodiments, X is S.

[0117] In some embodiments, X is C(R b )(R c )

[0118] In some embodiments, R a is H.

[0119] In some embodiments, R a is C1-C6 alkyl. In some embodiments, R 1 is methyl.

[0120] In some embodiments, Y is 3-8 membered heterocycloalkyl, C-C 10 aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 is optionally replaced by

[0121] In some embodiments, Y is 3-8 membered heterocycloalkyl, C-C 10aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 The aryl or 5- to 9-membered heteroaryl may be one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 is replaced by .

[0122] In some embodiments, Y is 3-8 membered heterocycloalkyl, C-C 10 aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 An aryl or 5- to 9-membered heteroaryl is selected from the group consisting of one C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 is replaced by .

[0123] In some embodiments, Y is 3-8 membered heterocycloalkyl, C-C 10 aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 Aryl, or 5- to 9-membered heteroaryl, is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 is replaced by two of the

[0124] In some embodiments, Y is 3-8 membered heterocycloalkyl, C-C 10 aryl, or 5-9 membered heteroaryl, 3-8 membered heterocycloalkyl, C-C 10 Aryl, or 5- to 9-membered heteroaryl, is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 It is replaced by three of the

[0125] In some embodiments, Y is one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 In some embodiments, Y is a 3-8 membered heterocycloalkyl substituted with one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 and piperidinyl substituted with

[0126] In some embodiments, Y is one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 C6-C substituted with 10 In some embodiments, Y is one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 is a phenyl substituted with

[0127] In some embodiments, Y is one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 In some embodiments, Y is a 5-9 membered heteroaryl substituted with one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 and pyridyl substituted with

[0128] In some embodiments, Y is optionally one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 C6-C 10 It is aryl.

[0129] In some embodiments, -Y is optionally one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 is a phenyl having the formula:

[0130] In some embodiments, Y is [ka] is.

[0131] In some embodiments, Y is [ka] is.

[0132] In some embodiments, Y is [ka] is.

[0133] In some embodiments, Y is [ka] is.

[0134] Variable R 2 , R 2a , and R 3 In some embodiments, R 2 is hydrogen.

[0135] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is methyl.

[0136] In some embodiments, R 3 is hydrogen.

[0137] In some embodiments, R3 is C1-C6 alkyl. In some embodiments, R 3 is methyl.

[0138] In some embodiments, R 3 is C1-C6 alkyl substituted with one or more halo. In some embodiments, R 3 is CF3.

[0139] In some embodiments, R 2 and R 3 together with the atoms to which they are attached, form C3-C8 cycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, C3-C8 cycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more R 2a is replaced by .

[0140] In some embodiments, R 2 and R 3 together with the atoms to which they are attached, form C3-C8 cycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, C3-C8 cycloalkyl, C6-C 10 An aryl or 5- to 9-membered heteroaryl may be one or more R 2a is replaced by .

[0141] In some embodiments, R 2 and R 3 together with the atoms to which they are attached, form C3-C8 cycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, C3-C8 cycloalkyl, C6-C 10 Aryl or 5- to 9-membered heteroaryl is one R 2a is replaced by .

[0142] In some embodiments, R 2a is hydrogen or deuterium.

[0143] In some embodiments, R 2a is halo. In some embodiments, R 2a is Cl.

[0144] In some embodiments, R 2 and R 3 along with the atoms to which they are attached, [ka] Form.

[0145] In some embodiments, R 2 and R 3 along with the atoms to which they are attached, [ka] Form.

[0146] In some embodiments, R 2 and R 3 along with the atoms to which they are attached, [ka] Form.

[0147] In some embodiments, R 2 and R 3 along with the atoms to which they are attached, [ka] Form.

[0148] In some embodiments, R 2 and R 3 along with the atoms to which they are attached, [ka] Form.

[0149] In some embodiments, R2 and R 3 along with the atoms to which they are attached, [ka] Form.

[0150] Variable R 1 , R 4 , R 5 , R 6 , R 7 , R 7 , R 8 , n, and t In some embodiments, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(3-8 membered heterocycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(5- to 9-membered heteroaryl), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, which is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of halo, CN, C1-C6 alkyl, -R 4 OR 5 , -NR 5 R6 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 aryl, or optionally substituted 5- to 9-membered heteroaryl.

[0151] In some embodiments, R 1 is C1-C6 alkyl, -(CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(3- to 8-membered heterocycloalkyl), or -(CH2) n -(5-9 membered heteroaryl), wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is optionally selected from one or more of halo, CN, C1-C6 alkyl, C6-C 10 Aryl, -NR 5 R 6 , or -R 4 OR 5 is replaced by .

[0152] In some embodiments, R 1 is one or more halo, C1-C6 alkyl, or -R 4 OR 5 optionally substituted with -(CH2) n -(C3-C 10 cycloalkyl).

[0153] In some embodiments, R 1 is one or more halo, C1-C6 alkyl, or -R 4 OR 5 optionally substituted with -(CH2) n -(3- to 8-membered heterocycloalkyl).

[0154] In some embodiments, R 1is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl optionally contains one or more halo, -R 4 OR 5 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 aryl, or optionally substituted 5- to 9-membered heteroaryl.

[0155] In some embodiments, R 1 is C1-C6 alkyl, optionally containing one or more halo, -R 4 OR 5 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 aryl, or optionally substituted 5- to 9-membered heteroaryl.

[0156] In some embodiments, R 1 is a 3- to 8-membered heterocycloalkyl, optionally containing one or more halo, -R 4 OR 5 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 aryl, or optionally substituted 5- to 9-membered heteroaryl.

[0157] In some embodiments, R 1 is a 3- to 8-membered heterocycloalkyl. In some embodiments, R 1 is tetrahydrofuranyl.

[0158] In some embodiments, R 1 is a 5- to 9-membered heteroaryl, optionally containing one or more halo, -R 4 OR 5 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 aryl, or optionally substituted 5- to 9-membered heteroaryl.

[0159] In some embodiments, R 1 is a 5- to 9-membered heteroaryl. In some embodiments, R 1 is furanyl.

[0160] In some embodiments, R 1 is one or more of CN, C1-C6 alkyl, or -R 4 OR 5 is C1-C6 alkyl optionally substituted with

[0161] In some embodiments, R 1 is one or more of CN, C1-C6 alkyl, or -R 4 OR 5 is a C1-C6 alkyl substituted with

[0162] In some embodiments, R 1 teeth, [ka] is.

[0163] In some embodiments, R 1 teeth, [ka] is.

[0164] In some embodiments, R 1 teeth, [ka] is.

[0165] In some embodiments, R 1 teeth, [ka] is.

[0166] In some embodiments, R 4is a bond, C-C alkyl, C-C alkenyl, or C-C alkynyl. In some embodiments, R 4 is a bond.

[0167] In some embodiments, R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl. In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is methyl.

[0168] In some embodiments, R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 It is aryl, or 5- to 9-membered heteroaryl.

[0169] In some embodiments, R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 It is aryl, or 5- to 9-membered heteroaryl.

[0170] In some embodiments, R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, or R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl.

[0171] In some embodiments, t is 1 or 2. In some embodiments, t is 1. In some embodiments, t is 2.

[0172] In some embodiments, R 1 is C1, C3, C5, or C6 alkyl.

[0173] In some embodiments, R 1 is one or more of halo, CN, C1-C6 alkyl, -R 4 OR 5 , -NR 5 R 6 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 It is a C1, C3, C5, or C6 alkyl optionally substituted with an aryl, or an optionally substituted 5-9 membered heteroaryl.

[0174] In some embodiments, R 1 is one or more of halo, CN, C1-C6 alkyl, -R 4 OR 5 , -NR 5 R 6 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 It is a C1, C3, C5, or C6 alkyl substituted with an aryl, or an optionally substituted 5- to 9-membered heteroaryl.

[0175] In some embodiments, R 1 is a C1, C3, C5, or C6 alkyl substituted with morpholinyl.

[0176] In some embodiments, R 1 is one or more of CN, C1-C6 alkyl, or -R 4 OR 5 is a C1, C3, C5, or C6 alkyl optionally substituted with

[0177] In some embodiments, R 1 is one or more of CN, C1-C6 alkyl, or -R 4 OR 5 is a C1, C3, C5, or C6 alkyl substituted with

[0178] In some embodiments, R 1 is not a C1-C6 alkyl substituted with morpholinyl.

[0179] In some embodiments, R 1 is not a C1-C3 alkyl substituted with morpholinyl.

[0180] In some embodiments, R 1 is not a C2 alkyl substituted with morpholinyl.

[0181] In some embodiments, R 1 is not a C4 alkyl substituted with morpholinyl.

[0182] In some embodiments, R 1 teeth, [ka] But not.

[0183] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0184] In some embodiments, the compound is selected from a compound set forth in Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0185] In some embodiments, the compound is selected from the compounds set forth in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the compound is selected from the compounds listed in Table 1 or Table 2.

[0187] In some embodiments, the compound is selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0188] In some embodiments, the compound is selected from the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0189] In some embodiments, the compound is selected from the compounds set forth in Table 1.

[0190] In some embodiments, the compound is selected from the compounds set forth in Table 2, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0191] In some embodiments, the compound is selected from the compounds set forth in Table 2, or a pharmaceutically acceptable salt thereof.

[0192] In some embodiments, the compound is selected from the compounds set forth in Table 2. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 2-1 Table 2-2 Table 2-3 Table 2-4 [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8]

[0193] In some embodiments, the compound is selected from any one of compounds 1-81, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0194] In some embodiments, the compound is selected from any one of compounds 1-81, or a pharmaceutically acceptable salt thereof.

[0195] In some embodiments, the compound is selected from any one of compounds 1-81.

[0196] In some embodiments, the compound is selected from any one of compounds 82-105, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0197] In some embodiments, the compound is selected from any one of compounds 82-105, or a pharmaceutically acceptable salt thereof.

[0198] In some embodiments, the compound is selected from any one of compounds 82-105.

[0199] In some embodiments, the compound is selected from any one of compounds 106-136, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0200] In some embodiments, the compound is selected from any one of compounds 106-136, or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the compound is selected from any one of compounds 106-136.

[0202] In some embodiments, the compound is selected from any one of compounds 1-4, 14-15, 27-28, 31-32, 34-54, 58-60, 62-65, 67-71, 73-74, or 77-136, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0203] In some embodiments, the compound is selected from any one of compounds 1-4, 14-15, 27-28, 31-32, 34-54, 58-60, 62-65, 67-71, 73-74, or 77-136, or a pharmaceutically acceptable salt thereof.

[0204] In some embodiments, the compound is selected from any one of compounds 1-4, 14-15, 27-28, 31-32, 34-54, 58-60, 62-65, 67-71, 73-74, or 77-136.

[0205] In some embodiments, the compound is selected from any one of compounds 55-56, 61, 72, or 75, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0206] In some embodiments, the compound is selected from any one of compounds 55-56, 61, 72, or 75, or a pharmaceutically acceptable salt thereof.

[0207] In some embodiments, the compound is selected from any one of compounds 55-56, 61, 72, or 75.

[0208] In some embodiments, the compound is selected from any one of compounds 5, 7-13, 16-26, 29-30, or 33, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0209] In some embodiments, the compound is selected from any one of compounds 5, 7-13, 16-26, 29-30, or 33, or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments, the compound is selected from any one of compounds 5, 7-13, 16-26, 29-30, or 33.

[0211] In some embodiments, the compound is selected from any one of Compound 66, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0212] In some embodiments, the compound is selected from any one of compounds 66, or a pharmaceutically acceptable salt thereof.

[0213] In some embodiments, the compound is selected from any one of compounds 66.

[0214] In some embodiments, the compound is selected from any one of compounds 6, 57, or 76, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or stereoisomer thereof.

[0215] In some embodiments, the compound is selected from any one of compounds 6, 57, or 76, or a pharmaceutically acceptable salt thereof.

[0216] In some embodiments, the compound is selected from any one of compounds 6, 57, or 76.

[0217] In some embodiments, the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, (S)-5-chloro-2-(4-((2,2 (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0218] In some embodiments, the compound is (R)-5-chloro-2-(4-((4,4-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, 5-(difluoromethyl)-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, (R)-5-chloro-2-(4-((3,3-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, (R)-2-(4-((5,5-dimethyltetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-methylphenol, or (S)-2-(4-(((4-methylmorpholin-2-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethyl)phenol.

[0219] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 1 or Table 2.

[0220] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 1.

[0221] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds set forth in Table 2.

[0222] In some aspects, the present disclosure provides compounds that are isotopic derivatives (e.g., isotopically labeled compounds) of any one of the compounds of the formulae disclosed herein.

[0223] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1 or Table 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0225] In some embodiments, the compound is an isotopic derivative of a prodrug of a compound listed in Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the compound is an isotopic derivative of a compound listed in Table 1 or Table 2.

[0227] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, or a prodrug or pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 1, or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the compound is an isotopic derivative of a prodrug of a compound listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the compounds are isotopic derivatives of the compounds listed in Table 1.

[0231] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 2, or a prodrug or pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the compound is an isotopic derivative of any one of the compounds set forth in Table 2, or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the compound is an isotopic derivative of a prodrug of a compound listed in Table 2, or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the compounds are isotopic derivatives of the compounds listed in Table 2.

[0235] It will be understood that isotopic derivatives can be prepared using any of a variety of art-recognized techniques. For example, isotopic derivatives can generally be prepared by substituting an isotopically labeled reagent for a non-isotopically labeled reagent by practicing the procedures disclosed in the schemes and / or examples described herein.

[0236] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0237] In some embodiments, an isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulae disclosed herein.

[0238] The term "isotopic derivative," as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labeled. For example, an isotopic derivative of a compound of formula (I) is isotopically enriched or labeled with one or more isotopes compared to the corresponding compound of formula (I). In some embodiments, an isotopic derivative is 2 H, 13 C. 14 C. 15 N, 18 O. 29 Si, 31 P, and 34 In some embodiments, the isotopic derivative is a compound labeled with deuterium (i.e., with respect to one or more atoms thereof) selected from S. 2 H). In some embodiments, the compound is 18 In some embodiments, the compound is a compound labeled with 123 Compounds labeled with I, 124 Compounds labeled with I, 125 Compounds labeled with I,129 Compounds labeled with I, 131 Compounds labeled with I, 135 I, or any combination thereof. In some embodiments, the compound is 33 S-labeled compounds, 34 S-labeled compounds, 35 S-labeled compounds, 36 S-labeled compounds, or any combination thereof.

[0239] 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It will be appreciated that S-labeled compounds can be prepared using any of a variety of art-recognized techniques. For example, deuterium-labeled compounds can generally be prepared by carrying out the procedures disclosed in the schemes and / or examples described herein using non-isotopically labeled reagents. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 It can be prepared by substituting S-labeled reagents.

[0240] The compound of the present invention or the compound described above 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and 36Pharmaceutically acceptable salts or solvates thereof containing one or more S atom(s) are within the scope of the present invention. 18 F, 123 I, 124 I, 125 I, 129 I, 131 I, 135 I, 32 S, 34 S, 35 S, and / or 36 S) substitution may confer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0241] For the avoidance of doubt, when a group is qualified herein by "as described herein," it is to be understood that the group includes the broadest definition first found, as well as each and every specific definition for that group.

[0242] Suitable pharmaceutically acceptable salts of the compounds of the present disclosure are, for example, acid addition salts of compounds of the present disclosure that are sufficiently basic, such as, for example, acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid methanesulfonate, or maleic acid. In addition, suitable pharmaceutically acceptable salts of compounds of the present disclosure that are sufficiently acidic are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide a pharmaceutically acceptable cation, such as, for example, methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris-(2-hydroxyethyl)amine.

[0243] It will be understood that the compounds of any one of the formulae disclosed herein, and any pharmaceutically acceptable salts thereof, include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

[0244] As used herein, the term "isomer" means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of one another are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is called a "racemic mixture."

[0245] As used herein, the term "chiral center" refers to a carbon atom bonded to four nonidentical substituents.

[0246] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having two or more chiral centers can exist as individual diastereomers or as a mixture of diastereomers, called a "diastereomeric mixture." When one chiral center is present, a stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to a considered chiral center are ranked according to the ranking rules of Cahn, Ingold, and Prelog. (Cahn et al.,Angew.Chem.Inter.Edit.1966,5,385;errata 511, Cahn et al.,Angew.Chem.1966,78,413, Cahn and Ingold,J.Chem.Soc.1951(London),612, Cahn et al.,Experientia 1956, 12, 81, Cahn, J. Chem. Educ. 1964, 41, 116).

[0247] As used herein, the term "geometric isomer" refers to diastereomers whose existence is due to hindered rotation about 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, which indicate that the groups are located on the same or opposite sides of the double bond in the molecule according to the Cahn-Ingold-Prelog sequencing rules.

[0248] It should be understood that the compounds of the present disclosure can be represented as different chiral isomers or geometric isomers.It should also be understood that when a compound has chiral isomers or geometric isomers, all isomeric forms are intended to be included in the scope of the present disclosure, and the name of the compound does not exclude any isomeric form.It should be understood that not all isomers can have the same level of activity.

[0249] It is understood that the structures and other compounds discussed in this disclosure include all atropisomers thereof. It is also understood that not all atropisomers may have the same level of activity.

[0250] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomeric sets in solution. In solutions where tautomerism is possible, a chemical equilibrium of the tautomers will be achieved. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed: keto-enol tautomerism, in which a simultaneous shift of electrons and hydrogen atoms occurs. Ring-chain tautomerism occurs as a result of the reaction of an aldehyde group (-CHO) in a sugar molecule with one of the hydroxyl groups (-OH) in the same molecule, resulting in a cyclic (ring-like) form, such as that exhibited by glucose.

[0251] It should be understood that the compounds of the present disclosure may be represented as different tautomers. It should also be understood that when a compound has tautomeric forms, all tautomeric forms are intended to be included within the scope of the present disclosure, and the name of the compound does not exclude any tautomeric form. It should be understood that certain tautomers may have a higher level of activity than other tautomers.

[0252] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog or by the way a molecule designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively) rotates the plane of polarized light. Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0253] The compounds of the present disclosure may have one or more asymmetric centers, and therefore, such compounds can be prepared as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless otherwise specified, the description or name of a particular compound in the specification and claims is intended to encompass both individual enantiomers and mixtures, racemic or otherwise. Methods for determining stereochemistry and separating stereoisomers, e.g., by synthesis from optically active starting materials or by resolution of racemic forms, are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley & Sons, New York, 2001). Some of the compounds of the present disclosure may have geometric isomeric centers (E- and Z-isomers). It should be understood that the present disclosure encompasses all optical, diastereomeric, and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity.

[0254] It should be understood that the compounds of any formula described herein include the compounds themselves, as well as their salts and solvates (if applicable). Salts can be formed, for example, between an anion and a positively charged group (e.g., amino) on the substituted compounds disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

[0255] 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 the substituted compounds 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. The substituted compounds disclosed herein also include salts thereof containing a quaternary nitrogen atom.

[0256] It should be understood that the compounds of the present disclosure, for example, salts of the compounds, can exist in either hydrated or non-hydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0257] As used herein, the term "solvate" refers to a solvent addition form that contains either stoichiometric or non-stoichiometric amounts of solvent.Some compounds tend to capture a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate.When the solvent is water, the solvate formed is a hydrate, and when the solvent is alcohol, the solvate formed is an alcoholate.A hydrate is formed by the combination of one or more molecules of water with one molecule of a substance, where water retains its molecular state as HO.

[0258] As used herein, the term "analog" refers to a compound that is structurally similar to another but differs slightly in composition (such as the replacement of one atom with an atom of a different element, or the presence or absence of a particular functional group, or the replacement of one functional group with another functional group). Thus, an analog is a compound that is similar or equivalent in function and appearance, but not in structure or origin, of the reference compound.

[0259] As used herein, the term "derivative" refers to compounds that share a common core structure and are substituted with various groups as described herein.

[0260] It should also be understood that any particular compound of the formula disclosed herein can exist in solvated form, such as hydrated form, or in unsolvated form.Suitable pharmaceutically acceptable solvates are hydrates such as hemihydrate, monohydrate, dihydrate or trihydrate.It should be understood that the present disclosure encompasses all such solvated forms that have inflammasome inhibitory activity.

[0261] It should also be understood that any particular compound of the formula disclosed herein may exhibit polymorphism, and the present 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 analysis, differential scanning calorimetry, thermogravimetry, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, solution and / or solid-state nuclear magnetic resonance spectroscopy.The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0262] Compounds of any one of the formulas disclosed herein can exist in several different tautomeric forms, and a reference to a compound of formula (I) includes all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms and only one is specifically described or shown, all other compounds are nevertheless encompassed by formula (I). Examples of tautomeric forms include the keto, enol, and enolate forms, such as in the following tautomeric pairs: keto / enol (shown below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enithiol, and nitro / aci-nitro. [ka]

[0263] The compounds of any one of the formulas disclosed herein can be administered in the form of a prodrug, which is broken down in the human or animal body to release the compounds of the present disclosure. Prodrugs can be used to modify the physical and / or pharmacokinetic properties of the compounds of the present disclosure. Prodrugs can be formed when the compounds of the present disclosure contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents in the ester or amide groups of any one of the formulas disclosed herein.

[0264] Thus, the present disclosure includes compounds of any one of the formulas disclosed herein as defined herein when made available by organic synthesis and when made available via cleavage of a prodrug thereof in the human or animal body. Thus, the present disclosure includes compounds of any one of the formulas disclosed herein produced by organic synthetic means, as well as such compounds produced in the human or animal body by metabolism of a precursor compound; compounds of any one of the formulas disclosed herein can be synthetically produced compounds or metabolically produced compounds.

[0265] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein are those that, based on sound medical judgment, are suitable for administration to the human or animal body without undesirable pharmacological activity and without undue toxicity. Various forms of prodrugs are described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder et al. (Academic Press, 1985); b) Design of Prodrugs, 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 Prodrugs", by H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al. 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.

[0266] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulas disclosed herein having a hydroxy group are, for example, in vivo cleavable esters or ethers thereof. The in vivo cleavable esters or ethers of a compound of any one of the formulas disclosed herein containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to generate the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramido cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for a hydroxy group include C1-C 10 Alkanoyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups, C-C 10 Alkoxycarbonyl groups include, for example, ethoxycarbonyl, N,N-(C1-C6 alkyl)2 carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for hydroxy groups include α-acyloxyalkyl groups, for example, acetoxymethyl and pivaloyloxymethyl.

[0267] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having a carboxy group are, for example, in vivo cleavable amides thereof, for example, amides formed with amines such as ammonia, C1-4 alkylamines such as methylamine, (C1-C4 alkyl)2-amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amino acids or esters thereof such as glycine.

[0268] Suitable pharmaceutically acceptable prodrugs of a compound of any one of the formulae disclosed herein having an amino group are, for example, in vivo cleavable amide derivatives thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example, C1-C 10 Alkanoyl groups include, for example, acetyl, benzoyl, phenylacetyl, and amides formed with substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0269] The in vivo effects of any one of the compounds of the formulas disclosed herein may be partially exerted by one or more metabolic products formed in the human or animal body after administration of any one of the compounds of the formulas disclosed herein.As described herein, the in vivo effects of any one of the compounds of the formulas disclosed herein may also be exerted by the metabolism of precursor compounds (prodrugs).

[0270] Suitable general routes for preparing the compounds of the present application can be described in Scheme 1 and Scheme 1A herein. [ka] [ka] The examples presented herein are synthesized according to the general procedures presented in Scheme 1 and Scheme 1A unless otherwise noted. Step 1 involves the S reaction between an amine (i) and an aryl dichloride (ii). N Step 1 involves a Br-Ar reaction to afford the target chloroaryl intermediate (iii). Step 2, unless otherwise indicated, involves a cross-coupling between intermediate (iii) and the desired boronic acid or boronate salt iv to produce the desired compound of Formula I. The amine i, aryl dichloride ii, and boronate or boronate salt iv are either commercially available or known in the chemical literature.

[0271] Biological assays Once produced, compounds designed, selected, and / or optimized by the above methods can be characterized using a variety of assays known to those of skill in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to, the assays described below, to determine whether they have the expected activity, binding activity, and / or binding specificity.

[0272] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it may be possible to rapidly screen the molecules described herein for activity using techniques known in the art. For example, Devlin (1998) High Throughput Screening, Marcel Dekker, and U.S. Patent No. 5,763,263 describe general methodologies for performing high-throughput screening. High-throughput assays can use one or more different assay techniques, including, but not limited to, those described below.

[0273] Various in vitro or in vivo biological assays may be suitable for detecting the effects of the disclosed compounds, including, but not limited to, enzyme activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and assays described herein.

[0274] In some embodiments, the biological assay is a PBMC NLRP3 assay. In some embodiments, PBMCs and cells are centrifuged and resuspended in medium. Cell counting can then be performed and seeded into well plates, followed by incubation. In some embodiments, assay medium can then be prepared, PBMCs can be centrifuged, serum-containing medium can be aspirated, and assay medium + LPS can then be added. In some embodiments, assay medium without LPS can be added to control wells.

[0275] In some embodiments, cells for PBMC NLRP3 assays can be primed and a concentration-response curve prepared (e.g., 1000x test compound in 100% DMSO) followed by incubation. In some embodiments, cells can then be stimulated and the plate centrifuged before being transferred to a clean well storage plate (e.g., using a mesoscale platform) for cytokine measurement.

[0276] In some embodiments, the biological assay is a human whole blood assay. In some embodiments, blood can be drawn and primed. In some embodiments, NLRP3 activation can be performed and the plate can be centrifuged. In some embodiments, IL-1β levels in the supernatant can be analyzed (e.g., using a mesoscale discovery assay (MSD K151TUK) according to the manufacturer's instructions).

[0277] In some embodiments, biological assays are described in the Examples herein.

[0278] Pharmaceutical Compositions In some aspects, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present 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 present disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1 or Table 2.

[0279] In some embodiments of the present disclosure, a pharmaceutical composition comprises a compound of Formula I described herein and a pharmaceutically acceptable carrier.

[0280] In some embodiments, the pharmaceutical composition comprises a compound of Formula I' described herein and a pharmaceutically acceptable carrier.

[0281] In some embodiments, the pharmaceutical composition comprises a compound of Formula I'' described herein and a pharmaceutically acceptable carrier.

[0282] In some embodiments, the pharmaceutical composition comprises a compound of Formula II described herein and a pharmaceutically acceptable carrier.

[0283] In some embodiments, the pharmaceutical composition comprises a compound of formula II-a described herein and a pharmaceutically acceptable carrier.

[0284] In some embodiments, the pharmaceutical composition comprises a compound of formula II-b described herein and a pharmaceutically acceptable carrier.

[0285] In some embodiments, the pharmaceutical composition comprises a compound of formula II-c described herein and a pharmaceutically acceptable carrier.

[0286] In some embodiments, the pharmaceutical composition comprises a compound of formula II-d described herein and a pharmaceutically acceptable carrier.

[0287] In some embodiments, the pharmaceutical composition comprises a compound of formula II-e described herein and a pharmaceutically acceptable carrier.

[0288] In some embodiments, the pharmaceutical composition comprises a compound of formula II-f described herein and a pharmaceutically acceptable carrier.

[0289] In some embodiments, the pharmaceutical composition comprises a compound of formula II-g described herein and a pharmaceutically acceptable carrier.

[0290] In some embodiments, the pharmaceutical composition comprises a compound of formula II-h described herein and a pharmaceutically acceptable carrier.

[0291] In some embodiments, the pharmaceutical composition comprises a compound of formula II-i described herein and a pharmaceutically acceptable carrier.

[0292] In some embodiments, the pharmaceutical composition comprises a compound of formula II-j described herein and a pharmaceutically acceptable carrier.

[0293] The compounds of the present disclosure can be formulated for oral administration in the form of tablets, capsules (each of which includes sustained- or time-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, emulsions, and the like. The compounds of the present disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0294] The formulation of the present disclosure may be in the form of an aqueous solution containing an aqueous vehicle. The aqueous vehicle component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of solubility enhancers, chelating agents, preservatives, tonicity agents, viscosity / suspension agents, buffers, and pH adjusters, and mixtures thereof.

[0295] Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, 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.

[0296] 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, edetate disodium, edetate trisodium, and edetate tetrasodium, and mixtures thereof.

[0297] Any suitable preservative can be used. Examples of preservatives include those selected from the group consisting of benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and quaternary ammonium salts such as butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0298] The aqueous vehicle may also contain a tonicity agent to adjust tonicity (osmotic pressure), which may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0299] The aqueous vehicle may contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropyl methyl cellulose, and crosslinked acrylic acid polymers (carbomers) such as acrylic acid polymers crosslinked with polyalkenyl ethers or divinyl glycols (Carbopols—e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

[0300] To adjust the formulation to an acceptable pH (typically in the pH range of 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 modifier. The pH modifier is typically a mineral acid or metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifiers are added to adjust the formulation to a target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base; depending on the formulation, the addition of either an acid or a base may be sufficient to bring the mixture into the desired pH range.

[0301] The aqueous vehicle may also contain a buffering agent to stabilize the pH. If used, the buffer is selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or salts thereof including disodium tetraborate), citrate buffers (such as citric acid or salts thereof including sodium citrate), and ε-aminocaproic acid, and mixtures thereof.

[0302] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oil, polyoxyethylated sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0303] Oral compositions generally contain an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, in which the compound in the fluid carrier is orally applied, swished, expectorated, or swallowed. Pharmaceutically compatible binders and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth, or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, primogel, or corn starch; a lubricant such as magnesium stearate or sterote; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0304] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, as defined above, in combination with a pharmaceutically acceptable diluent or carrier.

[0305] Compositions of the disclosure may be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), administration by inhalation (e.g., as a finely divided powder or liquid aerosol), administration by injection (e.g., as a finely divided powder), or parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as a suppository for rectal administration).

[0306] The compositions of the present disclosure can be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavoring agents, and / or preservatives.

[0307] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent, slow the progression of, and / or alleviate the symptoms associated with the inflammasome-associated conditions referred to herein.

[0308] An effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat, slow the progression of, and / or alleviate the symptoms associated with an inflammasome-associated condition referred to herein.

[0309] The magnitude of a dose of a compound of formula (I) for therapeutic or prophylactic purposes will naturally vary according to well-known medical principles depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0310] How to use In some aspects, the present disclosure provides a method of modulating NLRP3 activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0311] In some aspects, the present disclosure provides a method of modulating NLRP3 activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0312] In some aspects, the present disclosure provides a method of inhibiting NLRP3 activity (e.g., in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0313] In some aspects, the present disclosure provides a method of inhibiting NLRP3 activity (e.g., in vitro or in vivo), comprising contacting a cell with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

[0314] In some aspects, the present disclosure provides methods for treating or preventing a disease or disorder inhibited by NLRP3 disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0315] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0316] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder inhibited by NLRP3 disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0317] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0318] In some embodiments, the disease or disorder is a disease or disorder in which NLRP3 activity is implicated.

[0319] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychological disorder, graft-versus-host disease, allodynia, or an NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3.

[0320] In some aspects, the present disclosure provides a method of treating or preventing inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychological disease, graft-versus-host disease, allodynia, or an NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0321] In some aspects, the present disclosure provides a method of treating inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychological disease, graft-versus-host disease, allodynia, or an NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0322] In some aspects, the present disclosure provides a method of treating or preventing inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychological disease, graft-versus-host disease, allodynia, or an NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0323] In some aspects, the present disclosure provides a method of treating inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychological disease, graft-versus-host disease, allodynia, or an NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3 in a subject in need thereof, comprising administering to the subject a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0324] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in modulating NLRP3 activity (e.g., in vitro or in vivo).

[0325] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting NLRP3 activity (e.g., in vitro or in vivo).

[0326] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in modulating NLRP3 (e.g., in vitro or in vivo).

[0327] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in inhibiting NLRP3 (e.g., in vitro or in vivo).

[0328] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use as an antagonist of NLRP3 (e.g., in vitro or in vivo).

[0329] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or disorder disclosed herein.

[0330] In some aspects, the present disclosure provides a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in treating a disease or disorder disclosed herein.

[0331] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating NLRP3 activity (e.g., in vitro or in vivo).

[0332] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting NLRP3 activity (e.g., in vitro or in vivo).

[0333] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating NLRP3 (e.g., in vitro or in vivo).

[0334] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting NLRP3 (e.g., in vitro or in vivo).

[0335] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0336] In some aspects, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0337] In some aspects, the present disclosure provides uses of compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for modulating NLRP3 activity (e.g., in vitro or in vivo).

[0338] In some aspects, the present disclosure provides uses of compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for inhibiting NLRP3 activity (e.g., in vitro or in vivo).

[0339] In some aspects, the present disclosure provides uses of compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for modulating NLRP3 (e.g., in vitro or in vivo).

[0340] In some aspects, the present disclosure provides uses of compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for inhibiting NLRP3 (e.g., in vitro or in vivo).

[0341] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease or disorder disclosed herein.

[0342] In some aspects, the present disclosure provides the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for treating a disease or disorder disclosed herein.

[0343] The efficacy of the compounds of the present disclosure can be determined by industry-accepted assays / disease models according to standard practices that elucidate the same as those described in the art and are found in current general knowledge.

[0344] In some embodiments, the disease or disorder is associated with involved NLRP3 activity.

[0345] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychological disorder, graft-versus-host disease, allodynia, or an NLRP3-associated disease.

[0346] In some embodiments, the disease or disorder is inflammation.

[0347] In some embodiments, the disease or disorder is an autoimmune disease.

[0348] In some embodiments, the disease or disorder is cancer.

[0349] In some embodiments, the disease or disorder is an infectious disease.

[0350] In some embodiments, the disease or disorder is a disease or disorder of the central nervous system.

[0351] In some embodiments, the disease or disorder is a metabolic disease.

[0352] In some embodiments, the disease or disorder is a cardiovascular disease.

[0353] In some embodiments, the disease or disorder is a respiratory disease.

[0354] In some embodiments, the disease or disorder is a renal disease.

[0355] In some embodiments, the disease or disorder is a liver disease.

[0356] In some embodiments, the disease or disorder is an ocular disease.

[0357] In some embodiments, the disease or disorder is a skin disease.

[0358] In some embodiments, the disease or disorder is a lymphatic system disease.

[0359] In some embodiments, the disease or disorder is a rheumatic disease.

[0360] In some embodiments, the disease or disorder is a psychological disorder.

[0361] In some embodiments, the disease or disorder is graft-versus-host disease.

[0362] In some embodiments, the disease or disorder is allodynia.

[0363] In some embodiments, the disease or disorder is an NLRP3-associated disease.

[0364] In some embodiments, the disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychological disorder, graft-versus-host disease, allodynia, or an NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3.

[0365] In some embodiments, the disease or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0366] In some embodiments, the respiratory disease is steroid-resistant asthma.

[0367] In some embodiments, the respiratory disease is severe steroid-resistant asthma.

[0368] In some embodiments, the kidney disease is an acute kidney disease, a chronic kidney disease, or a rare kidney disease.

[0369] In some embodiments, the skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0370] In some embodiments, the rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0371] In some embodiments, the NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0372] In some embodiments, the cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease.

[0373] Route of administration The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can be administered alone as monotherapy or in addition to one or more other substances and / or treatments. Such combination treatment may be achieved by way of the simultaneous, sequential, or separate administration of the individual components of the treatment.

[0374] For example, therapeutic efficacy may be enhanced by administration of an adjuvant (i.e., by itself, an adjuvant may have only minimal therapeutic benefit, but in combination with another therapeutic agent, enhances the overall therapeutic benefit to the individual). Alternatively, by way of example only, the benefit experienced by an individual may be increased by administering a compound of Formula (I) together with another therapeutic agent (including a treatment regimen) that also has therapeutic benefit.

[0375] When the compound of the present disclosure is administered in combination with other therapeutic agents, the compound of the present disclosure does not need to be administered via the same route as the other therapeutic agents, and may be administered by different routes due to different physical and chemical properties. For example, the compound of the present disclosure may be administered orally to generate and maintain a good blood level, while the other therapeutic agents may be administered intravenously. The initial administration may be carried out according to established protocols known in the art, and then the dosage, administration mode, and administration time may be modified by those skilled in the art based on the observed effects.

[0376] The particular choice of other therapeutic agent will depend on the attending physician's diagnosis and judgment of the individual's condition and appropriate treatment protocol. According to this aspect of the disclosure, there is provided a combination for use in treating a disease involving inflammasome activity, comprising a compound of the disclosure, as defined above, or a pharmaceutically acceptable salt thereof, and another suitable agent.

[0377] According to a further aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with a suitable pharmaceutically acceptable diluent or carrier.

[0378] Any of the above pharmaceutical composition, process, method, use, medicament, and manufacturing features of the present disclosure also apply to any of the alternative embodiments of the macromolecules of the present disclosure described herein.

[0379] The compounds of the present disclosure, or pharmaceutical compositions containing these compounds, may be administered to a subject by any convenient route of administration, whether systemic / peripheral or local (ie, to the desired site of action).

[0380] Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (e.g., by patches, plasters, etc.); transmucosal (e.g., by patches, plasters, etc.); intranasal (e.g., by nasal spray); intraocular (e.g., by eye drops); pulmonary (e.g., via aerosol, e.g., through the mouth or nose, e.g., by inhalation or bolus therapy); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, e.g., subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intrathecal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; e.g., by implantation of a depot or reservoir subcutaneously or intramuscularly.

[0381] Exemplary Embodiments Exemplary Embodiment 1. A compound of Formula (I): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ), O, S, or C(R b )(R c ) and R a is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R a But R 1 cyclization to form a 3- to 8-membered heterocycloalkyl; R b is hydrogen or C1-C6 alkyl; R cis hydrogen or C1-C6 alkyl, Or R b and R c together with the atom to which they are attached form a C3-C8 cycloalkyl; Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl, or 5- to 9-membered heteroaryl may optionally contain one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; or R 2 and R 3together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a is hydrogen, C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is not absent, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; t is 1 or 2, but However, R 1is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0382] Exemplary Embodiment 2. A compound of Formula (I'): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ), O, S, or C(R b )(R c ) and R a is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R a But R 1 cyclization to form a 3- to 8-membered heterocycloalkyl; R b is hydrogen or C1-C6 alkyl; R c is hydrogen or C1-C6 alkyl, Or R b and R c together with the atom to which they are attached form a C3-C8 cycloalkyl; Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl, or 5- to 9-membered heteroaryl may optionally contain one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a is hydrogen, C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is not absent, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; t is 1 or 2, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0383] Exemplary Embodiment 3. A compound of Formula (I″): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ), O, S, or C(R b )(R c ) and R a is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R a But R 1 cyclization to form a 3- to 8-membered heterocycloalkyl; R b is hydrogen or C1-C6 alkyl; R c is hydrogen or C1-C6 alkyl, Or R b and R c together with the atom to which they are attached form a C3-C8 cycloalkyl; Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl, or 5- to 9-membered heteroaryl may optionally contain one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O)t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is absent, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; t is 1 or 2, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0384] Exemplary Embodiment 4. The compound is a compound of formula (II): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) tN(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl, or 5- to 9-membered heteroaryl may optionally contain one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4SF5, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; or R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a is hydrogen, C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is absent, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; t is 1 or 2, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0385] Exemplary embodiment 5. X is N(R a ), O, S, or C(R b )(R c) is a methyl group;

[0386] Exemplary embodiment 6. X is N(R a ) is a methyl group;

[0387] Exemplary Embodiment 7. The compound of any one of the preceding exemplary embodiments, wherein X is NH.

[0388] Exemplary Embodiment 8. The compound of any one of the preceding exemplary embodiments, wherein X is N(C1-C6 alkyl).

[0389] Exemplary Embodiment 9.R a The compound of any one of the preceding exemplary embodiments, wherein is H.

[0390] Exemplary Embodiment 10.R a The compound of any one of the preceding exemplary embodiments, wherein is methyl.

[0391] Exemplary Embodiment 11. Y is a 3-8 membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be selected from one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 The compound of any one of the preceding exemplary embodiments, substituted with:

[0392] Exemplary Embodiment 12. Y is one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 The compound of any one of the preceding exemplary embodiments, wherein R is 3-8 membered heterocycloalkyl substituted with R.

[0393] Exemplary Embodiment 13. Y is one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 The compound of any one of the preceding exemplary embodiments, wherein R is piperidinyl substituted with R.

[0394] Exemplary Embodiment 14. Y is one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 C5-C substituted with 10 The compound of any one of the preceding exemplary embodiments, wherein is aryl.

[0395] Exemplary Embodiment 15. Y is one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 The compound of any one of the preceding exemplary embodiments, wherein R is phenyl substituted with R.

[0396] Exemplary Embodiment 16. Y is one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 wherein at least one substitution is in the para position of the phenyl ring.

[0397] Exemplary Embodiment 17. Y is C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5

[0023] The compound of any one of the preceding exemplary embodiments, wherein the phenyl ring is substituted with

[0398] Exemplary Embodiment 18. Y is selected from two C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5wherein at least one substitution is in the para position of the phenyl ring.

[0399] Exemplary embodiment 19.Y is [ka] The compound of any one of the preceding exemplary embodiments, wherein

[0400] Exemplary embodiment 20.Y is [ka] The compound of any one of the preceding exemplary embodiments, wherein

[0401] Exemplary embodiment 21.Y is [ka] The compound of any one of the preceding exemplary embodiments, wherein

[0402] Exemplary embodiment 22.Y is [ka] The compound of any one of the preceding exemplary embodiments, wherein

[0403] Exemplary embodiment 23.R 2 The compound of any one of the preceding exemplary embodiments, wherein is hydrogen or C1-C6 alkyl.

[0404] Exemplary Embodiment 24.R 2 The compound of any one of the preceding exemplary embodiments, wherein is hydrogen.

[0405] Exemplary embodiment 25.R 2 The compound of any one of the preceding exemplary embodiments, wherein is C1-C6 alkyl.

[0406] Exemplary embodiment 26.R 2 The compound of any one of the preceding exemplary embodiments, wherein is methyl.

[0407] Exemplary embodiment 27.R 3 The compound of any one of the preceding exemplary embodiments, wherein is hydrogen or C1-C6 alkyl.

[0408] Exemplary embodiment 28.R 3 The compound of any one of the preceding exemplary embodiments, wherein is hydrogen.

[0409] Exemplary embodiment 29.R 3 The compound of any one of the preceding exemplary embodiments, wherein is C1-C6 alkyl.

[0410] Exemplary embodiment 30.R 3 The compound of any one of the preceding exemplary embodiments, wherein is methyl.

[0411] Exemplary embodiment 31.R 2 and R 3 together with the atoms to which they are attached, C3-C8 cycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a The compound of any one of the preceding exemplary embodiments, substituted with:

[0412] Exemplary embodiment 32.R 2a The compound of any one of the preceding exemplary embodiments, wherein is hydrogen or halo.

[0413] Exemplary embodiment 33.R 2a The compound of any one of the preceding exemplary embodiments, wherein is hydrogen.

[0414] Exemplary embodiment 34.R 2a The compound of any one of the preceding exemplary embodiments, wherein is halo.

[0415] Exemplary embodiment 35.R 2a The compound of any one of the preceding exemplary embodiments, wherein is Cl.

[0416] Exemplary embodiment 36.R 2 and R 3 but along with the atoms to which they are bonded, [ka]

[0023] The compound of any one of the preceding exemplary embodiments, wherein

[0417] Exemplary embodiment 37.R 2 and R 3 but along with the atoms to which they are bonded, [ka]

[0023] The compound of any one of the preceding exemplary embodiments, wherein

[0418] Exemplary embodiment 38.R 2 and R 3 but along with the atoms to which they are bonded, [ka]

[0023] The compound of any one of the preceding exemplary embodiments, wherein

[0419] Exemplary embodiment 39.R 2 and R 3 but along with the atoms to which they are bonded, [ka]

[0023] The compound of any one of the preceding exemplary embodiments, wherein

[0420] Exemplary embodiment 40.R 2and R 3 but along with the atoms to which they are bonded, [ka]

[0023] The compound of any one of the preceding exemplary embodiments, wherein

[0421] Exemplary embodiment 41.R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl, or 5- to 9-membered heteroaryl may optionally contain one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is substituted with an aryl, or an optionally substituted 5-9 membered heteroaryl.

[0422] Exemplary embodiment 42.R 1is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl optionally contains one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is substituted with an aryl, or an optionally substituted 5-9 membered heteroaryl.

[0423] Exemplary embodiment 43.R 1 is C1-C6 alkyl, optionally containing one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is substituted with an aryl, or an optionally substituted 5-9 membered heteroaryl.

[0424] Exemplary embodiment 44.R 1 is a 3- to 8-membered heterocycloalkyl, optionally containing one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is substituted with an aryl, or an optionally substituted 5-9 membered heteroaryl.

[0425] Exemplary embodiment 45.R 1 is a 5- to 9-membered heteroaryl, optionally containing one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is substituted with an aryl, or an optionally substituted 5-9 membered heteroaryl.

[0426] Exemplary embodiment 46.R 1is C1-C6 alkyl or 3- to 8-membered heterocycloalkyl, and said C1-C6 alkyl is optionally selected from one or more -R 4 OR 5 The compound of any one of the preceding exemplary embodiments, substituted with:

[0427] Exemplary embodiment 47.R 1 but, [ka] The compound of any one of the preceding exemplary embodiments, wherein

[0428] Exemplary embodiment 48.R 1 but, [ka] The compound of any one of the preceding exemplary embodiments, wherein

[0429] Exemplary embodiment 49.R 1 but, [ka] The compound of any one of the preceding exemplary embodiments, wherein

[0430] Exemplary embodiment 50.R 1 but, [ka] The compound of any one of the preceding exemplary embodiments, wherein

[0431] Exemplary embodiment 51.R 4 The compound of any one of the preceding exemplary embodiments, wherein is absent and is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0432] Exemplary embodiment 52.R 4The compound of any one of the preceding exemplary embodiments, wherein

[0433] Exemplary embodiment 53.R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the aryl is aryl, or 5-9 membered heteroaryl.

[0434] Exemplary embodiment 54.R 5 The compound of any one of the preceding exemplary embodiments, wherein is hydrogen.

[0435] Exemplary embodiment 55.R 5 The compound of any one of the preceding exemplary embodiments, wherein is C1-C6 alkyl.

[0436] Exemplary embodiment 56.R 5 The compound of any one of the preceding exemplary embodiments, wherein is methyl.

[0437] Exemplary embodiment 57.R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the aryl is aryl, or 5-9 membered heteroaryl.

[0438] Exemplary embodiment 58.R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the aryl is aryl, or 5-9 membered heteroaryl.

[0439] Exemplary embodiment 59.R 8is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the aryl is aryl, or 5-9 membered heteroaryl.

[0440] Exemplary embodiment 60.R 7 and R 8

[0039] The compound of any one of the preceding exemplary embodiments, wherein, together with the atom to which they are attached, form a 3- to 8-membered heterocycloalkyl.

[0441] Exemplary Embodiment 61. The compound of any one of the preceding exemplary embodiments, wherein t is 1 or 2.

[0442] Exemplary embodiment 62.R 1 but, [ka] The compound of any one of the preceding exemplary embodiments, wherein the compound is not

[0443] Exemplary Embodiment 63. The compound of Formula (II) is a compound of Formula (II-a): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein

[0444] Exemplary Embodiment 64. The compound of Formula (II) is a compound of Formula (II-b): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atoms to which they are attached, optionally one or more R 2a or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0445] Exemplary Embodiment 65. The compound of Formula (II) is a compound of Formula (II-c): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5, an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atoms to which they are attached, optionally one or more R 2a or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0446] Exemplary Embodiment 66. The compound of Formula (II) is a compound of Formula (II-d): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5 , a C1-C6 alkyl substituted with a 3- to 8-membered heterocycloalkyl, or a 5- to 9-membered heteroaryl; R 2 and R 3 together with the atoms to which they are attached, optionally one or more R 2a C5-C substituted with 10 The compound of exemplary embodiment 4, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, which forms an aryl.

[0447] Exemplary Embodiment 67. The compound of Formula (II) is a compound of Formula (II-d): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5, an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atoms to which they are attached, optionally one or more R 2a or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0448] Exemplary Embodiment 68. The compound of Formula (II) is a compound of Formula (II-e): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 However, along with the atoms to which they are attached, C5-C 10 aryl or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by Y is a 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound of exemplary embodiment 4 is substituted with any one, two, or three of:

[0449] Exemplary Embodiment 69. The compound of Formula (II) is a compound of Formula (II-f): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; Y is a 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound of exemplary embodiment 4 is substituted with any one, two, or three of:

[0450] Exemplary Embodiment 70. The compound of Formula (II) is a compound of Formula (II-g): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5, an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; Y is a 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound of exemplary embodiment 4 is substituted with any one, two, or three of:

[0451] Exemplary Embodiment 71. The compound of Formula (II) is a compound of Formula (II-h): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; Y is a 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound of exemplary embodiment 4 is substituted with any one, two, or three of:

[0452] Exemplary Embodiment 72. The compound of Formula (II) is a compound of Formula (II-i): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; Y is a 3- to 8-membered heterocycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and the 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound of exemplary embodiment 4 is substituted with any one, two, or three of:

[0453] Exemplary Embodiment 73. The compound of Formula (II) is a compound of Formula (II-j): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: R 1 But there are more than one halo, -R 4 OR 5 , an optionally substituted 3- to 8-membered heterocycloalkyl, or an optionally substituted 5- to 9-membered heteroaryl; Y is a 3- to 8-membered heterocycloalkyl, C5-C 10aryl, or 5- to 9-membered heteroaryl, and the 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein the compound of exemplary embodiment 4 is substituted with any one, two, or three of:

[0454] Exemplary Embodiment 74. The compound of any one of the preceding exemplary embodiments, wherein said compound is selected from compounds 1-81, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0455] Exemplary Embodiment 75. The compound of any one of the preceding exemplary embodiments, wherein said compound is selected from a compound set forth in Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0456] Exemplary Embodiment 76. The compound of any one of the preceding exemplary embodiments, wherein said compound is selected from a compound set forth in Table 2, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0457] Exemplary Embodiment 77. A compound according to any one of Exemplary Embodiments 74-76, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0458] Exemplary Embodiment 78. A compound according to any one of exemplary embodiments 74-76, or a pharmaceutically acceptable salt thereof.

[0459] Exemplary Embodiment 79 An isotopic derivative of a compound of any one of the preceding exemplary embodiments.

[0460] Exemplary Embodiment 80 A pharmaceutical composition comprising a compound of any one of the preceding exemplary embodiments and one or more pharmaceutically acceptable carriers.

[0461] Exemplary Embodiment 81. A method of treating or preventing an NLRP3-associated disease or disorder, comprising administering to a subject at least one therapeutically effective amount of a compound of any one of the preceding exemplary embodiments.

[0462] Exemplary Embodiment 82 A method of inhibiting NLRP3, comprising administering to a subject at least one therapeutically effective amount of a compound of any one of the preceding exemplary embodiments.

[0463] Exemplary Embodiment 83 A compound of any one of the preceding exemplary embodiments for use in treating or preventing an NLRP3-associated disease or disorder.

[0464] Exemplary Embodiment 84 Use of a compound of any one of the preceding exemplary embodiments in the manufacture of a medicament for treating or preventing an NLRP3-associated disease or disorder.

[0465] Exemplary Embodiment 85 The method, compound, or use of any one of the preceding exemplary embodiments, wherein said subject is a human.

[0466] Exemplary Embodiment 86. The method, compound, or use of any one of the preceding exemplary embodiments, wherein said NLRP3-associated disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychological disorder, graft-versus-host disease, allodynia, or an NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in NLRP3.

[0467] Exemplary Embodiment 87. The method, compound, or use of any one of the preceding exemplary embodiments, wherein said disease or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0468] Exemplary Embodiment 88 The method, compound, or use of any one of the preceding exemplary embodiments, wherein said kidney disease is an acute kidney disease, a chronic kidney disease, or a rare kidney disease.

[0469] Exemplary Embodiment 89 The method, compound, or use of any one of the preceding exemplary embodiments, wherein said skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0470] Exemplary Embodiment 90 The method, compound, or use of any one of the preceding exemplary embodiments, wherein said rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0471] Exemplary Embodiment 91 The method, compound, or use of any one of the preceding exemplary embodiments, wherein the NLRP3-associated disease in a subject determined to have a germline or somatic non-silent mutation in said NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0472] Exemplary Embodiment 92 The method, compound, or use of any one of the preceding exemplary embodiments, wherein said cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease.

[0473] Exemplary Embodiment A Exemplary Embodiment 1A. A compound of Formula (II-h): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Each R2a is hydrogen, R 1 is C1-C6 alkyl, -(CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(3- to 8-membered heterocycloalkyl), or -(CH2) n -(5- to 9-membered heteroaryl), wherein said alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl optionally includes one or more of halo, CN, C1-C6 alkyl, C6-C 10 Aryl, -R 4 OR 5 , or -NR 5 R 6 is replaced by Y is C6-C 10 aryl, wherein the aryl is optionally selected from one or more of halo, C-C alkyl, C-C haloalkyl, or -R 4 OR 5 is replaced by R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 and R 6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; The compound, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein n is an integer of 0 to 4.

[0474] Exemplary Embodiment 2A.R 1 may contain one or more of halo, CN, C1-C6 alkyl, C1-C6 haloalkyl, C6-C 10 Aryl, -NR 4 R 5 , or -R4 OR 5 The compound according to Exemplary Embodiment 1A, wherein R is C1-C6 alkyl optionally substituted with R.

[0475] Exemplary Embodiment 3A.R 1 is one or more of CN, C1-C6 alkyl, or -R 4 OR 5 The compound according to Exemplary Embodiment 2A, wherein R is C1-C6 alkyl optionally substituted with R.

[0476] Exemplary Embodiment 4A.R 4 The compound of Exemplary Embodiment 3A, wherein is a bond.

[0477] Exemplary Embodiment 5A.R 5 The compound according to Exemplary Embodiment 3A, wherein is hydrogen or C1-C6 alkyl.

[0478] Exemplary Embodiment 6A.R 1 But -(CH2) n The compound of Exemplary Embodiment 1A, wherein: -(3-8 membered heterocycloalkyl).

[0479] Exemplary Embodiment 7A. Heterocycloalkyl is one or more of halo, C1-C6 alkyl, or -R 4 OR 5 The compound of Exemplary Embodiment 6A, wherein the compound is substituted with:

[0480] Exemplary Embodiment 8A. The compound of Exemplary Embodiment 6A, wherein n is an integer selected from 0 or 1.

[0481] Exemplary Embodiment 9A.R 1 But -(CH2) n -(C3-C 10 The compound of Exemplary Embodiment 1A, wherein R is 1 or 2;

[0482] Exemplary Embodiment 10A. The cycloalkyl is one or more of halo, C1-C6 alkyl, or -R 4 OR 5The compound of Exemplary Embodiment 9A, wherein the compound is substituted with:

[0483] Exemplary embodiment 11A.Y is C6-C 10 The compound of Exemplary Embodiment 1A, wherein:

[0484] Exemplary Embodiment 12A. The compound of Exemplary Embodiment 11A, wherein Y is phenyl.

[0485] Exemplary Embodiment 13A. The phenyl is selected from the group consisting of one or more halo, C1-C6 alkyl, or -R 4 OR 5 The compound of Exemplary Embodiment 12A, wherein the compound is substituted with:

[0486] Exemplary embodiment 14A. [ka] [ka] The compound of Exemplary Embodiment 1A, selected from:

[0487] Exemplary embodiment 15A. 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, 5-chloro-2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, 5-methoxy-2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, 2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)-5-(trifluoromethoxy)phenol, (S)-5-chloro-2-(4-((tetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, (S)-5-chloro-2-(4-(((3,3-difluorocyclopentyl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, (R)-5-chloro-2-(4-(((3-fluorotetrahydrofuran-3-yl)methyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, 5-chloro-2-(4-((2-(methoxy-d3)-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, 5-chloro-2-(4-((oxazol-4-ylmethyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, and The compound according to Exemplary Embodiment 14A, wherein the compound is selected from 5-chloro-2-(4-((4-fluorobenzyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0488] Exemplary embodiment 16A. 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, 5-methoxy-2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, (S)-5-chloro-2-(4-((tetrahydrofuran-3-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, 5-chloro-2-(4-((oxazol-4-ylmethyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol, and The compound according to Exemplary Embodiment 15A, wherein the compound is selected from 5-chloro-2-(4-((4-fluorobenzyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0489] Exemplary Embodiment 17A. A pharmaceutical composition comprising a compound of Exemplary Embodiment 1A and a pharmaceutically acceptable carrier.

[0490] Exemplary Embodiment 18A. A pharmaceutical composition comprising a compound of Exemplary Embodiment 14A and a pharmaceutically acceptable carrier.

[0491] Exemplary Embodiment 19A. A pharmaceutical composition comprising a compound of Exemplary Embodiment 15A and a pharmaceutically acceptable carrier.

[0492] Exemplary Embodiment 20A. A pharmaceutical composition comprising a compound of Exemplary Embodiment 16A and a pharmaceutically acceptable carrier.

[0493] Exemplary Embodiment B Exemplary Embodiment 1B. A compound of Formula (I): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ), O, S, or C(R b )(R c ) and R a is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R a But R 1 cyclization to form a 3- to 8-membered heterocycloalkyl; R b is hydrogen or C1-C6 alkyl; R c is hydrogen or C1-C6 alkyl, or R b and R c together with the atom to which they are attached form a C3-C8 cycloalkyl; Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(3-8 membered heterocycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(5- to 9-membered heteroaryl), -R 4 SR 6 , -R 4 C(O)OR 6 , -R4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of halo, CN, C1-C6 alkyl, -R 4 OR 5 , -NR 5 R 6 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; or R 2 and R 3together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a is hydrogen, deuterium, C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; t is 1 or 2, but However, R1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0494] Exemplary Embodiment 2B. A compound of Formula I': [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ), O, S, or C(R b )(R c ) and R a is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R a But R 1 cyclization to form a 3- to 8-membered heterocycloalkyl; R b is hydrogen or C1-C6 alkyl; R c is hydrogen or C1-C6 alkyl, or R b and R c together with the atom to which they are attached form a C3-C8 cycloalkyl; Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(3- to 8-membered heterocycloalkyl), or -(CH2) n -(5- to 9-membered heteroaryl), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of halo, CN, C1-C6 alkyl, -NR 5 R 6 , -R 4 OR 5 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a is hydrogen, deuterium, C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; t is 1 or 2, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0495] Exemplary Embodiment 3B. A compound of Formula I″: [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N(R a ), O, S, or C(R b )(R c ) and R a is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R a But R 1 cyclization to form a 3- to 8-membered heterocycloalkyl; R b is hydrogen or C1-C6 alkyl; R c is hydrogen or C1-C6 alkyl, or R b and R c together with the atom to which they are attached form a C3-C8 cycloalkyl; Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, CH2)n -(C3-C 10 cycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(3- to 8-membered heterocycloalkyl), or -(CH2) n -(5- to 9-membered heteroaryl), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of halo, CN, C1-C6 alkyl, -NR 5 R 6 , -R 4 OR 5 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, where R 4 Only, -R 4 OR 5 and R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; t is 1 or 2, but However, R 1is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0496] Exemplary Embodiment 4B. A compound of Formula II: [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 Aryl, 5-9 membered heteroaryl, halo, cyano, -R 4 OR 5 , -R 4 N(R 5 )(R 6 ), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -CH2) n -(C3-C 10 cycloalkyl), -(CH2) n -(C6-C 10 aryl), -(CH2) n -(3- to 8-membered heterocycloalkyl), or -(CH2) n -(5- to 9-membered heteroaryl), -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), or -R 4 P(O)(R 5 )2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of halo, CN, C1-C6 alkyl, -NR 5 R 6 , -R 4 OR 5 , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C-C 10 substituted with an aryl or an optionally substituted 5- to 9-membered heteroaryl; R 2is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R 5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 3 is hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 9-membered heteroaryl, -R 4 OR 5 , -R 4 SR 6 , -R 4 C(O)OR 6 , -R 4 C(O)N(R 7 )(R 8 ), -R 4 N(R 7 )C(O)R 8 , -R 4 S(O) t R5 , -R 4 S(O) t N(R 7 )(R 8 ), -R 4 N(R 7 )S(O) t (R 8 ), -R 4 P(O)(R 5 )2, or -R 4 SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is optionally substituted with one or more C1-C6 alkyl, halo, or C1-C6 haloalkyl; or R 2 and R 3 together with the atom to which they are attached, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, and the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a is hydrogen, deuterium, C1-C6 alkyl, halo, or C1-C6 haloalkyl; R 4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R 5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl is optionally substituted with one or more D; R 6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl; R 7 and R 8 together with the atom to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; t is 1 or 2, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0497] Exemplary embodiment 5B. X is N(R a ) or O, R a is hydrogen or C1-C6 alkyl; Y is a 3- to 8-membered heterocycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, and the 3- to 8-membered heterocycloalkyl, C-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, -R 4 OR 5 , -R 4 SR 6 , or -R 4 It has been replaced by SF5, R 1 is C1-C6 alkyl, C1-C6 haloalkyl, -(CH2) n -(C3-C 10 cycloalkyl), -(CH2)n -(3-8 membered heterocycloalkyl), -(CH2) n -(C6-C 10 aryl), or -(CH2) n -(5- to 9-membered heteroaryl), and the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C 10 The aryl or 5- to 9-membered heteroaryl is optionally selected from one or more of halo, CN, C1-C6 alkyl, or -R 4 OR 5 is replaced by R 2 is hydrogen or C1-C6 alkyl optionally substituted with one or more halo; R 3 is hydrogen or C1-C6 alkyl optionally substituted with one or more halo, or R 2 and R 3 together with the atoms to which they are attached, C3-C8 cycloalkyl, C6-C 10 aryl, or 5- to 9-membered heteroaryl, and 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a is replaced by R 2a But it's a halo, R 4 is a bond or C1-C6 alkyl; R 5 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl, said alkyl optionally substituted with one or more D; n is 0, 1, 2, 3, or 4, but However, R 1 is not a C2 alkyl or C4 alkyl substituted with morpholinyl.

[0498] Exemplary Embodiment 6B. X is N(R a ) or O.

[0499] Exemplary Embodiment 7B. The compound of any one of the preceding exemplary embodiments, wherein X is NH.

[0500] Exemplary embodiment 8B.Y is a 3- to 8-membered heterocycloalkyl, C-C 10 aryl, or 5- to 9-membered heteroaryl, and the 3- to 8-membered heterocycloalkyl, C5-C 10 The aryl or 5- to 9-membered heteroaryl may optionally be selected from one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 The compound of any one of the preceding exemplary embodiments, substituted with:

[0501] Exemplary Embodiment 9B. Y is piperidinyl or phenyl, and said piperidinyl or phenyl is selected from one or more of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R 4 OR 5 The compound of any one of the preceding exemplary embodiments, substituted with:

[0502] Exemplary embodiment 10B.Y includes: [ka] The compound of any one of the preceding exemplary embodiments, wherein

[0503] Exemplary Embodiment 11B.R 2 The compound of any one of the preceding exemplary embodiments, wherein is hydrogen or C1-C6 alkyl.

[0504] Exemplary Embodiment 12B.R 3 The compound of any one of the preceding exemplary embodiments, wherein is hydrogen or C1-C6 alkyl.

[0505] Exemplary Embodiment 13B.R 2and R 3 together with the atoms to which they are attached, C3-C8 cycloalkyl, C5-C 10 aryl, or 5- to 9-membered heteroaryl, and 10 aryl, or 5- to 9-membered heteroaryl, optionally with one or more R 2a The compound of any one of the preceding exemplary embodiments, substituted with:

[0506] Exemplary Embodiment 14B.R 2a The compound of any one of the preceding exemplary embodiments, wherein is hydrogen or halo.

[0507] Exemplary Embodiment 15B.R 2 and R 3 but along with the atoms to which they are bonded, [ka]

[0023] The compound of any one of the preceding exemplary embodiments, wherein

[0508] Exemplary Embodiment 16B.R 1 is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein said C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl optionally contains one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is substituted with an aryl, or an optionally substituted 5-9 membered heteroaryl.

[0509] Exemplary Embodiment 17B.R 1 is a 3- to 8-membered heterocycloalkyl, optionally containing one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10The compound of any one of the preceding exemplary embodiments, wherein the compound is substituted with an aryl, or an optionally substituted 5-9 membered heteroaryl.

[0510] Exemplary Embodiment 18B.R 1 is a 5- to 9-membered heteroaryl, optionally containing one or more halo, -R 4 OR 5 , optionally substituted 3-8 membered heterocycloalkyl, optionally substituted C5-C 10 The compound of any one of the preceding exemplary embodiments, wherein the compound is substituted with an aryl, or an optionally substituted 5-9 membered heteroaryl.

[0511] Exemplary Embodiment 19B.R 1 but, [ka] The compound of any one of the preceding exemplary embodiments, wherein

[0512] Exemplary Embodiment 20B.R 4 The compound of any one of the preceding exemplary embodiments, wherein is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0513] Exemplary Embodiment 21B.R 5 The compound of any one of the preceding exemplary embodiments, wherein is hydrogen or C1-C6 alkyl.

[0514] Exemplary Embodiment 22B.R 6 The compound of any one of the preceding exemplary embodiments, wherein is hydrogen or C1-C6 alkyl.

[0515] Exemplary Embodiment 23B. The compound of any one of the preceding exemplary embodiments, wherein n is 0, 1, or 2.

[0516] Exemplary Embodiment 24B.R 1 but, [ka] The compound of any one of the preceding exemplary embodiments, wherein the compound is not

[0517] Exemplary Embodiment 25B. The compound is a compound of Formula (II-f), (II-g), (II-h), (II-i), or (II-j): [ka] or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0518] Exemplary Embodiment 26B. The compound of any one of the preceding exemplary embodiments, wherein the compound is selected from a compound set forth in Table 1 or Table 2, or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

[0519] Exemplary Embodiment 27B. A pharmaceutical composition comprising a compound of any one of the preceding exemplary embodiments and one or more pharmaceutically acceptable carriers.

[0520] Exemplary embodiment 28B. A method for modulating NLRP3, comprising administering to a subject a compound described in any one of exemplary embodiments 1B-26B, or a pharmaceutical composition described in exemplary embodiment 27B.

[0521] Exemplary Embodiment 29B. A method of treating or preventing a disease or disorder, comprising administering to a subject a compound described in any one of Exemplary Embodiments 1B-26B, or a pharmaceutical composition described in Exemplary Embodiment 27B.

[0522] Exemplary Embodiment 30B. A compound of any one of Exemplary Embodiments 1B-26B, or a pharmaceutical composition of Exemplary Embodiment 27B, for use in treating or preventing a disease or disorder.

[0523] Exemplary Embodiment 31B. Use of a compound of any one of Exemplary Embodiments 1B-26B in the manufacture of a medicament for the treatment or prevention of a disease or disorder.

[0524] Exemplary Embodiment 32B. Use of a compound of any one of Exemplary Embodiments 1B-26B for the treatment or prevention of a disease or disorder.

[0525] Exemplary Embodiment 33B. The method, compound, or use of any one of Exemplary Embodiments 28B-32B, wherein said disease or disorder is an NLRP3-associated disease or disorder.

[0526] Exemplary Embodiment 34B. The method, compound, or use of any one of Exemplary Embodiments 28B-33B, wherein the subject is a human.

[0527] Exemplary Embodiment 35B. The method, compound, or use of any one of Exemplary Embodiments 28B-34B, wherein the disease or disorder is inflammation, an autoimmune disease, cancer, an infectious disease, a disease or disorder of the central nervous system, a metabolic disease, a cardiovascular disease, a respiratory disease, a renal disease, a liver disease, an eye disease, a skin disease, a lymphatic system disease, a rheumatic disease, a psychological disorder, graft-versus-host disease, allodynia, or an NLRP3-associated disease.

[0528] Exemplary Embodiment 36B. The method, compound, or use of Exemplary Embodiment 35B, wherein said disease or disorder of the central nervous system is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0529] Exemplary Embodiment 37B. The method, compound, or use of Exemplary Embodiment 35B, wherein said kidney disease is an acute kidney disease, a chronic kidney disease, or a rare kidney disease.

[0530] Exemplary Embodiment 38B. The method, compound, or use of Exemplary Embodiment 35B, wherein said skin disease is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0531] Exemplary Embodiment 39B. The method, compound, or use of Exemplary Embodiment 35B, wherein said rheumatic disease is dermatomyositis, Still's disease, or juvenile idiopathic arthritis.

[0532] Exemplary Embodiment 40B. The method, compound, or use of Exemplary Embodiment 35B, wherein the NLRP3-associated disease is present in a subject who has been determined to have a germline or somatic non-silent mutation in NLRP3.

[0533] Exemplary Embodiment 41B. The method, compound, or use of Exemplary Embodiment 40B, wherein the NLRP3-associated disease is present in a subject who has been determined to have a germline or somatic non-silent mutation in NLRP3, and is cryopyrin-associated autoinflammatory syndrome.

[0534] Exemplary Embodiment 42B. The method, compound, or use of Exemplary Embodiment 35B, wherein said cryopyrin-associated autoinflammatory syndrome is familial cold autoinflammatory syndrome, Muckle-Wells syndrome, or neonatal-onset multisystem inflammatory disease. [Example]

[0535] For illustrative purposes, neutral compounds of formula (I) are synthesized and tested in the Examples. It should be understood that neutral compounds of formula (I) can be converted to the corresponding pharmaceutically acceptable salts of the compounds using routine techniques in the art (e.g., by saponifying an ester to a carboxylic acid salt, or by hydrolyzing an amide to form the corresponding carboxylic acid and then converting the carboxylic acid to a carboxylic acid salt).

[0536] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz as indicated and at 300.3 K unless otherwise stated, and chemical shifts (δ) are reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument with 8, 16, or 32 scans.

[0537] LC-MS chromatograms and spectra were recorded using a Shimadzu LCMS-2020. The injection volume was 0.7-8.0 μl, and the flow rate was typically 0.8 or 1.2 ml / min. The detection method was diode array (DAD) or evaporative light scattering (ELSD) with positive ion electrospray ionization. The MS range was 100-1000 Da. The solvent was a gradient of water and acetonitrile containing modifiers such as trifluoroacetic acid or ammonium carbonate (typically 0.01-0.04%).

[0538] [Table 3]

[0539] A suitable general route for preparing the compounds of the present application can be described using Protocol A in Scheme 2 herein. [ka]

[0540] Step 1 is the S reaction between an amine (i) and an aryl dichloride (ii). N Step 1 involves a Br-Ar reaction to afford the target chloroaryl intermediate (iii). Step 2, unless otherwise indicated, involves a cross-coupling between intermediate (iii) and the desired boronic acid or boronate salt iv to produce the desired compound of Formula I. The amine i, aryl dichloride ii, and boronate or boronate salt iv are either commercially available or known in the chemical literature.

[0541] A suitable general route for preparing the compounds of the present application is also described using Protocol B in Scheme 3 herein. [ka]

[0542] Step 1 involves the cleavage of commercially available 3,4-pyridinedicarboxylic anhydride vi with a Grignard reagent to give carboxylic acid vii. Step 2 features chlorination followed by condensation with hydrazine to give pyridazinol viii. Step 3 then involves another chlorination to give key intermediate ix, which can then be coupled in Step 4 as an SNAr reaction with amine i to form azaphthalazine x. Step 5 then features methyl ether deprotection to give compounds of Formula I.

[0543] Example 1. Synthesis of (S)-1-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazin-4-amine (Compound 1) and (S)-4-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazin-1-amine (Compound 2) [ka] Step 1. Synthesis of (S)-1-chloro-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazin-4-amine and (S)-4-chloro-N-((tetrahydrofuran-2-yl)methyl)pyrido[4,3-d]pyridazin-1-amine [ka]

[0544] To an 8 mL microwave tube was added 1,4-dichloropyrido[3,4-d]pyridazine (250 mg, 1.25 mmol, 1.00 equiv), 1-[(2S)-oxolan-2-yl]methanamine (152 mg, 1.50 mmol, 1.20 equiv), Na2CO3 (397 mg, 3.75 mmol, 3.00 equiv), and DMF (2 mL). The final reaction mixture was irradiated with microwave radiation at 130 °C for 30 minutes. The progress of the reaction was monitored by LCMS. The reaction was then quenched by adding 20 mL of water. The resulting solution was extracted with 3 × 15 mL of ethyl acetate. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (1:9) to give (S)-1-chloro-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazin-4-amine and (S)-4-chloro-N-((tetrahydrofuran-2-yl)methyl)pyrido[4,3-d]pyridazin-1-amine (150 mg, 45%, mixture of two isomers) as a yellow oil. LCMS (ES, m / z): RT = 0.54 min, m / z = 265.0 [M+1]+.

[0545] Step 2. Synthesis of (S)-1-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazin-4-amine (Compound 1) and (S)-4-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazin-1-amine (Compound 2) [ka]

[0546] In an 8 mL microwave tube purged and maintained with an inert atmosphere of nitrogen, (S)-1-chloro-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazin-4-amine and (S)-4-chloro-N-((tetrahydrofuran-2-yl)methyl)pyrido[4,3-d]pyridazin-1-amine (150 mg, 0.56 mmol, 1.00 equiv.), p- A mixture of chloro-benzeneboronic acid (106 mg, 0.68 mmol, 1.20 equiv.), Pd(dppf)Cl (82.9 mg, 0.11 mmol, 0.20 equiv.), NaCO (180 mg, 1.70 mmol, 3.00 equiv.), dioxane (2.0 mL, 23.61 mmol, 41.7 equiv.), and HO (0.4 mL, 22.20 mmol, 39.2 equiv.) was added. The resulting solution was stirred in an oil bath at 80 °C for 2 h. The progress of the reaction was monitored by LCMS. The resulting solution was extracted with 3 × 5 mL of ethyl acetate, and the resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (1:5) to give (S)-1-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazin-4-amine and (S)-4-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[4,3-d]pyridazin-1-amine (160 mg, mixture of two isomers) as a yellow solid. The crude product (160 mg, purity = 83.23%) was purified by preparative HPLC (2#SHIMADZU (HPLC-01)) under the following conditions: Column: XBridge Preparative OBD C18, 30*150 mm, 5 μm; Mobile Phase A: water (10 mmol / L NH4HCO3); Mobile Phase B: ACN; Flow Rate: 60 mL / min; Gradient: 25% B to 42% B in 8 min; Wavelength: 254 / 220 nm. This afforded compound 1 (53.3 mg, 27%) as an off-white solid and compound 2 (5.6 mg, 7.3%) as an off-white solid. Compound 1: LCMS (ES, m / z): RT = 0.66 min, m / z = 341.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 9.80 (d, J = 1.0 Hz, 1H), 8.92 (d, J = 5.7 Hz, 1H), 8.21 (t, J1 = J2 =5.7 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.66 - 7.59 (m, 3H), 4.28-4.25 (m, 1H), 3.87-3.82 (m, 1H), 3.80 - 3.63 (m, 3H), 2.02-1.97(m, 1H), 1.97 - 1.77 (m, 2H), 1.71-1.66 (m, 1H).Compound 2: LCMS (ES, m / z): RT=0.65 min, m / z=341.2[M+1]+. 1 H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1H), 9.01 (d, J = 5.6 Hz, 1H), 8.31 (d, J = 5.6 Hz, 1H), 8.00 (t, J1 = J1 = 5.7 Hz, 1H), 7.78 - 7.71 (m, 2H), 7.67 - 7.60 (m, 2H), 4.31 - 4.20 (m, 1H), 3.84-3.81 (m, 1H), 3.77 - 3.61 (m, 3H), 2.07 - 1.77 (m, 3H), 1.74 - 1.61 (m, 1H).

[0547] Example 2. Synthesis of (R)-1-(4-chlorophenyl)-4-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d]pyridazine (Compound 3) and (R)-4-(4-chlorophenyl)-1-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d]pyridazine (Compound 4) [ka] Step 1: Synthesis of (R)-1-chloro-4-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d]pyridazine and (R)-4-chloro-1-((tetrahydrofuran-2-yl)methoxy)pyrido[4,3-d]pyridazine [ka]

[0548] A 50 mL three-necked round-bottom flask was charged with (R)-(tetrahydrofuran-2-yl)methanol (61.3 mg, 0.60 mmol, 0.80 equiv.), DMF (1.5 mL, 19.38 mmol, 25.9 equiv.), and NaH (36.0 mg, 1.50 mmol, 2.00 equiv., 60% in mineral oil). The resulting mixture was stirred at 0° C. for 1 hour. Subsequently, 1,4-dichloropyrido[3,4-d]pyridazine (150 mg, 0.75 mmol, 1.00 equiv.) was added portionwise at 0° C. The resulting solution was stirred at 25° C. for 2 hours. The progress of the reaction was monitored by LCMS. The reaction was then quenched by adding 5 mL of water. The resulting solution was extracted with 3×5 mL of ethyl acetate. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give (R)-1-chloro-4-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d]pyridazine and (R)-4-chloro-1-((tetrahydrofuran-2-yl)methoxy)pyrido[4,3-d]pyridazine (160 mg, 80%, mixture of two isomers) as a pale yellow oil. LCMS (ES, m / z): RT = 0.60 min, m / z = 266 [M+1] + .

[0549] Step 2: Synthesis of (R)-1-(4-chlorophenyl)-4-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d]pyridazine (Compound 3) and (R)-4-(4-chlorophenyl)-1-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d]pyridazine (Compound 4) [ka]

[0550] To a 10 mL sealed tube was added (R)-1-chloro-4-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d]pyridazine and (R)-4-chloro-1-((tetrahydrofuran-2-yl)methoxy)pyrido[4,3-d]pyridazine (150 mg, 0.56 mmol, 1.00 equiv), p-chloro-benzeneboronic acid (106 mg, 0.67 mmol, 1.20 equiv), Pd(dppf)Cl (82.6 mg, 0.11 mmol, 0.20 equiv), NaCO (119 mg, 1.13 mmol, 2.0 equiv), dioxane (1.5 mL, 17.7 mmol, 31.4 equiv), and HO (0.3 mL, 16.7 mmol, 29.5 equiv) at 25 °C. The resulting mixture was stirred at 80° C. for 2 hours under a nitrogen atmosphere. The progress of the reaction was monitored by LCMS. The resulting solution was extracted with 3×5 mL of ethyl acetate. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (1:3) to give (R)-1-(4-chlorophenyl)-4-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d]pyridazine and (R)-4-(4-chlorophenyl)-1-((tetrahydrofuran-2-yl)methoxy)pyrido[4,3-d]pyridazine (150 mg, purity=78.30%, mixture of two isomers) as a pale yellow oil. The crude product (150 mg, purity = 78.30%) was purified by preparative HPLC (2#SHIMADZU (HPLC-01)) under the following conditions: column, XBridge Shield RP18 OBD, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (hold 35% ACN in 12 min); detector, UV 254 / 220 nm. This gave compound 3 (3.3 mg, 12%) as a white solid and compound 4 (75.8 mg, 39%) as a white solid. Compound 3: LCMS (ES, m / z): RT = 1.57 min, m / z = 342 [M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 9.63 (d, J = 1.0 Hz, 1H), 9.08 (d, J = 5.7 Hz, 1H), 7.83 - 7.73 (m, 3H), 7.73 - 7.66 (m, 2H), 4.69-4.59 (m, 2H), 4.42-4.39 (m, 1H), 4.01-3.86 (m, 1H), 3.80 - 3.71 (m, 1H), 2.19 - 2.06 (m, 1H), 2.06 - 1.79 (m, 3H).Compound 4: LCMS (ES, m / z): RT=1.04 min, m / z=342[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.63-9.30 (m, 1H), 9.13-9.07(m, 1H), 8.12-7.77 (m, 3H), 7.76 - 7.74 (m, 1H), 7.72-7.66(m, 1H), 4.76 - 4.58 (m, 2H), 4.42-4.37 (m, 1H), 3.88-3.81 (m, 1H), 3.79-3.71 (m, 1H), 2.12-2.08 (m, 1H), 2.00-1.95 (m, 1H), 1.94 - 1.82 (m, 2H).

[0551] Example 3. 5-Chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 82) Step 1: Synthesis of 1-({1-chloropyrido[3,4-d]pyridazin-4-yl}amino)-2-methylpropan-2-ol [ka] To a 20 mL sealed tube, 1,4-dichloropyrido[3,4-d]pyridazine (1.00 g, 5.00 mmol, 1.00 equiv.), 1-amino-2-methylpropan-2-ol (0.42 g, 4.75 mmol, 0.95 equiv.), and Na2CO3 (1.59 g, 15.00 mmol, 3.00 equiv.) in DMF (10.00 mL) were added at room temperature. The final reaction mixture was microwaved at 130 °C for 30 min. The reactions were run 200 times in parallel. All reaction solutions were then collected and filtered to remove inorganic salts. The filtrate was then concentrated under reduced pressure to 160–200 mL. The residue was diluted with DCM (200 mL) and shaken in an ultrasonic bath for 10 min (causing a dark brown solid to precipitate in the solution), followed by the addition of petroleum ether (200 mL). After stirring for 20 minutes, the resulting mixture was diluted with another portion of petroleum ether (80 mL). The precipitated solid was collected by filtration, and the filter cake was then washed with water (2 x 60 mL). The solid was collected and dried under vacuum. (If the undesired regioisomer was still detected by LC-MS and H-NMR, the solid was redissolved in DMF and the above work-up procedure was repeated.) This gave 1-({1-chloropyrido[3,4-d]pyridazin-4-yl}amino)-2-methylpropan-2-ol (103.0 g, yield: 40%) as a yellow solid. LCMS (LCMS, ESI): RT = 0.83 min, m / z = 253.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.83 (d, J = 1.0 Hz, 1H), 9.06 (d, J = 5.6 Hz, 1H), 7.96 (t, J = 6.0 Hz, 1H), 7.93 - 7.77 (m, 1H), 4.82 (s, 1H), 3.64 (d, J = 5.9 Hz, 2H), 1.19 (s, 6H).

[0552] Step 2: Synthesis of 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (compound 82) [ka] To a stirred solution of 1-({1-chloropyrido[3,4-d]pyridazin-4-yl}amino)-2-methylpropan-2-ol (500 mg, 1.98 mmol, 1.00 equiv.) and 4-chloro-2-hydroxyphenylboronic acid (375 mg, 2.176 mmol, 1.10 equiv.) in dioxane and HO (5:1, 8 mL), Pd(dppf)Cl (275 mg, 0.376 mmol, 0.19 equiv.) and NaCO (426 mg, 4.019 mmol, 2.03 equiv.) were added portionwise at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 1 h. The residue was purified by reverse flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 30% gradient in 10 min; detector, UV 254 nm. The crude product was obtained. The crude product was then purified by preparative HPLC under the following conditions (Column: XSelect CSH Preparative C18 OBD Column, 19*250 mm, 5 μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: DCM:EtOH = 9:1 - HPLC; Flow rate: 25 mL / min; Gradient: 55% B to 55% B, 55% B in 13 min; Wavelength: 254 nm; RT1 (min): 11.5 to give 5-chloro-2-{4-[(2-hydroxy-2-methylpropyl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (118.7 mg, 17.38%) as a yellow solid. LCMS (ES, m / z): m / z = 345.10 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.80 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 5.6 Hz, 1H), 7.84 (t, J = 5.9 Hz, 1H), 7.39 - 7.25 (m, 2H), 7.03 (d, J = 7.7 Hz, 2H), 5.07 (s, 1H), 3.70 (d, J = 5.8 Hz, 2H), 1.23 (s, 6H).

[0553] Example 4. Synthesis of 5-chloro-2-(4-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 83) Step 1: Synthesis of 1-chloro-N-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(2-methoxy-2-methylpropyl)pyrido[4,3-d]pyridazin-1-amine [ka] To an 8 mL microwave-sealed tube was added 1,4-dichloropyrido[3,4-d]pyridazine (200 mg, 1.00 mmol, 1.00 equiv), 2-methoxy-2-methylpropan-1-amine (103 mg, 1.00 mmol, 1.00 equiv), NaCO (318 mg, 3.00 mmol, 3.00 equiv), and DMF (3.00 mL). The final reaction mixture was irradiated with microwave radiation at 130 °C for 0.5 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 1-chloro-N-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyridazin-4-amine and 4-chloro-N-(2-methoxy-2-methylpropyl)pyrido[4,3-d]pyridazin-1-amine (180.0 mg, yield = 67.5%, mixture of two isomers) as a yellow solid. LCMS (ES, m / z): RT = 0.61 min, m / z = 267 [M+1] + .

[0554] Step 2: Synthesis of 5-chloro-2-{4-[(2-methoxy-2-methylpropyl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (compound 83) [ka] To an 8 mL sealed tube was added 1-chloro-N-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyridazin-4-amine (140 mg, 0.52 mmol, 1.00 equiv.), 4-chloro-2-hydroxyphenylboronic acid (181 mg, 1.05 mmol, 2.00 equiv.), Pd(dppf)Cl (76.8 mg, 0.10 mmol, 0.20 equiv.), NaCO (167 mg, 1.57 mmol, 3.00 equiv.), dioxane (2.00 mL), and HO (0.30 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. The resulting mixture was extracted with EA (3 × 5 mL). The combined organic layers were washed with water (3 × 5 mL) and dried over anhydrous MgSO. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 5-chloro-2-{4-[(2-methoxy-2-methylpropyl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol and 5-chloro-2-{4-[(2-methoxy-2-methylpropyl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (68.0 mg, purity=85.00%, mixture of two isomers) as a yellow oil. The crude product (68.0 mg, purity = 85.00%, mixture of two isomers) was purified by preparative HPLC (2# SHIMADZU (HPLC-01)) under the following conditions: column, XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (35% to 45% ACN in 8 min); detector, UV 254 nm. This afforded 5-chloro-2-{4-[(2-methoxy-2-methylpropyl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (28.1 mg, yield = 14.9%) as a yellow solid and 5-chloro-2-{4-[(2-methoxy-2-methylpropyl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (4.00 mg, yield = 2.12%) as a yellow-green solid. 5-Chloro-2-{4-[(2-methoxy-2-methylpropyl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (Compound 83) LCMS(ES, m / z): RT=0.65 min, m / z=359[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.23 ( s, 1H),9.82 (s, 1H), 8.85 (d, J = 2.4Hz ,1H), 7.68-7.65(m, 1H), 7.36-7.29(m, 2H), 7.04-7.02 (m, 2H), 3.80(d, J = 6Hz, 2H), 3.23(s, 3H), 1.24 (s, 6H). 5-chloro-2-{4-[(2-methoxy-2-methylpropyl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol LCMS(ES,m / z): RT=1.23 min, m / z=359[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.93 (d, J = 5.6Hz ,1H), 8.85 (s,1H),8.36 (s ,1H), 7.40 (d, J = 8.8Hz ,2H), 7.06-7.04 (m, 2H), 3.77(d, J = 6Hz, 2H), 3.22(s, 3H), 1.23 (s, 6H).

[0555] Example 5. 5-Chloro-2-[4-({[(1S)-3,3-difluorocyclopentyl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]phenol (Compound 91) Step 1: 1-chloro-N-[(3,3-difluorocyclopentyl)methyl]pyrido[3,4-d]pyridazin-4-amine [ka] To a 20 mL pressure tank reactor was added 1-(3,3-difluorocyclopentyl)methanamine (300 mg, 2.22 mmol, 1.00 equiv), 1,4-dichloropyrido[3,4-d]pyridazine (444 mg, 2.22 mmol, 1.00 equiv), Na2CO3 (707 mg, 6.66 mmol, 3.00 equiv), and DMF (6.00 mL). The resulting mixture was irradiated with microwave radiation at 130 °C for 30 minutes. The progress of the reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 × 5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions: Column: XBridge Preparative Phenyl OBD Column, 19*250 mm, 5 μm; Mobile Phase A: Water (10 mmol / L NH4HCO3); Mobile Phase B: ACN; Flow Rate: 25 mL / min; Gradient: 40% B to 55% B in 10 min; Wavelength: 254 nm; RT1 (min): 9. This gave 1-chloro-N-[(3,3-difluorocyclopentyl)methyl]pyrido[3,4-d]pyridazin-4-amine (150 mg, yield = 22.62%) as a yellow solid. LCMS: (ES, m / z): RT = 0.791 min, m / z = 299.0 [M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.06 (d, J = 5.6 Hz, 1H), 8.23 ​​(t, J = 5.5 Hz, 1H), 7.87 (d, J = 5.6 Hz, 1H), 3.61- 3.57 (m, 5.6 Hz, 2H), 2.71 - 2.63 (m, 1H), 2.46 - 1.75 (m, 5H), 1.65 - 1.55 (m, 1H).

[0556] Step 2: 5-chloro-2-[4-({[(1S)-3,3-difluorocyclopentyl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]phenol (Compound 91) [ka] To an 8 mL vial was added 1-chloro-N-[(3,3-difluorocyclopentyl)methyl]pyrido[3,4-d]pyridazin-4-amine (100 mg, 0.33 mmol, 1.00 equiv.), 4-chloro-2-hydroxyphenylboronic acid (69.2 mg, 0.40 mmol, 1.20 equiv.), Pd(dppf)Cl (73.5 mg, 0.10 mmol, 0.30 equiv.), dioxane (0.50 mL), NaCO (106.44 mg, 1.00 mmol, 3.0 equiv.), and HO (0.10 mL). The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 1-chloro-N-((3,3-difluorocyclopentyl)methyl)pyrido[3,4-d]pyridazin-4-amine (105 mg, purity = 92%, mixture of two isomers). The mixture product (105 mg) was purified by chiral preparative HPLC under the following conditions: Column: CHIRALPAK IF, 2*25 cm, 5 μm; Mobile phase A: Hex (0.2% FA)-HPLC, Mobile phase B: MeOH:EtOH = 1:1-HPLC; Flow rate: 20 mL / min, Gradient: 15% B to 15% B in 21 min, Wavelength: 220 / 254 nm; RT1 (min): 13.98; RT2 (min): 17.41; Sample solvent: MeOH:DCM = 1:1; Injection volume: 0.5 mL; Run number: 4. This gave 5-chloro-2-[4-({[(1S)-3,3-difluorocyclopentyl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]phenol (26.10 mg, yield=19.17%) as a yellow solid and 5-chloro-2-[4-({[(1R)-3,3-difluorocyclopentyl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]phenol (14.00 mg, yield=10.69%) as a yellow solid. First eluting peak (compound 91): LCMS:(ES,m / z):RT=1.09 min, m / z=391.1[M+1] + . 1H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.74 (s, 1H), 8.86 (d, J = 5.6 Hz, 1H), 8.11 (s, 1H), 7.38 - 7.28 (m, 2H), 7.08 - 7.00 (m, 2H), 3.67-3.31 (m, 2H), 2.75 - 2.67 (m, 1H), 2.35 - 2.31 (m, 1H), 2.24 - 1.95 (m, 4H), 1.66 - 1.61 (m, 1H). Second eluting peak: LCMS:(ES,m / z):RT=1.09 min, m / z=391.1[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (s, 1H), 9.73 (s, 1H), 8.86 (d, J = 5.6 Hz, 1H), 8.09 - 8.06 (m, 1H), 7.38 - 7.28 (m, 2H), 7.03 (d, J = 7.3 Hz, 2H), 3.73 - 3.58 (m, 2H), 2.77 - 2.69 (m, 1H), 2.46 - 2.29 (m, 1H), 2.29 - 1.81 (m, 4H), 1.66 - 1.61 (m, 1H).

[0557] Similarly, the stereochemistry of compounds 94, 97, 100, and 105 was arbitrarily assigned.

[0558] Example 6. 5-Chloro-2-(4-{[(1S,2S)-2-hydroxycyclopentyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 95) Step 1: Synthesis of (1S,2S)-2-((1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol [ka] To a stirred solution of furo[3,4-c]pyridine-1,3-dione (30.0 g, 201.20 mmol, 1.00 equiv.) and tetrahydrofuran (300 mL), bromo(4-chloro-2-methoxyphenyl)magnesium (0.5 M in THF) (241 mL, 120 mmol, 0.60 equiv.) was added dropwise at −78° C. under a nitrogen atmosphere. The resulting mixture was stirred at 25° C. for 2 hours under a nitrogen atmosphere. The progress of the reaction was monitored by LCMS. The reaction was quenched by adding water (150 mL) at 0° C. The precipitated solid was collected by filtration and washed with water (3×50 mL). This gave 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (20 g, yield=34.08%) as a light brown solid. LCMS(ES, m / z): RT=0.662 min, m / z=292.0[M+1] + .

[0559] Step 2: Synthesis of 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol [ka] To a 250 mL round-bottom flask were added 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (5.00 g, 17.1 mmol, 1.00 equiv) and SOCl2 (50 mL). The resulting mixture was stirred at 70 °C for 2 hours. The reaction was monitored by TLC. After the reaction was completed, the resulting mixture was concentrated in vacuo. The residue was dissolved in DCM (50 mL) and added to a solution of NH2NH2.H2O (3.43 g, 68.6 mmol, 4.00 equiv) in MeOH (50 mL) at 0 °C. The resulting mixture was stirred in an oil bath at 70 °C for 3 hours. The progress of the reaction was monitored by LCMS. The precipitated solid was collected by filtration. The crude product (4 g, purity = 90%) was purified by preparative HPLC (2#SHIMADZU (HPLC-01)) under the following conditions: column, XBridge Shield RP18 OBD column, 19*250 mm, 10 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (retained 39% ACN in 17 min); detector, UV 254 / 220 nm. This gave 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.0 g, yield = 40.6%) as an off-white solid. LCMS: (ES, m / z): RT = 0.723 min, m / z = 288.0 [M+H]. + . 1 H NMR (400 MHz, DMSO-d6) δ 12.90 (s, 1H), 9.50 (s, 1H), 8.94 (d, J = 5.5 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.23 - 7.15 (m, 2H), 3.75 (s, 3H).

[0560] Step 3: Synthesis of 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine [ka] To a 250 mL round-bottom flask was added 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.5 g, 8.69 mmol, 1.00 equiv), POCl (40 mL), and pyridine (4 mL). The resulting mixture was stirred at 100 °C for 3 h. The reaction progress was monitored by LCMS. The reaction was quenched with 500 mL of sodium bicarbonate (aq) and 500 mL of EtOAc at 0 °C. The resulting mixture was extracted with EtOAc (3 × 500 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (1.5 g, yield = 56.38%) as a brown solid. LCMS(ES, m / z): RT=0.845 min, m / z=306.0[M+1] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.84 - 9.68 (m, 1H), 9.12 (d, J = 5.7 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.32 - 7.25 (m, 1H), 3.74 (s, 3H).

[0561] Step 4: Synthesis of (1S,2S)-2-((1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol [ka] To an 8 mL microwave tube, 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (90 mg, 0.29 mmol, 1.00 equiv.), (1S,2S)-2-aminocyclopentan-1-ol (44.6 mg, 0.44 mmol, 1.50 equiv.), Na2CO3 (93.5 mg, 0.88 mmol, 3.00 equiv.), and 2 mL of NMP were added at room temperature, and the final reaction mixture was stirred at 60 °C for 2 h. The progress of the reaction was monitored by LCMS. The reaction mixture was used in the next step without further purification. LCMS (ES, m / z): RT = 0.629 min, m / z = 371 [M+1] + .

[0562] Step 5: Synthesis of 5-chloro-2-(4-{[(1S,2S)-2-hydroxycyclopentyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol) (Compound 95) [ka] To the reaction mixture from VTT-2772-1 was added (ethylsulfanyl)sodium (371.80 mg, 4.43 mmol, 15.00 equiv.) at room temperature. The final reaction mixture was stirred at 120° C. for 2 hours. The progress of the reaction was monitored by LCMS. The reaction was quenched with 20 ml of water, extracted with DCM (3 × 20 ml), and concentrated. The residue was purified by preparative HPLC using an XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm column; mobile phase A: water (10 mmol / L NH₄HCO₃); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 46% B in 8 min; wavelength: 254 nm; RT (min): 6.5 to give 5-chloro-2-(4-{[(1S,2S)-2-hydroxycyclopentyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol) (44.2 mg, yield = 42%) as an off-white solid. LCMS (ES, m / z): RT = 0.598 min, m / z = 357 [M+1]. + . 1H NMR (400 MHz, methanol-d4) δ 9.73 (d, J = 1.0 Hz, 1H), 8.87 (d, J = 5.7 Hz, 1H), 7.52 (d, J = 5.7 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 4.42-4.34 (m, 1H), 4.27-4.21 (m, 1H), 2.45-2.35 (m, 1H), 2.16-2.06 (m, 1H), 1.97-1.80 (m, 3H), 1.80-1.70 (m, 1H).

[0563] Example 7. 5-Chloro-2-(4-{[2-(d3)methoxy-2-methylpropyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 99) Step 1: Synthesis of 1-{bis[(4-methoxyphenyl)methyl]amino}-2-methylpropan-2-ol [ka] To a 40 mL vial, 1-amino-2-methylpropan-2-ol (2.00 g, 22.43 mmol, 1.00 equiv.), PMBCl (17.57 g, 112.18 mmol, 5.00 equiv.), TEA (11.35 g, 112.18 mmol, 5.00 equiv.), and DMF (20 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction progress was monitored by LCMS. After quenching with 30 mL of water and extraction with DCM (30 mL × 3), the organic layer was concentrated in vacuo, and the residue was purified by reverse flash chromatography using the following conditions: column, C18; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This gave 1-{bis[(4-methoxyphenyl)methyl]amino}-2-methylpropan-2-ol (2.9 g, yield = 39.23%) as a brown oil. LCMS (ES, m / z): RT = 0.758 min, m / z = 330.0 [M+1] +. 1H NMR (400 MHz, methanol-d4) δ 7.38 - 7.17 (m, 4H), 6.88 (d, J = 8.2 Hz, 4H), 4.07 (q, J = 7.1 Hz, 1H), 3.73 (d, J = 5.9 Hz, 9H), 2.57 (s, 2H), 1.09 (s, 6H).

[0564] Step 2: Synthesis of [2-(d3)methoxy-2-methylpropyl]bis[(4-methoxyphenyl)methyl]amine [ka] To a 100 mL three-necked round-bottom flask were added 1-{bis[(4-methoxyphenyl)methyl]amino}-2-methylpropan-2-ol (500 mg, 1.51 mmol, 1.00 equiv), THF (15 mL), and KH (30%) (1.00 g, 7.55 mmol, 5.00 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. Then, CD3I (660 mg, 4.55 mmol, 3.00 equiv) was added in THF (15 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The progress of the reaction was monitored by LCMS. The reaction was quenched with 50 mL of NH4Cl (aq), and the resulting mixture was extracted with EtOEt (3 × 50 mL). The combined organic layers were washed with NaCl (aq) (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography using the following conditions: column, C18; mobile phase, MeCN in water, 0% to 100% gradient in 30 min; detector, UV 254 nm. This gave [2-(d3) methoxy-2-methylpropyl]bis[(4-methoxyphenyl)methyl]amine) (400 mg, yield = 76.04%) as a yellow oil. LCMS (ES, m / z): RT = 0.812 min, m / z = 357.0 [M+H] + . 1H NMR (400 MHz, methanol-d4) δ 7.31 - 7.18 (m, 4H), 6.95 - 6.79 (m, 4H), 3.79 (s, 6H), 3.56 (s, 4H), 2.45 (s, 2H), 1.06 (s, 6H).

[0565] Step 3: Synthesis of 2-(d3) methoxy-2-methylpropan-1-amine [ka] To a 250 mL round-bottom flask were added [2-(d3)methoxy-2-methylpropyl]bis[(4-methoxyphenyl)methyl]amine (1.00 g, 2.88 mmol, 1.00 equiv.), Pd / C (154 mg, 1.44 mmol, 0.50 equiv.), and MeOH (100 mL) at room temperature. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The progress of the reaction was monitored by LCMS. 5 mL of HCl (2 M) was added to the solution, and the reaction mixture was then stirred at room temperature for 30 minutes. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 10 mL). The filtrate was concentrated under reduced pressure. This gave 2-(d3)methoxy-2-methylpropan-1-amine (200 mg, yield = 48.90%) as a red solid. LCMS:(ES,m / z):RT=0.268 min, m / z=107.0[M+H]+.

[0566] Step 4: Synthesis of 1-(4-chloro-2-methoxyphenyl)-N-(2-(methoxy-d3)-2-methylpropyl)pyrido[3,4-d]pyridazin-4-amine [ka] To a 20 mL vial was added 2-(d3) methoxy-2-methylpropan-1-amine acid salt (104 mg, 0.98 mmol, 2.00 equiv.), 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (150 mg, 0.49 mmol, 1.00 equiv.), Na2CO3 (259 mg, 2.45 mmol, 5.00 equiv.), and DMSO (3 mL) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The progress of the reaction was monitored by LCMS. The resulting mixture was used directly in the next step without further purification. LCMS 110: (ES, m / z): RT = 0.828 min, m / z = 376.0 [M+1] + .

[0567] Step 5: Synthesis of 5-chloro-2-(4-{[2-(d3)methoxy-2-methylpropyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 99) [ka] The reaction mixture from VTT-2628-4 was added to a 50 mL round-bottom flask, and (ethylsulfanyl)sodium (179 mg, 2.13 mmol, 10.00 equiv.) and DMSO (4 mL) were added at room temperature. The resulting mixture was stirred at 120° C. for 1 hour. The progress of the reaction was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeOH (3×10 mL). The filtrate was concentrated under reduced pressure. The crude product (80 mg, purity = 60%) was purified by preparative HPLC (2#SHIMADZU (HPLC-01)) under the following conditions: column, XBridge preparative OBD C18 column, 30*150 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (20% to 70% ACN in 8 min); detector, UV 254 nm. This gave 5-chloro-2-(4-{[2-(d3)methoxy-2-methylpropyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (24.8 mg, yield = 32.20%) as a yellow solid. LCMS: (ES, m / z): RT = 1.266 min, m / z = 362.0 [M+1] + . 1H NMR (400 MHz, methanol-d4) δ 9.68 (s, 1H), 8.86 (d, J = 5.7 Hz, 1H), 7.54–7.50 (m, 1H), 7.42–7.29 (m, 1H), 7.04 (d, J = 7.1 Hz, 2H), 3.88 (s, 2H), 1.34 (s, 6H).

[0568] compound synthesis Compounds 1-82 were synthesized according to Protocol A.

[0569] Compounds 82-105 were synthesized according to either protocol A or B.

[0570] Compounds 106-116, 127, 129-130, and 132-136 were synthesized according to Protocol A.

[0571] Compounds 117-126, 128, and 131 were synthesized according to protocol B.

[0572] Example 8 1 H NMR data [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6]

[0573] Example 9. Biological activity of compounds of the present disclosure The biological activity of the compounds of the present disclosure was determined using the assays described herein.

[0574] Human PBMC NLRP3 assay Reagents: Human PBMC (normal): iXCells catalog number 10HU-003; RPMI 1640 medium with GlutaMAX: ThermoFisher catalog number 61870127 (complete medium: 4.5 g / L D-glucose, 10% FBS, 100 mM NaPyr, 1% Pen / Strep, 10 mM HEPES, and 0.05 mM mercaptoethanol; assay medium: 4.5 g / L D-glucose, 100 mM NaPyr, 1% Pen / Strep, 10 mM HEPES, and 0.05 mM mercaptoethanol; 96-well V-bottom plates: Costar catalog number 3894; LPS (E. coli O26:B6): Sigma Cat. No. L2654, 5 mg / mL stock in PBS, ATP: Sigma Cat. No. A6419, prepared in 250 mM stock in 1 M HEPES (adjusted to pH 7.4).

[0575] Human PBMC NLRP3 assay: Cryopreserved PBMCs were rapidly thawed in a 37°C water bath for 2 minutes. Cells were then centrifuged at 1200 rpm for 5 minutes and resuspended in approximately 50 mL of fresh RPMI 1640 complete medium. Counts were performed using a hemocytometer to determine 2.5 x 10 5 A V-shaped 96-well plate was filled with 200 μL of PMBCs (5 × 10 cells / mL) per well. 4) and subsequently incubated overnight at 37°C with 5% CO2. Assay medium containing 100 ng / ml LPS was then prepared. PBMCs were then centrifuged at 1,200 rpm for 5 minutes, the serum-containing medium was aspirated, and 150 μL / well of assay medium + LPS was immediately added. Assay medium without LPS was added to untreated control wells. Cells were then primed with LPS for 4 hours at 37°C with 5% CO2. Concentration-response curves (CRCs) of 1000x test compounds in 100% DMSO were prepared. The CRCs were then diluted 1:50 in assay medium and then further diluted 1:5 in assay medium to obtain a final 4x CRC in 0.4% DMSO / assay medium. 50 μL / well of 4x test compound CRC or vehicle (0.4% DMSO / assay medium) was then transferred to each well, followed by incubation for 30 minutes at 37°C with 5% CO2. Cells were stimulated using a 250 mM stock solution prepared in 1 M Hepes without further dilution (for a final concentration of 5 mM) by adding 4 μL of 250 mM ATP for 1 hour at 37°C with 5% CO2. Plates were then centrifuged at 1200 rpm for 5 minutes, and 50 μL of medium was transferred to a clean 96-well storage plate for cytokine measurement using the Mesoscale platform and stored at -80°C until analysis. When TNFα was required to be quantified in a cytokine panel to confirm selectivity, compounds were added 30 minutes before priming cells with LPS.

[0576] Table A assigns each compound a code for potency in the human PBMC NLRP3 assay: A, B, C, or D. According to the code, A indicates an IC 50 A represents an IC value <0.3 μM. 50 values ​​≥ 0.3 μM and < 0.5 μM, and C represents the IC 50 values ​​≥ 0.5 μM and < 1.0 μM, and D represents the IC 50 Values ​​≥ 1.0 μM represent [Table 5]

[0577] Human whole blood-NLRP3 Blood was collected from volunteers using lithium heparin-coated tubes. Blood samples were distributed onto a 96-well plate using 90 μl per well. Priming was performed by adding 5 μl of LPS (O26:B6; Sigma L-2654) at a final concentration of 1 μg / ml for 4.5 hours at 37°C in a humidified incubator containing 5% CO2. Thirty minutes before NLRP3 activation, 5 μl of 20x compound solution or vehicle (2% DMSO) was added to each well, and the plate was incubated on a shaker (450 rpm) at 37°C in a humidified incubator containing 5% CO2. Activation was then performed by adding 3.3 μl of 31x ATP solution per well. At the end of the 30-minute stimulation, the plate was centrifuged (800 g, 10 minutes, room temperature), and plasma from each well was frozen at -80°C. IL-1β levels in the supernatants were analyzed using a mesoscale detection assay (MSD K151TUK) according to the manufacturer's instructions. Human whole blood was collected from healthy volunteers after obtaining written informed consent.

[0578] Table B assigns each compound a code for potency in the human whole blood (hWB) NLRP3 assay: A or B. According to the code, A is the IC 50 A represents a value ≤ 1.0 μM, and B represents the IC 50 >1.0 μM. [Table 6-1] [Table 6-2]

[0579] Example 10. Compound efficacy The table below shows the improved potency observed. Note that in the present disclosure, the fused bicyclic pyridine analogs exhibit improved activity over the monocyclic pyridazines as demonstrated by potency in the PBMC assay: [Table 7]

[0580] It is further noted that certain pyridopyridazine positional isomers of the present disclosure exhibit improved potency compared to other positional isomers. The introduction of a nitrogen atom into the bicyclic structure also allows for protein binding, which correlates with improved whole blood potency. [Table 8]

[0581] equivalent Details of one or more embodiments of the present disclosure are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, preferred methods and materials are described below. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference.

[0582] The foregoing description has been presented for purposes of illustration only and is not intended to limit the disclosure to the precise form disclosed, but is limited only by the claims appended hereto.

Claims

1. A compound of formula II, 【Chemistry 1】 or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y is phenyl, said phenyl having one or more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, halo, cyano, or -R ４ OR ５ wherein at least one substitution is in the para position of the phenyl ring; R １ but: 1) optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C ５ -C １０ substituted with aryl, or optionally substituted 5- to 9-membered heteroaryl; １ -C ６ Is it alkyl; 2) optionally one or more halo, -R ４ OR ５ , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C ５ -C １０ a 3-8 membered heterocycloalkyl substituted with an aryl, or an optionally substituted 5-9 membered heteroaryl; 3) optionally one or more halo, -R ４ OR ５ , optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted C ５ -C １０ aryl, or a 5- to 9-membered heteroaryl substituted with an optionally substituted 5- to 9-membered heteroaryl; R ２ and R ３ together with the atoms to which they are attached, optionally one or more R ２ａ forming a 5- to 9-membered heteroaryl substituted with R ２ａ is hydrogen, C １ -C ６ Alkyl, halo, or C １ -C ６ is haloalkyl, R ４ is bond, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, or C ２ -C ６ is alkynyl, R ５ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocycloalkyl, C ５ -C １０ aryl, or 5-9 membered heteroaryl, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

2. Y is one or more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, halo, cyano, or -R ４ OR ５ phenyl, independently substituted with at least one substitution at the para position of the phenyl ring; R １ is substituted with an optionally substituted 3- to 8-membered heterocycloalkyl; １ -C ６ is alkyl, R ２ and R ３ but along with the atoms to which they are attached, 【Chemistry 2】 Forming R ４ is a bond, R ５ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocycloalkyl, C ５ -C １０ The compound of claim 1 which is aryl, or 5-9 membered heteroaryl.

3. Y is C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, halo, cyano, or -R ４ OR ５ 2. The compound of claim 1, wherein the phenyl ring is substituted in the para position with

4. Y is two C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, halo, cyano, or -R ４ OR ５ 2. The compound of claim 1 , wherein the phenyl is substituted with at least one of the substitutions at the para position of the phenyl ring.

5. R ５ The compound of claim 1 , wherein is hydrogen.

6. R ２ and R ３ but, 【Chemistry 3】 and participates in the formation of the compound of formula II-h 【Chemistry 4】 (Here, R ２a is H) 2. The compound of claim 1 , or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof,

7. The compound of claim 2, selected from the group consisting of: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】 or a pharma- ceutically acceptable salt of any of the foregoing compounds.

8. The compound of claim 2, selected from the group consisting of: 【Table 7】 or a pharma- ceutically acceptable salt of any of the foregoing compounds.

9. The compound of claim 2, selected from the group consisting of: 【Table 8】 or a pharma- ceutically acceptable salt of any of the foregoing compounds.

10. The compound is 【Table 9】 10. The compound of claim 9, which is: or a pharma- ceutically acceptable salt thereof.

11. The compound is 【Table 10】 10. The compound of claim 9, which is: or a pharma- ceutically acceptable salt thereof. Claim 12: A compound of formula II: 【Chemistry 5】 or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: Y is one or more C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, halo, cyano, or -R ４ OR ５ phenyl, independently substituted with at least one substitution at the para position of the phenyl ring; R １ optionally one or more halo, C １ -C ６ Alkyl, or -R ４ OR ５ tetrahydrofuranyl substituted with R ２ and R ３ but along with the atoms to which they are attached, 【Chemistry 6】 Forming R ４ is a bond, R ５ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, 3-8 membered heterocycloalkyl, C ５ -C １０ aryl, or 5-9 membered heteroaryl, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof.

13. Y is C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, halo, cyano, or -R ４ OR ５ 13. The compound of claim 12, wherein the phenyl ring is substituted in the para position with:

14. Y is two C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C ３ -C ８ Cycloalkyl, halo, cyano, or -R ４ OR ５ 13. The compound of claim 12, wherein the phenyl is substituted with at least one substitution in the para position of the phenyl ring.

15. R ５ The compound of claim 12 , wherein is hydrogen.

16. R ２ and R ３ but, 【Chemistry 7】 and participates in the formation of the compound of formula II-h 【Chemistry 8】 (Here, R ２a is H) 13. The compound of claim 12, or a pharma- ceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein

17. The compound of claim 12, selected from the group consisting of: 【Table 11】 or a pharma- ceutically acceptable salt of any of the foregoing compounds.

18. 13. An isotopic derivative of the compound of claim 1 or 12.

19. 13. A pharmaceutical composition comprising a compound of claim 1 or 12 and one or more pharma- ceutically acceptable carriers.

20. 20. The pharmaceutical composition of claim 19 for use in the treatment or prevention of an NLRP3-related disease or disorder, wherein a therapeutically effective amount of the composition is administered to a human subject.

Images