Compounds for inhibiting nlrp3 and uses thereof

Abstract

This disclosure relates to an inhibitor of NLRP3, which is useful in the treatment of diseases and disorders inhibited by this protein and has the formula (I): .

Description

[Technical Field]

[0001] This invention relates to inhibitors of NLR family pyrin domain-containing 3 (NLRP3) proteins. The inhibitors described herein can be used to treat diseases and disorders associated with modulation of the NLRP3 protein. In particular, this invention focuses on compounds and pharmaceutical compositions that inhibit NLRP3, methods for treating NLRP3-related diseases and disorders using these compounds and pharmaceutical compositions, and methods for synthesizing such compounds and compositions. Related Applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 171,932, filed April 7, 2021, and U.S. Patent Application No. 17 / 528,928, filed November 17, 2021, the entire contents of which are incorporated herein by reference in their whole. [Previous 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). Once bound, these receptors trigger activation of downstream inflammatory pathways, which helps resolve damage. However, in many cases, this activation can be uncontrolled and lead to disease.

[0004] Inflammasomes represent a class of proton pump inhibitors (PRRs), which are key components of the innate immune response. Activation of inflammasomes triggers a cascade of events, releasing IL-1β and IL-18, and promoting an inflammatory form of cell death called pyroptosis induced by Gasdermin activation. Pyroptosis is a unique form of inflammatory cell death that not only leads to the release of intercytokines but also to the release of other intracellular components that promote a broader immune response in both the innate and acquired immune systems. Therefore, inflammasome activation is a major regulator of the inflammatory cascade.

[0005] NLRP3 is the most characteristic inflammasome and has been shown to play a key role in innate immunity and inflammatory responses. While several other NLR complexes, such as NLRC4, are activated under very specific conditions, NLRP3 can be activated by a wide variety of stimuli and should be considered a sensor of intracellular homeostasis imbalance. Therefore, its precise function is essential. In addition to its role in host immune defense, dysregulation of NLRP3 has been linked to the pathogenesis of many inflammatory disorders. These include genetic diseases such as cryopyrin-associated periodic syndrome (CAPS) caused by gain-of-function mutations in the NLRP3 gene, as well as many common neurological and systemic diseases. Importantly, NLRP3 overactivation has been preclinically demonstrated to play a key role in a large number of inflammatory and degenerative diseases, including NASH, atherosclerosis and other cardiovascular diseases, Alzheimer's disease, Parkinson's disease, diabetes, gout, and many other autoinflammatory diseases. Therefore, there is an unmet need in this technological field to develop small molecules that modulate NLRP3 activity to treat a wide range of diseases and disorders. [Summary of the Invention]

[0006] In a first aspect, this disclosure particularly provides a compound of formula (I): , or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, stereoisomer, or tautomer thereof, wherein: X is N (Ra), O, S, or C (Rb)(Rc); Ra 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; or Ra cyclizes with R1 to form 3-to-8-membered heterocycloalkyl; Rb is hydrogen or C1-C6 alkyl; Rc is hydrogen or C1-C6 alkyl; or Rb and Rc together with the atoms to which they are attached form a C3-C8 cycloalkyl; Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl may be derived from one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl groups as desired. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(3-to-8-membered heterocycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(5-to-9-membered heteroaryl), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), - R4N(R7)S(O)t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as required by one or more halogroups, CN, C1-C6 alkyl, -R4OR5, -NR5R6, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C10 aryl, or substituted 5- to 9-membered heteroaryl as required;R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R3) R5)2 or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogen, or C1-C6 haloalkyl groups as required; or R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group is substituted with one or more R2a groups as required; R2a is hydrogen, deuterium, C1-C6 alkyl, haloyl, or C1-C6 haloalkyl; R4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; R5 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, wherein the alkyl group is substituted with one or more D groups as required; R6 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; R7 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; R8 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; or R7 and R8 together with the atoms to which they are attached form 3-to-8-membered heterocycloalkyl;n is 0, 1, 2, 3, or 4; and t is 1 or 2; the constraint is that R1 is not a C2 or C4 alkyl group substituted with a morpholino group.

[0007] Another aspect of this disclosure relates to a compound of formula (I'): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X is N (Ra), O, S, or C (Rb)(Rc); Ra 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; or Ra cyclizes with R1 to form 3- to 8-membered heterocycloalkyl; Rb is hydrogen or C1-C6 alkyl; Rc is hydrogen or C1-C6 alkyl; or Rb and Rc together with the atoms to which they are attached form a C3-C8 cycloalkyl; Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl may be derived from one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl groups as desired. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(3- to 8-membered heterocycloalkyl), or -(CH2)n-(5- to 9-membered heteroaryl), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8). -R4N(R7)S(O)t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as required by one or more halogroups, CN, C1-C6 alkyl, -NR5R6, -R4OR5, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C10 aryl, or substituted 5- to 9-membered heteroaryl as required;R2 and R3, together with the atoms to which they are attached, form a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl is substituted with one or more R2a as required; R2a is hydrogen, deuterium, C1-C6 alkyl, haloyl, or C1-C6 haloalkyl; R4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; R5 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, wherein the alkyl group is substituted with one or more D as required; R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heterocycloalkyl; R7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heterocycloalkyl; R8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heterocycloalkyl; or R7 and R8 together with the atoms to which they are attached form a 3-to-8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; and t is 1 or 2; the restriction is that R1 is not a C2 or C4 alkyl group substituted with a morpholinoyl group.

[0008] Another aspect of this disclosure relates to a compound of formula (I''): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X is N (Ra), O, S, or C (Rb)(Rc); Ra 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; or Ra cyclizes with R1 to form 3-to-8-membered heterocycloalkyl; Rb is hydrogen or C1-C6 alkyl; Rc is hydrogen or C1-C6 alkyl; or Rb and Rc together with the atoms to which they are attached form a C3-C8 cycloalkyl; Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl may be derived from one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl groups as desired. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(3- to 8-membered heterocycloalkyl), or -(CH2)n-(5- to 9-membered heteroaryl), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8). -R4N(R7)S(O)t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as required by one or more halogroups, CN, C1-C6 alkyl, -NR5R6, -R4OR5, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C10 aryl, or substituted 5- to 9-membered heteroaryl as required;R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl, wherein for -R4OR5, R4 can only be a bond; R5 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, wherein the alkyl group is substituted with one or more D groups as required; R6 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; R7 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; R8 is hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C3-C8 cycloalkyl, a 3- to 8-membered heterocycloalkyl, a C6-C10 aryl, or a 5- to 9-membered heteroaryl; or R7 and R8 together with the atoms to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; and t is 1 or 2; the restriction is that R1 is not a C2 or C4 alkyl group substituted with a morpholinoyl group.

[0009] Another aspect of this disclosure relates to a compound of formula (II): , or a pharmaceutically acceptable salt, solvate, inclusion complex, hydrate, stereoisomer, or tautomer thereof, wherein: Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl is optionally mediated by one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(3- to 8-membered heterocycloalkyl), or -(CH2)n-(5- to 9-membered heteroaryl), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8). -R4N(R7)S(O)t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as required by one or more halogroups, CN, C1-C6 alkyl, -NR5R6, -R4OR5, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C10 aryl, or substituted 5- to 9-membered heteroaryl as required;R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R3) R5)2 or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogen, or C1-C6 haloalkyl groups as required; or R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group is substituted with one or more R2a groups as required; R2a is hydrogen, deuterium, C1-C6 alkyl, haloyl, or C1-C6 haloalkyl; R4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; R5 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, wherein the alkyl group is substituted with one or more D groups as required; R6 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; R7 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; R8 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; or R7 and R8 together with the atoms to which they are attached form 3-to-8-membered heterocycloalkyl;n is 0, 1, 2, 3, or 4; and t is 1 or 2; the constraint is that R1 is not a C2 or C4 alkyl group substituted with a morpholino group.

[0010] In some aspects, this disclosure provides compounds that can be obtained by or by methods for preparing compounds as described herein (e.g., methods comprising one or more steps as described in schemes 1, 2, and 3).

[0011] In some aspects, this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable diluents or carriers.

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

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

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

[0015] In some aspects, this disclosure provides a compound of the disclosed herein or a pharmaceutically acceptable salt thereof for the treatment or prevention of the diseases or ailments disclosed herein.

[0016] In some aspects, this disclosure provides a compound of the disclosed herein or a pharmaceutically acceptable salt thereof for the treatment of the disease or ailment disclosed herein.

[0017] In some aspects, this disclosure provides the use of the disclosed compounds or pharmaceutically acceptable salts thereof in the manufacture of medicaments for the treatment or prevention of the diseases or ailments disclosed herein.

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

[0019] In some embodiments, the disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, mental illness, graft-versus-host disease, abnormal pain, or NLRP3-related disease in subjects who have been identified as carrying germline or somatic non-silent mutations in NLRP3.

[0020] In some embodiments, the central nervous system disease or disorder 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 acute kidney disease, chronic kidney disease, or 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-related disease in subjects who have been identified as carrying germline or somatic non-silent mutations 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, this disclosure provides a method for preparing the compounds disclosed herein.

[0027] In some aspects, this disclosure provides a method for preparing a compound, which includes one or more 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 pertains. In this specification, the singular form also includes the plural unless the context clearly specifies otherwise. Although similar or equivalent methods and materials to those described herein may be used in the practice or testing of this 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 considered prior art to the claimed invention. In case of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and not intended to be restrictive. In case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structure shall prevail.

[0029] Other features and advantages of this disclosure will become clear from the following embodiments and the claims.

Implementation Method

[0030] Detailed Description

[0031] This disclosure relates to methods for using pyridazine and phthalazine derivatives, their pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, single stereoisomers, mixtures of stereoisomers, or racemic mixtures of stereoisomers, which can inhibit NLRP3 activity and thereby be used to treat humans or animals. This disclosure also relates to methods for preparing these compounds, pharmaceutical compositions comprising them, and their use in treating diseases involving NLRP3, such as inflammation, autoimmune diseases, cancer, infections, central nervous system diseases or disorders, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, mental illnesses, graft-versus-host disease, abnormal pain, or NLRP3-related diseases in subjects who have been identified as carrying germline or somatic non-silent mutations in NLRP3. Definitions

[0032] Unless otherwise stated, the following terms used in the specification and the claims have the following meanings as listed below.

[0033] 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 (linear) 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 groups include portions having one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n-pentyl, isopentyl, or n-hexyl. In some embodiments, the straight-chain or branched alkyl group has six or fewer carbon atoms (e.g., for straight-chain C1-C6, for branched C3-C6), and in another embodiment, the straight-chain or branched alkyl group has four or fewer carbon atoms.

[0034] As used herein, the term "substituted alkyl group as required" means an unsubstituted alkyl group or an alkyl group having one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone replaced by a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amine The group includes alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino, acetoamino (including alkylcarbonylamino, arylcarbonylamino, aminomethylamino and urea), formamidinyl, imino, hydrogen sulfide, alkyl thio, aryl thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, aminosulfonyl, sulfoamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moiety.

[0035] As used herein, the term "alkenyl" includes an unsaturated aliphatic group that is similar in length and possible substitutions to the alkyl groups described above, but contains at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In some embodiments, the straight-chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., C2-C6 for straight-chain, C3-C6 for branched). The term "C2-C6" includes alkenyl groups containing two to six carbon atoms. The term "C3-C6" includes alkenyl groups containing three to six carbon atoms.

[0036] As used herein, the term "alkenyl group substituted as desired" refers to an unsubstituted alkenyl group or an alkenyl group having a specified substituent replacing one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, and phosphinato. Amine (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acetoamino (including alkylcarbonylamino, arylcarbonylamino, aminomethylamino and urea), formamidinyl, imino, hydrogen sulfide, alkyl thio, aryl thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, aminosulfonyl, sulfoamino, nitro, trifluoromethyl, cyano, heterocyclic, alkylaryl, or aromatic or heteroaromatic moiety.

[0037] As used herein, the term "alkynyl" includes an unsaturated aliphatic group that is similar in length and possible substituents to the alkyl groups described above, but contains at least one determinate bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, penynyl, hexynyl, hepynyl, octyynyl, nonynyl, decyynyl) and branched-chain alkynyl groups. In some embodiments, the straight-chain or branched alkynyl group has six or fewer carbon atoms in its main chain (e.g., C2-C6 for straight-chain, C3-C6 for branched-chain). The term "C2-C6" includes alkynyl groups containing two to six carbon atoms. The term "C3-C6" includes alkynyl groups containing three to six carbon atoms. As used herein, "C2-C6 alkenyl linker" or "C2-C6 alkyne linker" is intended to include C2, C3, C4, C5, or C6 chain (linear or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, C2-C6 enylene linkers are intended to include C2, C3, C4, C5 and C6 enylene linkers.

[0038] As used herein, the term "substituted alkynyl group as desired" refers to an unsubstituted alkynyl group or an alkynyl group having one or more hydrogen atoms on the main carbon atom of a hydrocarbon backbone replaced by a specified substituent. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amine The group includes alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino, acetoamino (including alkylcarbonylamino, arylcarbonylamino, aminomethylamino and urea), formamidinyl, imino, hydrogen sulfide, alkyl thio, aryl thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, aminosulfonyl, sulfoamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moiety.

[0039] Other substituted portions (such as substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups) include both the unsubstituted portion and the portion having one or more of the specified substituents. For example, substituted heterocycloalkyl groups 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.

[0040] As used herein, the term “cyano” refers to an nitrile group (e.g., -CN).

[0041] As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic (e.g., fused, bridged, or screwed) system of saturated or partially unsaturated hydrocarbons having 3 to 30 carbon atoms (e.g., C3-C12, C3-C10, or C3-C8). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl. In the case of polycyclic cycloalkyl, only one ring in the cycloalkyl group needs to be non-aromatic.

[0042] As used herein, the term “heterocyclic alkyl” means, unless otherwise stated, a saturated or partially unsaturated 3 to 8-member monocyclic or bicyclic, 7 to 12-member bicyclic (fused, bridged or screwed) or 11 to 14-member cyclic ring system (fused, bridged or screwed) having one or more heteroatoms (such as O, N, S, P or Se) independently selected from the group consisting of nitrogen, oxygen and sulfur, for example 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or for example 1, 2, 3, 4, 5 or 6 heteroatoms. Examples of heterocyclic alkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxalyl, tetrahydrofuranyl, isoindolinyl, indololinyl, imidazodiphenyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, ethylene oxide, azacyclobutyl, oxacyclobutyl, thiocyclobutyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropiperanyl, dihydropiperanyl, piperanyl, morpholinyl, tetrahydrothiaranyl, 1,4-diazacycloheptyl, 1,4-oxacycloheptyl, and 2-oxa-5-azacycloheptyl. Heterobicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-diaza-8-azaspiro[4.5]decyl, 1,4-diazaspiro[4.5]decyl, 1-oxaspiro[4.5]decyl, 1-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7'H-spiro[cyclohexane-1,5'- [3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furano[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-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]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl, 5,6-dihydro-4H-cyclopentano[b]thiophene, etc. In the case of polycyclic heterocyclic alkyl groups, only one ring in the heterocyclic alkyl group needs to be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0043] As used herein, the term "heterocyclic alkyl group that is substituted as required" means an unsubstituted heterocyclic alkyl group or a heterocyclic alkyl group having a specified substituent replacing one or more hydrogen atoms on one or more carbons or heteroatoms. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amine The group includes alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino, acetoamino (including alkylcarbonylamino, arylcarbonylamino, aminomethylamino and urea), formamidinyl, imino, hydrogen sulfide, alkyl thio, aryl thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, aminosulfonyl, sulfoamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moiety.

[0044] 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. In the case of two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be connected at a single point (e.g., biphenyl) or fused (e.g., naphthyl). The aryl group may be substituted with one or more substituents at any attachment point as needed, for example, one to five substituents. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1-C6)alkyl, (C1-C6)alkyl, -O-(C2-C6)alkenyl, -O-(C2-C6)ynyl, (C2-C6)alkenyl, (C2-C6)ynyl, -OH, -OP(O)(OH)2, -OC(O)(C1-C6)alkyl, -C(O)(C1-C6)alkyl, -OC(O)O(C1-C6)alkyl, -NH2, NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -S(O)2-(C1-C6)alkyl, -S(O)NH(C1-C6)alkyl, and -S(O)N((C1-C6)alkyl)2. The substituent itself may be substituted as needed. Furthermore, when containing two or more fused rings, the aryl group defined herein may 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, anthracene, ferroyl, phenanthryl, indanyl, indenyl, tetrahydronaphthyl, tetrahydrobenzoannullenyl, 10,11-dihydro-5H-dibenzo[a,d][7]annullenyl, etc.

[0045] Unless otherwise specifically defined, “heteroaryl” means a monovalent monocyclic or polycyclic aromatic group of 5 to 24 ring atoms, containing one or more cyclic heteroatoms selected from N, O, S, P, Se, or B, with the remaining ring atoms being C. As defined herein, a heteroaryl also means a bicyclic heteroaryl, wherein the heteroatom is selected from N, O, S, P, Se, or B. As defined herein, a heteroaryl also means a tricyclic heteroaryl containing one or more cyclic heteroatoms selected from N, O, S, P, Se, or B. The aromatic group may be independently substituted with one or more substituents as described herein, as required.Examples include, but are not limited to, furanyl, thiophene, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazoleyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indoleyl, thiophene-2-yl, quinolinyl, benzopiperanyl, isothiazolyl, thiazolyl, thiazolyl, thiadiazolyl, indazoleyl, benzimidazolyl, thieno[3,2-b]thiopheneyl, triazolyl, triazinyl, imidazo[1,2-b]pyrazolyl, furan[2,3-c]pyridyl, imidazo[1,2-a]pyridyl, indazoleyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrazolo[3,4-c]pyridyl, thieno[3,2-c]pyridyl, and thieno[2,3-c]pyridyl. Pyridyl, thieno[2,3-b]pyridyl, benzothiazolyl, indole, indolinyl, indolinonyl, dihydrobenzothiophene, dihydrobenzofuranyl, benzofuranyl, benzodihydropiperanyl, thiobenzodihydropiperanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, quinolinyl, isoquinolinyl, 1,6-naphthidyl, benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthidyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazo[1,5-a]pyridyl, [1,2,4]triazo[4,3-a]pyridyl, isoindolyl, pyrrolo[2,3-b]pyridyl , pyrrolo[3,4-b]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[5,4-b]pyridyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1λ2-pyrrolo[2,1-b]pyrimidinyl, dibenzo[b,d]thiopheneyl, pyridin-2-one, furano[3,2-c]pyridyl, furano[2,3-c]pyridyl, 1H-pyrido[3,4-b][1,4]thiazinyl, benzoxazoleyl, benzoisoxazoleyl, furano[2,3-b]pyridyl, benzothiopheneyl, 1,5-naphthidyl, furano[3,2-b]pyridine, [1,2,4] Triazolo[1,5-a]pyridyl, 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]oxadiazolyl, 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]pyridyl, triazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrroleyl, 3H-indolyl, and their derivatives.Furthermore, when containing two or more fused rings, the heteroaryl group defined herein may have one or more saturated or partially unsaturated rings fused to a fully unsaturated aromatic ring, such as a 5-membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, S, P, Se, or B, or a 6-membered heteroaryl ring containing 1 to 3 nitrogen atoms, wherein the saturated or partially unsaturated ring comprises 0 to 4 heteroatoms selected from N, O, S, P, Se, or B, and is substituted with one or more side oxygen groups as needed. In a heteroaryl ring system containing more than two fused rings, the saturated or partially unsaturated ring may be further fused to the saturated or partially unsaturated rings described herein. Exemplary ring systems of these heteroaryl groups include, for example, indololinyl, indololinone, dihydrobenzothiophene, dihydrobenzofuranyl, benzodihydropiperanyl, thiobenzodihydropiperanyl, tetrahydroquinolinyl, dihydrobenzothiazinyl, 3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranone, indololinyl, indolone, indolyl, 1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-one, and 7,8-dihydro-6H-pyridine. [3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl, 1,5,6,7-tetrahydrocyclopentano[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, pyrazolo[1,5-a]pyrimidine-7(4H)-keto, 3,4-dihydropyrazolo[1,2-a]indole-1(2H)-keto, or benzo[c][1,2]oxaborhecyclopentadien-1(3H)-ol.

[0046] The cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring may be substituted at one or more ring positions (e.g., the cyclic carbon or heteroatom such as N) with substituents such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonic acid The group can be phosphonato, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acetoamino (including alkylcarbonylamino, arylcarbonylamino, aminomethylamino, and urea), formamidinyl, imino, hydrogen sulfide, alkyl thio, aryl thiocarboxylate, sulfate, alkylsulfinyl, sulfonyl, aminosulfonyl, sulfoamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties. Aryyl and heteroaryl groups can also be fused or bridged with non-aromatic alicyclic rings or heterocycles to form polycyclic systems (e.g., tetrahydronaphthalene, methylenedioxyphenyl, such as benzo[d][1,3]dioxacyclopenten-5-yl).

[0047] As used herein, the term “substituted” means that any one or more hydrogen atoms on a specified atom are replaced by an option from the group, limited to not exceeding the normal bond valence of the specified atom, and that the substitution yields a stable compound. When the substituent is a side oxygen or ketone group (i.e., =O), two hydrogen atoms on that atom are substituted. Ketone substituents do not appear on aromatic moieties. As used herein, a cyclic 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” mean a compound that is robust enough to survive from isolation from RM to a useful level of purity and to be formulated into an effective therapeutic agent.

[0048] When the bond with a substituent shows a cross bond with two atoms in the linking ring, such a substituent may be bonded to any atom in that ring. When a substituent is listed but not specified via which atom it is bonded to the remainder of the compound in the given formula, such a substituent may be bonded via any atom in that formula. Combinations of substituents and / or variables are permitted, but only if such combinations result in a stable compound.

[0049] When any variable (e.g., R) appears more than once in any component or formula of a compound, its definition for each occurrence is independent of its definition for each subsequent occurrence. Thus, for example, if a group appears to be partially substituted by 0-2 R, then the group may be partially substituted by at most two R as needed, and R is chosen independently from the definition of R for each occurrence. Also, combinations of substituents and / or variables are permitted, but only if such combinations result in a stable compound.

[0050] As used herein, the term “hydroxyl” or “hydroxyl” includes groups having -OH or -O-.

[0051] As used herein, the term “halogen” or “halogen” refers to fluorine, chlorine, bromine and iodine groups.

[0052] The terms “haloalkyl” or “haloalkoxy” refer to alkyl or alkoxy groups that have been substituted with one or more halogen atoms.

[0053] As used herein, the term "haloalkyl group substituted as required" means an unsubstituted haloalkyl group or a haloalkyl group having a specified substituent replacing one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amine The group includes alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino, acetoamino (including alkylcarbonylamino, arylcarbonylamino, aminomethylamino and urea), formamidinyl, imino, hydrogen sulfide, alkyl thio, aryl thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, aminosulfonyl, sulfoamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moiety.

[0054] 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 or alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy groups include haloalkoxy groups. Alkoxy groups can be represented by groups such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate, phosphonato, phosphinato, amino ( This includes alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino groups; acetylamides (including alkylcarbonylamino, arylcarbonylamino, aminomethylamino, and urea); formamidinyl; imino; hydrogen sulfide; alkyl thio; aryl thio; thiocarboxylate; sulfate; alkylsulfinyl; sulfonate; aminosulfonyl; sulfoamino; nitro; trifluoromethyl; cyano; azide; heterocyclic; alkylaryl; or partially substituted aromatic or heteroaromatic groups. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

[0055] It should be understood that this disclosure provides methods for synthesizing compounds of any of the formulas described herein. This disclosure also provides detailed methods for synthesizing various compounds disclosed herein according to the schemes shown in the following examples and embodiments.

[0056] It should be understood that throughout the specification, when a composition is described as having, including, or containing specific ingredients, it is anticipated that the composition is substantially composed of, or consists of, the listed ingredients. Similarly, when a method or program is described as having, including, or containing specific program steps, these programs are also substantially composed of, or consist of, the listed processing steps. Furthermore, it should be understood that the order of the steps or the order in which certain actions are performed is irrelevant, as long as the invention remains operable. Moreover, two or more steps or actions may be performed simultaneously.

[0057] It should be understood that the synthetic procedures disclosed herein can tolerate a wide variety of functional groups, and therefore a variety of substituted starting materials can be used. These procedures generally provide the desired final compound at or near the end of the procedure, although in some cases it may be desirable to further convert the compound into its pharmaceutically acceptable salt.

[0058] It should be understood that the compounds disclosed herein can be prepared in various ways using commercially available starting materials, compounds known in the literature, or from easily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art, or clearly understood by those skilled in the art in light of the teachings herein. Standard synthetic methods and procedures for preparing organic molecules and for functional group conversions and manipulations can be obtained from relevant scientific literature or from standard textbooks in the art. Although not limited to any one or a few sources, classic texts such as Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; Greene, TW, Wuts, PGM, 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 and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) (all of which are incorporated herein by reference) are reference textbooks of organic synthesis known and understood by those of ordinary skill in the art.

[0059] Those skilled in the art will notice that the order of certain steps, such as the introduction and removal of protecting groups, can be altered during the reaction sequence and synthetic scheme described herein. Those skilled in the art will recognize that certain groups may require protection from the effects of reaction conditions by using protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove these groups can be found in Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999.

[0060] It should be understood that, unless otherwise stated, any description of a method of treatment or prevention includes using the compound as described herein to provide such treatment or prevention. It should be further understood that, unless otherwise stated, any description of a method of treatment or prevention includes using the compound to prepare a medicament for treating or preventing such a condition. Treatment or prevention includes treating or preventing human or non-human animals, including rodents and other disease models.

[0061] It should be understood that, unless otherwise stated, any description of a method of treatment includes using the compound as described herein to provide such treatment. It should be further understood that, unless otherwise stated, any description of a method of treatment includes using the compound to prepare an agent for treating such a condition. Treatment includes treating human or non-human animals, including rodents and other disease models. As used herein, the term “object” is interchangeable with the term “object in need,” both referring to an object having a disease or having an increased risk of developing that disease. “Object” includes mammals. Mammals can be, for example, humans or suitable non-human mammals such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. In one embodiment, the mammal is a human. An object in need can be an object previously diagnosed or identified as having the disease or ailment disclosed herein. An object in need can also be an object suffering from the disease or ailment disclosed herein. Alternatively, an object in need can be someone who has an increased risk of developing such a disease or ailment relative to the majority of the population (i.e., an object who is susceptible to developing such a disease relative to the majority of the population). The subject of need may have a refractory or resistant form of the disease or ailment disclosed herein (i.e., a disease or ailment disclosed herein that is unresponsive to treatment 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 of need has received all known effective therapies for the disease or ailment disclosed herein and these have failed. In some embodiments, the subject of need has received at least one prior therapy.

[0062] As used herein, the terms “treating” or “treatment” describe the management and care of a patient for the purpose of combating a disease, condition, or ailment, and include administering the compounds disclosed herein, or their pharmaceutically acceptable salts, polymorphs, or solvates, to alleviate or eliminate symptoms or complications of the disease, condition, or ailment. The term “treatment” may also include treatment of cells in vitro or in animal models. It should be understood that references to “treating” or “treatment” include the relief of established symptoms of a condition. Therefore, “treatment” or “treatment of” a state, disease or ailment includes: (1) preventing or delaying the development of clinical symptoms of the state, disease or ailment in a person who may be susceptible to or is vulnerable to the state, disease or ailment but has not yet experienced or exhibited clinical or subclinical symptoms of the state, disease or ailment; (2) suppressing the state, disease or ailment, i.e. preventing, reducing or delaying the development of the disease or its recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviating or attenuating the disease, i.e. causing the disappearance of the state, disease or ailment or at least one of its clinical or subclinical symptoms.

[0063] It should be understood that the compounds disclosed herein, or their pharmaceutically acceptable salts, polymorphs or solvates, may or may be used to prevent related diseases, symptoms or ailments, or to identify suitable candidates for such purposes.

[0064] As used herein, the terms “preventing,” “prevent,” or “protection against” describe the reduction or elimination of the onset of symptoms or complications of such disease, condition, or illness.

[0065] It should be understood that those skilled in the art can refer to general reference texts to obtain a detailed description of the known or equivalent techniques discussed herein. 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; Fingle et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th edition (1990). Of course, these texts may also be referenced when making or using any aspect of this disclosure.

[0066] It should be understood that this disclosure also provides pharmaceutical compositions comprising at least one pharmaceutically acceptable excipient or carrier in any combination of compounds described herein.

[0067] As used herein, the term "pharmaceutical composition" is a formulation containing the compounds disclosed herein, in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or in unit dosage form. Unit dosage form is any of various forms, including, for example, capsules, IV bags, tablets, a single pump or vial on an aerosol inhaler. The amount of the active component (e.g., formulations of the disclosed compound or its salts, hydrates, solvates or isomers) in a unit dose of the composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that, depending on the patient's age and condition, routine variations in dosage may sometimes be necessary. The dosage will also depend on the route of administration. Various routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, etc. The disclosed compounds can be administered topically or transdermally in dosage forms including powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

[0068] As used herein, the term “pharmaceutically acceptable” means, to a reasonable extent of medical judgment, those compounds, anions, cations, materials, components, carriers, and / or dosage forms that are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0069] As used herein, the term "pharmaceuticalally acceptable excipient" means an excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable for the preparation of a pharmaceutical composition, and includes excipients acceptable for both veterinary and human pharmaceutical uses. As used in the specification and claims, "pharmaceuticalally acceptable excipient" includes both one and more such excipients.

[0070] It should be understood that the pharmaceutical compositions disclosed herein are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral, such as intravenous, intradermal, subcutaneous, oral (e.g., ingestion), inhalation, transdermal (topical), and transmucosal administration. Solutions or suspensions intended for parenteral, intradermal, or subcutaneous administration may include the following components: sterile diluents, such as water for injection, saline solution, non-volatile oils, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antimicrobial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetates, citrates, or phosphates; and tonic agents, such as sodium chloride or dextran. The pH may be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials.

[0071] It should be understood that the compounds or pharmaceutical compositions disclosed herein can be administered to a subject using a variety of methods currently known for chemotherapeutic treatment. For example, the compounds disclosed herein can be injected into the bloodstream or body cavities, or taken orally, or applied through the skin as a patch. The chosen dose should be sufficient to constitute an effective treatment, but not so high as to cause unacceptable side effects. The status of the disease condition (e.g., the disease or ailment disclosed herein) and the patient's health should preferably be closely monitored during treatment and for a reasonable period after treatment.

[0072] As used herein, the term "therapeutic effective amount" refers to the amount of a pharmaceutical agent used to treat, improve, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay method known in the art. The exact effective amount for a subject will depend on the subject's weight, body type, and health status; the nature and severity of the condition; and the choice of the therapeutic agent or combination of therapeutic agents to be administered. The therapeutic effective amount for a given situation can be determined by routine experiments within the scope of the clinician's skill and judgment.

[0073] It should be understood that for any compound, the therapeutically effective dose can initially be estimated in cell culture assays (e.g., tumor cells) or in animal models (typically 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 the useful dose and route of administration to humans. Therapeutic / prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or laboratory animals, such as ED50 (the dose that is 50% therapeutically effective in the population) and LD50 (the dose that is 50% lethal in the population). The dose ratio of toxicity to therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Pharmaceutical compositions exhibiting a large therapeutic index are preferred. The dose can vary within this range, depending on the dosage form used, patient sensitivity, and route of administration.

[0074] Adjust the dosage and administration to provide an adequate amount of active agent or maintain the desired effect. Factors to consider include the severity of the disease state, the subject's general health status, the subject's age, weight, sex, diet, timing and frequency of administration, drug combination, sensitivity to response, and tolerance / response to the therapy.

[0075] Pharmaceutical compositions containing the active compounds disclosed herein can be manufactured using known methods, such as by conventional mixing, dissolving, granulation, tablet preparation, grinding, emulsification, encapsulation, embedding, or lyophilization processes. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and / or adjuvants that facilitate the processing of the active compound into a pharmaceutically usable formulation. Of course, the appropriate formulation depends on the chosen route of administration.

[0076] Suitable pharmaceutical compositions for injection include sterile aqueous solutions (in the case of water solubility) or dispersions and sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor ELTM (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should be an injectable fluid. It must be stable under manufacturing and storage conditions and must be protected against microbial contamination such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. For example, appropriate flowability can be maintained by using coatings such as lecithin, by maintaining the required fineness in the case of dispersions, and by using surfactants. Microbial activity can be prevented by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, polyols like mannitol and sorbitol, and sodium chloride. The absorption of injectable compositions can be prolonged by including absorption-delaying agents, such as aluminum monostearate and gelatin.

[0077] A sterile injectable solution can be prepared by incorporating the desired amount of the active compound with one or a combination of the components listed above (when necessary) into a suitable solvent, followed by filtration and sterilization. Generally, a dispersion is prepared by incorporating the active compound into a sterile medium containing a basic dispersion medium and other desired components listed above. In the case of preparing a sterile powder for a sterile injectable solution, the preparation method is vacuum drying and freeze-drying to obtain a powder containing the active component plus any additional desired components from a previously sterile filtered solution.

[0078] Oral formulations generally include an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be combined with excipients and administered in tablet, lozenge, or capsule form. Oral formulations may also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is administered orally and rinsed and spat out or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the formulation. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0079] For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser containing a suitable propellant, such as a gaseous substance like carbon dioxide, or an atomizing agent.

[0080] Systemic administration can also be performed via mucosal or transdermal means. For mucosal or transdermal administration, a penetrant suitable for the osmotic barrier is used in the formulation. Such penetrants are known in the art and include, for example, cleansers, bile salts, and clostridial acid derivatives used for mucosal administration. Mucosal administration can be accomplished by using a nasal spray or suppository. For transdermal administration, the active compound is formulated into ointments, creams, gels, or lotions known in the art.

[0081] The active compound can be prepared with a pharmaceutically acceptable carrier that protects the compound against rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as vinyl ethylene acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations will be clear to those skilled in the art. These materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting infected cells with monoclonal antibodies against antiviral 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. Patent No. 4,522,811.

[0082] Formulating oral or enteral components into dosage units is particularly advantageous for ease of administration and dosage uniformity. As used herein, a dosage unit refers to a physically discrete unit suitable as a unit dose to the target of treatment; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect, as well as the required pharmaceutical carrier. The specifications of the dosage unit forms disclosed herein are determined by and directly depend on the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

[0083] In therapeutic applications, the dosage of the pharmaceutical composition used according to this disclosure depends on the agent, the age, weight, and clinical condition of the recipient patient, the experience and judgment of the clinician or practitioner administering the therapy, and other factors influencing the chosen dosage. Generally, the dosage should be sufficient to reduce and preferably eliminate the symptoms of the disease or ailment disclosed herein, and preferably to achieve complete elimination of the disease or ailment. Dosage ranges from about 0.01 mg / kg per day to about 5000 mg / kg per day. An effective amount of the pharmaceutical agent is one that provides an objectively identifiable improvement that is noted by a clinician or other qualified observer. Improvement in survival and growth indicates elimination. As used herein, the term "dosage-effective manner" refers to the amount of active compound that produces the desired biological effect in the subject or cells.

[0084] It should be understood that pharmaceutical composition may be contained in a container, package or dispenser together with the instructions for administration.

[0085] It should be understood that all these forms are also expected to be within the scope of the disclosure claimed for the compounds that are capable of further forming salts.

[0086] As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the disclosed compound, wherein the parent compound is modified by preparing its acidic or basic salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines, and alkali metal or organic salts of acidic residues such as carboxylic acids. 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, but are not limited to, salts derived from the following inorganic and organic acids: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, hydrocarbonic acid, carbonic acid, citric acid, ethylenediamine tetraacetate, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucohepatic acid, gluconic acid, glutamic acid, glycolic acid, glycolylarsine, hexylresorcinol, hydatid acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxybutenedioic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, lacturonic acid, lauryl sulfonic acid, maleic acid, malic acid, phenylethanolic acid, methanesulfonic acid, and naphthyl sulfonic acid. Acids, nitric acid, oxalic acid, primordial acid, pantothenic acid, phenylacetic acid, phosphorous acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, hypoacetic acid, succinic acid, sulfanilic acid, para-amine benzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, and arginine.

[0087] In some embodiments, pharmaceutically acceptable salts are sodium salts, potassium salts, calcium salts, magnesium salts, diethylamine salts, choline salts, meglumine salts, benzathine salts, trimethylamine salts, ammonium salts, arginine salts, or lysine salts.

[0088] Other pharmaceutically acceptable examples of salts include hexanoic acid, cyclopentylpropionic 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-en-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, mucoconic acid, etc. This disclosure also covers salts formed when the acidic proton system present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, trimethylamine, N-methylglucosamine, etc. In salt form, it should be understood that the ratio of the cation or anion of the compound to the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

[0089] It should be understood that references to pharmaceutically acceptable salts include the same salt in its solvation form (solvent) or crystalline form (polymorph) as defined herein.

[0090] The compound, or a pharmaceutically acceptable salt thereof, may be administered orally, nasally, dermatologically, pulmonaryly, by inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectically, intrapleurally, intrathecally, or parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

[0091] The dosing regimen for these compounds is selected based on various factors, including the patient's type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or its salt used. A physician or veterinarian with ordinary knowledge can readily determine and prescribe an effective amount of the drug required to prevent, counteract, or halt the progression of the disease. A physician or veterinarian with ordinary knowledge can readily determine and prescribe an effective amount of the drug required to counteract or halt the progression of the disease.

[0092] Techniques for formulating and administering the disclosed compounds of this 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, along with their pharmaceutically acceptable salt systems, are combined with pharmaceutically acceptable carriers or diluents in a pharmaceutical formulation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the scope described herein.

[0093] Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of this disclosure will become apparent from the various embodiments. The provided embodiments illustrate different ingredients and methodologies useful in practicing this disclosure. The embodiments do not limit the claimed disclosure. Based on this disclosure, those skilled in the art can identify and employ other ingredients and methodologies useful in practicing this disclosure.

[0094] In the synthetic schemes described herein, for simplicity, compounds may be drawn to have a particular configuration. Such a particular configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, regio isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regio isomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, regio isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regio isomer, or stereoisomer.

[0095] All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were specifically and individually stated to be referenced herein. References to publications and patent documents are not intended to acknowledge any as prior art, nor do they constitute any admission of their content or dates. The invention has now been described by written description; those skilled in the art will recognize that the invention can be practiced in various embodiments, and the foregoing description and the following examples are for illustrative purposes only and not to limit the scope of the following claims.

[0096] As used herein, the phrase "the compound disclosed herein" refers to both the general and specific compounds disclosed herein.

[0097] In one aspect, this disclosure particularly provides a compound of formula (I): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer or tautomer thereof, wherein: X is N (Ra), O, S or C (Rb)(Rc); Ra 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; or Ra cyclizes with R1 to form 3-to-8-membered heterocycloalkyl; Rb is hydrogen or C1-C6 alkyl; Rc is hydrogen or C1-C6 alkyl; or Rb and Rc together with the atoms to which they are attached form a C3-C8 cycloalkyl; Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl may be derived from one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl groups as desired. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(3-to-8-membered heterocycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(5-to-9-membered heteroaryl), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), - R4N(R7)S(O)t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as required by one or more halogroups, CN, C1-C6 alkyl, -R4OR5, -NR5R6, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C10 aryl, or substituted 5- to 9-membered heteroaryl as required;R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R3) R5)2 or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogen, or C1-C6 haloalkyl groups as required; or R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group is substituted with one or more R2a groups as required; R2a is hydrogen, deuterium, C1-C6 alkyl, haloyl, or C1-C6 haloalkyl; R4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; R5 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, wherein the alkyl group is substituted with one or more D groups as required; R6 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; R7 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; R8 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; or R7 and R8 together with the atoms to which they are attached form 3-to-8-membered heterocycloalkyl;n is 0, 1, 2, 3, or 4; and t is 1 or 2; the constraint is that R1 is not a C2 or C4 alkyl group substituted with a morpholino group.

[0098] In some embodiments, the compound is of formula (I) or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X is N (Ra) or O; Ra is hydrogen or C1-C6 alkyl; Y is 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as desired with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, -R4OR5, -R4SR6, or -R4SF5; R1 is a C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(3-to-8-membered heterocycloalkyl), -(CH2)n-(C6-C10 aryl), or -(CH2)n-(5-to-9-membered heteroaryl), wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl is substituted with one or more halogen groups, CN, C1-C6 alkyl, or -R4OR5 as required; R2 is hydrogen or a C1-C6 alkyl group substituted with one or more halogen groups as required; R3 is hydrogen or a C1-C6 alkyl group substituted with one or more halogen groups as desired; or R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group, wherein the C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group is substituted with one or more R2a groups as desired; R2a is a halogen group; R4 is a bond or a C1-C6 alkyl group; R5 is hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group, wherein the alkyl group is substituted with one or more D groups as desired; and n is 0, 1, 2, 3, or 4; the limitation is that R1 is not a C2 or C4 alkyl group substituted with a morpholino group.

[0099] In some embodiments, the compound is of formula (I'): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X, Y, and R1 are described herein as set forth in formula (I'); R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl is substituted by one or more R2a as desired; and R2a is hydrogen, deuterium, C1-C6 alkyl, halogroup, or C1-C6 haloalkyl.

[0100] In some embodiments, the compound is of formula (I''):, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X, Y, and R1 are described herein as set forth in formula (I''); R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required.

[0101] In some embodiments, the compound of formula (I) is a compound of formula (II):, or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R1, R2, and R3 are described herein as set forth in formula (II).

[0102] In some embodiments, the compound of formula (II) is a compound of formula (II-a): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R2a, R4, and R5 are described herein as set forth in formula (II); R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group is substituted with one or more R2a groups as desired.

[0103] In some embodiments, the compound of formula (II) is a compound of formula (II-b): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R2a, R4, and R5 are described herein as set forth in formula (II); R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl group substituted with one or more R2a groups as desired.

[0104] In some embodiments, the compound of formula (II) is a compound of formula (II-c): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R2a, R4, and R5 are described herein as set forth in formula (II); R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocyclic alkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and R2 and R3 together with the atoms to which they are attached form 3- to 8-membered heterocyclic alkyl groups substituted with one or more R2a groups as desired.

[0105] In some embodiments, the compound of formula (II) is a compound of formula (II-d): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R2a, R4, and R5 are described herein as set forth in formula (II); R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, 3- to 8-membered heterocycloalkyl, or 5- to 9-membered heteroaryl; and R2 and R3 together with the atoms to which they are attached form a C6-C10 aryl group substituted with one or more R2a as desired.

[0106] In some embodiments, the compound of formula (II) is a compound of formula (II-d-1): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: Y, R2a, R4, and R5 are described herein as set forth in formula (II); R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocyclic alkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and R2 and R3 together with the atoms to which they are attached form 5- to 9-membered heteroaryl groups substituted with one or more R2a groups as desired.

[0107] In some embodiments, the compound of formula (II) is a compound of formula (II-e): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R2a, R4, and R5 are described herein as set forth in formula (II); R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted with a 3- to 8-membered heterocycloalkyl group as desired, or substituted with a 5- to 9-membered heteroaryl group as desired; R2 and R3, together with the atoms to which they are attached, form a C6-C10 aryl or a 5- to 9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl is substituted by one or more R2a as desired; and Y is a 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted by one, two, or three of the following as desired: C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R4OR5.

[0108] In some embodiments, the compound of formula (II) is a compound of formula (II-f): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R2a, R4, and R5 are described herein as set forth in formula (II); R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and Y is a 3- to 8-membered heterocycloalkyl group, a C6-C10 aryl group, or a 5- to 9-membered heteroaryl group, wherein the 3- to 8-membered heterocycloalkyl group, the C6-C10 aryl group, or the 5- to 9-membered heteroaryl group is substituted with one, two, or three of the following as desired: C1-C6 haloalkyl group, C3-C8 cycloalkyl group, halogen group, cyano group, or -R4OR5 group.

[0109] In some embodiments, the compound of formula (II) is a compound of formula (II-g): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R2a, R4, and R5 are described herein as set forth in formula (II); R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and Y is a 3- to 8-membered heterocycloalkyl group, a C6-C10 aryl group, or a 5- to 9-membered heteroaryl group, wherein the 3- to 8-membered heterocycloalkyl group, the C6-C10 aryl group, or the 5- to 9-membered heteroaryl group is substituted with one, two, or three of the following as desired: C1-C6 haloalkyl group, C3-C8 cycloalkyl group, halogen group, cyano group, or -R4OR5 group.

[0110] In some embodiments, the compound of formula (II) is a compound of formula (II-h): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: each R2a is hydrogen or deuterium; R1 is a C1-C6 alkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(3-to-8-membered heterocycloalkyl), or -(CH2)n-(5-to-9-membered heteroaryl), wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is substituted with one or more halogens, CN, C1-C6 alkyl, C6-C10 aryl, -NR5R6, or -R4OR5 as desired; and Y is a C6-C10 aryl, wherein the aryl is substituted with one or more halogens, C1-C6 alkyl, C1-C6 haloalkyl, or -R4OR5 as desired. R4 is a bond, a C1-C6 alkyl, a C2-C6 alkenyl, or a C2-C6 alkynyl; R5 and R6 are independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C3-C8 cycloalkyl, a 3- to 8-membered heterocycloalkyl, a C6-C10 aryl, or a 5- to 9-membered heteroaryl, wherein the alkyl group is substituted with one or more D groups as required; and n is 0, 1, 2, 3, or 4.

[0111] In some embodiments, the compound of formula (II) is a compound of formula (II-i): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R2a, R4, and R5 are described herein as set forth in formula (II); R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and Y is a 3- to 8-membered heterocycloalkyl group, a C6-C10 aryl group, or a 5- to 9-membered heteroaryl group, wherein the 3- to 8-membered heterocycloalkyl group, the C6-C10 aryl group, or the 5- to 9-membered heteroaryl group is substituted with one, two, or three of the following as desired: C1-C6 haloalkyl group, C3-C8 cycloalkyl group, halogen group, cyano group, or -R4OR5 group.

[0112] In some embodiments, the compound of formula (II) is a compound of formula (II-j): , or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R2a, R4, and R5 are described herein as set forth in formula (II); R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and Y is a 3- to 8-membered heterocycloalkyl group, a C6-C10 aryl group, or a 5- to 9-membered heteroaryl group, wherein the 3- to 8-membered heterocycloalkyl group, the C6-C10 aryl group, or the 5- to 9-membered heteroaryl group is substituted with one, two, or three of the following as desired: C1-C6 haloalkyl group, C3-C8 cycloalkyl group, halogen group, cyano group, or -R4OR5 group. It should be understood that for compounds of formulas (I), (I'), (I”), or (II), X, Ra, Rb, Rc, Y, R1, R2, R3, R2a, R4, R5, R6, R7, R8, n, or t may, where applicable, be each selected from the groups described herein, and any group described herein for any of X, Ra, Rb, Rc, Y, R1, R2, R3, R2a, R4, R5, R6, R7, R8, n, or t may, where applicable, be combined with any group described herein for one or more of the remaining parts of X, Ra, Rb, Rc, Y, R1, R2, R3, R2a, R4, R5, R6, R7, R8, n, or t. Variables X, Y, Ra, Rb, and Rc

[0113] In some embodiments, X is N (Ra), O, S or C (Rb)(Rc).

[0114] In some implementations, X is N(Ra).

[0115] In some implementations, X is O.

[0116] In some implementations, X is S.

[0117] In some implementations, X is C(Rb)(Rc).

[0118] In some implementations, Ra is H.

[0119] In some embodiments, Ra is a C1-C6 alkyl group. In some embodiments, R1 is a methyl group.

[0120] In some embodiments, Y is a 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as desired with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5.

[0121] In some embodiments, Y is a 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5.

[0122] In some embodiments, Y is a 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted with a C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R4OR5.

[0123] In some embodiments, Y is a 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted by two of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R4OR5.

[0124] In some embodiments, Y is 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted by three of C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R4OR5.

[0125] In some embodiments, Y is a 3- to 8-membered heterocyclic alkyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R4OR5. In some embodiments, Y is a piperidinyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R4OR5.

[0126] In some embodiments, Y is a C6-C10 aryl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5. In some embodiments, Y is a phenyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5.

[0127] In some embodiments, Y is a 5- to 9-membered heteroaryl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R4OR5. In some embodiments, Y is a pyridyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R4OR5.

[0128] In some embodiments, Y is a C6-C10 aryl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5 as required.

[0129] In some embodiments, -Y is a phenyl group that is substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5 as required.

[0130] In some implementations, Y is , , , , , , , , , , , , , , , , , , , or.

[0131] In some implementations, Y is , , , , , , , , , , , , , , or.

[0132] In some implementations, Y is or.

[0133] In some implementations, Y is... variables R2, R2a, and R3.

[0134] In some embodiments, R2 is hydrogen.

[0135] In some embodiments, R2 is a C1-C6 alkyl group. In some embodiments, R2 is a methyl group.

[0136] In some embodiments, R3 is hydrogen.

[0137] In some embodiments, R3 is a C1-C6 alkyl group. In some embodiments, R3 is a methyl group.

[0138] In some embodiments, R3 is a C1-C6 alkyl group substituted with one or more halogen groups. In some embodiments, R3 is CF3.

[0139] In some embodiments, R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted by one or more R2a as required.

[0140] In some embodiments, R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted by one or more R2a.

[0141] In some embodiments, R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted by an R2a.

[0142] In some embodiments, R2a is hydrogen or deuterium.

[0143] In some embodiments, R2a is a halogen group. In some embodiments, R2a is Cl.

[0144] In some embodiments, R2 and R3 together with the atoms to which they are attached form , , , , , , , , , , , or.

[0145] In some embodiments, R2 and R3 together with the atoms to which they are attached form , , or .

[0146] In some embodiments, R2 and R3 together with the atoms to which they are attached form , , , , , , , , , , or.

[0147] In some embodiments, R2 and R3 are formed together with the atoms to which they are attached, or

[0148] In some embodiments, R2 and R3 together with the atoms to which they are attached form , , , , , , or.

[0149] In some embodiments, R2 and R3 are formed together with the atoms to which they are attached. Variables R1, R4, R5, R6, R7, R8, n, and t

[0150] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(3- to 8-membered heterocycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(5- to 9-membered heteroaryl), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4S(O)tR5, -R4S(O)tN(R7)(R8) -R4P(O)(R5)2 or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as desired by one or more halogroups, CN, C1-C6 alkyl, -R4OR5, -NR5R6, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C10 aryl, or substituted 5- to 9-membered heteroaryl as desired.

[0151] In some embodiments, R1 is a C1-C6 alkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(3-to-8-membered heterocycloalkyl), or -(CH2)n-(5-to-9-membered heteroaryl), wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is substituted as required by one or more halogen groups, CN, C1-C6 alkyl, C6-C10 aryl, -NR5R6, or -R4OR5.

[0152] In some embodiments, R1 is -(CH2)n-(C3-C10 cycloalkyl) substituted with one or more halogen groups, C1-C6 alkyl groups, or -R4OR5 as required.

[0153] In some embodiments, R1 is -(CH2)n-(3-to-8-membered heterocyclic alkyl) substituted with one or more halogen groups, C1-C6 alkyl groups, or -R4OR5 as required.

[0154] In some embodiments, R1 is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is substituted with one or more halogen groups, -R4OR5, substituted with substituted 3- to 8-membered heterocyclic alkyl, substituted with substituted C6-C10 aryl, or substituted with substituted 5- to 9-membered heteroaryl as desired.

[0155] In some embodiments, R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted with 3- to 8-membered heterocyclic alkyl groups, substituted with C6- to C10 aryl groups, or substituted with 5- to 9-membered heteroaryl groups as needed.

[0156] In some embodiments, R1 is a 3- to 8-membered heterocyclic alkyl group substituted with one or more halogen groups, -R4OR5, substituted with a C6- to C10 aryl group ...

[0157] In some embodiments, R1 is a 3- to 8-membered heterocyclic alkyl group. In some embodiments, R1 is a tetrahydrofuranyl group.

[0158] In some embodiments, R1 is, as needed, a 5-to-9-membered heterocyclic alkyl group substituted with one or more halogen groups, -R4OR5, a substituted 3-to-8-membered heterocyclic alkyl group substituted with one or more halogen groups, a substituted C6-C10 aryl group substituted with one or more ...

[0159] In some embodiments, R1 is 5- to 9-membered heteroaryl. In some embodiments, R1 is furanyl.

[0160] In some embodiments, R1 is a C1-C6 alkyl group substituted with one or more CN, C1-C6 alkyl, or -R4OR5 as required.

[0161] In some embodiments, R1 is a C1-C6 alkyl group substituted with one or more CN, C1-C6 alkyl, or -R4OR5.

[0162] In some implementations, R1 is , ...

[0163] In some implementations, R1 is , , , , , , , , , , , , , , , , , , or.

[0164] In some implementations, R1 is.

[0165] In some implementations, R1 is , , , , , , or.

[0166] In some embodiments, R4 is a bond, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group. In some embodiments, R4 is a bond.

[0167] In some embodiments, R5 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. In some embodiments, R5 is hydrogen. In some embodiments, R5 is C1-C6 alkyl. In some embodiments, R5 is methyl.

[0168] In some embodiments, R6 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.

[0169] In some embodiments, R7 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.

[0170] In some embodiments, R8 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; or R7 and R8 together with the atoms to which they are attached form 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, R1 is a C1, C3, C5, or C6 alkyl group.

[0173] In some embodiments, R1 is a C1, C3, C5, or C6 alkyl group substituted with one or more halogen groups, CN, C1-C6 alkyl, -R4OR5, -NR5R6, substituted with 3- to 8-membered heterocyclic alkyl groups substituted as needed, substituted with C6- to C10 aryl groups substituted as needed, or substituted with 5- to 9-membered heteroaryl groups substituted as needed.

[0174] In some embodiments, R1 is a C1, C3, C5, or C6 alkyl group substituted with one or more halogen groups, CN, C1-C6 alkyl groups, -R4OR5, -NR5R6, 3- to 8-membered heterocyclic alkyl groups substituted as needed, C6- to C10 aryl groups substituted as needed, or 5- to 9-membered heteroaryl groups substituted as needed.

[0175] In some embodiments, R1 is a C1, C3, C5, or C6 alkyl group substituted with a morpholinoyl group.

[0176] In some embodiments, R1 is a C1, C3, C5, or C6 alkyl group substituted with one or more CN, C1-C6 alkyl, or -R4OR5 as required.

[0177] In some embodiments, R1 is a C1, C3, C5, or C6 alkyl group substituted with one or more CN, C1-C6 alkyl, or -R4OR5.

[0178] In some embodiments, R1 is not a C1-C6 alkyl group substituted with morpholino.

[0179] In some embodiments, R1 is not a C1-C3 alkyl group substituted with morpholino.

[0180] In some embodiments, R1 is not a C2 alkyl group substituted with morpholino.

[0181] In some embodiments, R1 is not a C4 alkyl group substituted with morpholino.

[0182] In some implementations, R1 is not OR.

[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 the compounds listed in Table 1 or Table 2, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, or stereoisomers thereof.

[0185] In some embodiments, the compound is selected from the compounds described in Table 1 or Table 2, or pharmaceutically acceptable salts thereof.

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

[0187] In some embodiments, the compound is selected from the compounds listed in Table 1, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, or stereoisomers thereof.

[0188] In some embodiments, the compound is selected from the compounds listed in Table 1 or pharmaceutically acceptable salts thereof.

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

[0190] In some embodiments, the compound is selected from the compounds listed in Table 2, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, or stereoisomers thereof.

[0191] In some embodiments, the compound is selected from the compounds listed in Table 2 or pharmaceutically acceptable salts thereof.

[0192] In some embodiments, the compound is selected from the compounds described in Table 2.

[0193] In some embodiments, the compound is selected from compounds 1-81, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, or stereoisomers thereof.

[0194] In some embodiments, the compound is selected from compounds 1-81 or any of their pharmaceutically acceptable salts.

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

[0196] In some embodiments, the compound is selected from compounds 82-105, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, or stereoisomers thereof.

[0197] In some embodiments, the compound is selected from compounds 82-105, or any of their pharmaceutically acceptable salts.

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

[0199] In some embodiments, the compound is selected from compounds 106-136, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, or stereoisomers thereof.

[0200] In some embodiments, the compound is selected from compounds 106-136 or any of their pharmaceutically acceptable salts.

[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 their pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, or stereoisomers.

[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 compounds 55-56, 61, 72, or 75, or their pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, or stereoisomers.

[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 their pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, or stereoisomers.

[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 compound 66, or its pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, or stereoisomer.

[0212] In some embodiments, the compound is selected from compound 66 or any of its pharmaceutically acceptable salts.

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

[0214] In some embodiments, the compound is selected from any one of compounds 6, 57, or 76, or their pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, or stereoisomers.

[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 not (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-piperan-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (S)-5-chloro-2 -(4-((2,2-dimethyltetrahydro-2H-piperan-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, or a pharmaceutically acceptable salt, solvate, inclusion complex, hydrate, stereoisomer, or tautomer thereof.

[0218] In some embodiments, the compound is not (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-piperan-4-yl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol; (S)-5-chloro-2-(4-((2,2-dimethyltetrahydro-2H-piperan-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 of the compounds described in Table 1 or Table 2.

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

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

[0222] In some aspects, this disclosure provides a compound that is an isotopic derivative (e.g., an isotopically labeled compound) of any of the compounds of the formula disclosed herein.

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

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

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

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

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

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

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

[0230] In some embodiments, the compound is an isotopic derivative of the compounds described in Table 1.

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

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

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

[0234] In some embodiments, the compound is an isotopic derivative of the compound described in Table 2.

[0235] It should be understood that the isotope derivative can be prepared using any of the various techniques known in the art. For example, the isotope derivative can generally be prepared by using an isotopically labeled reagent instead of an unisotopically labeled reagent by implementing the procedures disclosed in the schemes and / or examples described herein.

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

[0237] In some embodiments, the isotope derivative is a deuterated compound of any of the compounds of the formula disclosed herein.

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

[0239] It should be understood that any of the various techniques known in the art can be used to prepare compounds labeled with 18F, 123I, 124I, 125I, 129I, 131I, 135I, 32S, 34S, 35S, and / or 36S. For example, such deuterium-labeled compounds can generally be prepared by implementing the procedures disclosed in the schemes and / or examples described herein, by using reagents labeled with 18F, 123I, 124I, 125I, 129I, 131I, 135I, 32S, 34S, 35S, and / or 36S instead of non-isotope-labeled reagents.

[0240] Compounds of the present invention containing one or more of the aforementioned 18F, 123I, 124I, 125I, 129I, 131I, 135I, 32S, 34S, 35S, and 36S atoms, or their pharmaceutically acceptable salts or solvates, are within the scope of the present invention. Furthermore, substitution with isotopes (e.g., 18F, 123I, 124I, 125I, 129I, 131I, 135I, 32S, 34S, 35S, and / or 36S) may provide certain therapeutic advantages stemming from greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirements).

[0241] For the avoidance of doubt, it should be understood that when a group is defined as “described herein” in this specification, the group encompasses the first and broadest definition and each and every one of the specific definitions of the group.

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

[0243] It should be understood that compounds of any of the formulas disclosed herein and any pharmaceutically acceptable salts thereof include stereoisomers of the compound, mixtures of stereoisomers, and polymorphs of all isomer forms.

[0244] As used herein, the term "isomerism" refers to compounds that have the same molecular formula but differ in the bond arrangement of their atoms or in the spatial arrangement of their atoms. Isomers whose atoms are arranged differently in space are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "non-mirror image isomers," while stereoisomers that are non-overlapping mirror images of each other are called "mirror image isomers" or sometimes optical isomers. A mixture containing equal amounts of individual mirror image isomers with opposite chirality is called a "racemic mixture."

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

[0246] As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having multiple chiral centers may exist individually as non-mirror image isomers or as mixtures of non-mirror image isomers, referred to as "non-mirror image isomer mixtures." When a chiral center is present, the stereoisomer is characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ordered according to the Cahn, Ingold, and Prelog ordering rules. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0247] As used herein, the term “geometric isomer” refers to non-mirror image isomers that are rotationally hindered around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished by their names using the prefixes cis and trans, or Z and E, according to the Cahn-Ingold-Prelog rule, which indicate whether the groups are located on the same or opposite sides of the double bond in the molecule.

[0248] It should be understood that the compounds disclosed herein may be described as different chiral isomers or geometric isomers. It should also be understood that when a compound has chiral or geometric isomers, all isomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any isomer. It should be understood that not all isomers may have the same level of activity.

[0249] It should be understood that the structures and other compounds discussed in this disclosure include all their configurational isomers. It should also be understood that not all configurational isomers 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 readily transform from one isomer to another. This transformation results in the formal migration of hydrogen atoms, accompanied by the switching of adjacent conjugated double bonds. Tautomers exist as a mixture of tautomer groups in solution. In solutions where tautomerism is possible, chemical equilibrium of tautomers will be reached. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerism is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, electrons and hydrogen atoms shift simultaneously. Ring-chain tautomerism results from the reaction of an aldehyde group (-CHO) in a sugar molecule with a hydroxyl group (-OH) in the same molecule, giving it a cyclic (cyclic) form, as seen in glucose.

[0251] It should be understood that the compounds disclosed herein may be described as different tautomers. It should also be understood that when a compound has tautomers, all tautomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer. It should be understood that some tautomers may have a higher level of activity than others.

[0252] Compounds with the same molecular formula but different atomic bonding properties, arrangements, or spatial arrangements are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "non-mirror image isomers," while those that are non-overlapping mirror images of each other are called "mirror image isomers." When a compound has an asymmetry center, for example, when it is bonded to four different groups, there may be a pair of mirror image isomers. Mirror image isomers can be characterized by the absolute configuration of their asymmetry center and described by the R and S ordering rules of Cahn and Prelog, or by rotating the molecular polarization plane and specifying it as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual mirror image isomers or mixtures thereof. A mixture containing equal proportions of these mirror image isomers is called a "racemic mixture."

[0253] The compounds disclosed herein may have one or more asymmetric centers; thus, such compounds may yield individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise stated, the description or nomenclature of a particular compound in the specification and claims is intended to include both individual mirror-image isomers and mixtures thereof (racemic or other mixtures). The stereochemistry for determining stereoisomers and the methods for isolating stereoisomers are well known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolving racemic forms. Some of the compounds disclosed herein may have geometric isomer centers (E and Z isomers). It should be understood that this disclosure covers all optical, non-mirror-image, and geometric isomers and mixtures thereof with inflammasome inhibitory activity.

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

[0255] As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming pharmaceutically acceptable salts. Similarly, salts can also be formed between a cation and a negatively charged group (e.g., a carboxyl group) on the substituted compounds disclosed herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium or diethylamine ions. The substituted compounds disclosed herein also include salts containing a quaternary nitrogen atom.

[0256] It should be understood that the compounds disclosed herein, such as salts of the compounds, may exist in hydrated or dehydrated (anhydrous) forms 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 "solvent" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap solvent molecules in a fixed molar ratio in a crystalline solid, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate; if the solvent is an alcohol, the solvate formed is an alcohol. A hydrate is formed by the combination of one or more molecules of water with one molecule of the substance, wherein the water retains its molecular state as H₂O.

[0258] As used herein, the term "analogue" refers to a chemical compound that is structurally similar to another but has a slightly different composition (e.g., one atom is replaced by an atom of a different element, or one functional group is replaced by another functional group in the presence of a specific functional group). Thus, an analogue is a compound that is similar or equivalent in function and appearance but differs from the reference compound in structure or origin.

[0259] As used herein, the term “derivative” refers to a compound having a common core structure and being substituted with various groups as described herein.

[0260] It should also be understood that some compounds of any of the formulas disclosed herein may exist in solvated and non-solvated forms, such as hydrated forms. Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure covers all such solvated forms having inflammasome-inhibiting activity.

[0261] It should also be understood that some compounds of any of the formulas disclosed herein may exhibit polymorphism, and this disclosure covers all such forms, or mixtures thereof, that have inflammasome-inhibiting activity. It is known that conventional techniques can be used to analyze crystalline materials, such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0262] Compounds of any of the formulas disclosed herein may exist in many different tautomeric forms, and references to compounds of formula (I) include all such forms. To avoid ambiguity, when a compound may exist in one of several tautomeric forms, and only one is specifically described or shown, all other forms are still included in formula (I). Examples of tautomeric forms include keto-, enol-, and enol- forms, such as the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidinium, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0263] Compounds of any of the formulas disclosed herein may be administered as prodrugs, which decompose in a human or animal body to release the disclosed compound. Prodrugs may be used to modify the physical and / or pharmacokinetic properties of the disclosed compound. Prodrugs can be formed when the disclosed compound contains suitable groups or substituents (which may be attached to modifying groups). Examples of prodrugs include derivatives containing in vivo cleavable alkyl or amide substituents at the ester or amide group in any of the formulas disclosed herein.

[0264] Accordingly, this disclosure includes compounds of any of the formulas disclosed herein as defined above, which can be obtained by organic synthesis and in humans or animals by cleavage of their prodrugs. Accordingly, this disclosure includes compounds of any of the formulas disclosed herein produced by organic synthesis, and also includes such compounds produced in humans or animals by metabolism of prodrug compounds; that is, compounds of any of the formulas disclosed herein can be synthetically produced or metabolically produced compounds.

[0265] A suitable pharmaceutically acceptable prodrug of any of the formulas disclosed herein is a prodrug that is suitable for administration to humans or animals without undesirable pharmaceutical activity and without excessive toxicity, based on reasonable medical judgment. Various forms of prodrugs have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396 (Academic Press, 1985), edited by K. Widder, et al.; b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985); c) Textbook of Drug Design and Development, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard, pp. 113-191 (1991), edited by Krogsgaard-Larsen and H. Bundgaard; d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al. Chem.Pharm.Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0266] A suitable pharmaceutically acceptable prodrug of a compound having a hydroxyl group in any of the formulas disclosed herein is, for example, an ester or ether that is cleavable in vivo. A cleavable ester or ether of a compound containing a hydroxyl group in any of the formulas disclosed herein is, for example, a pharmaceutically acceptable ester or ether that is cleaved in a human or animal body to produce a parent hydroxyl compound. The group forming the hydroxyl group in a suitable pharmaceutically acceptable ester includes inorganic esters, such as phosphate esters (including phosphoramidic cyclic esters). The group forming the hydroxyl group in a suitable pharmaceutically acceptable ester also includes C1-C10 alkyl groups, such as acetyl, benzoyl, phenacetyl, and substituted benzoyl and phenacetyl groups; C1-C10 alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C1-C6 alkyl)-aminomethyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of cyclic substituents on the phenacetin and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, N-morpholinylmethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether groups for the formation of hydroxyl groups include α-acetoxyalkyl, such as acetoxymethyl and neopentyloxymethyl.

[0267] A suitable pharmaceutically acceptable prodrug of a compound having a carboxyl group in any of the formulas disclosed herein is, for example, an amide that is cleavable in vivo, such as an amide formed with an amine such as ammonia, a C1-4 alkylamine (such as methylamine), a (C1-C4 alkyl)2amine (such as dimethylamine, N-ethyl-N-methylamine or diethylamine), a C1-C4 alkoxy-C2-C4 alkylamine (such as 2-methoxyethylamine), a phenyl C1-C4 alkylamine (such as benzylamine) and an amine of an amino acid (such as glycine or an ester thereof).

[0268] Suitable pharmaceutically acceptable prodrugs of compounds having an amino group in any of the formulas disclosed herein are, for example, acetylamine derivatives that are cleavable in vivo. Suitable pharmaceutically acceptable acetylamines derived from an amino group include, for example, acetylamines formed with C1-C10 alkyl (such as acetyl), benzoyl, phenacetyl, and substituted benzoyl and phenacetyl groups. Examples of cyclic substituents on the phenacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, N-morpholinylmethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0269] The in vivo effects of compounds of any of the formulas disclosed herein may be partially exerted by one or more metabolites formed in the human or animal body after administration of a compound of any of the formulas disclosed herein. As mentioned above, the in vivo effects of compounds of any of the formulas disclosed herein may also be exerted by metabolism of a prodrug.

[0270] Suitable general routes for preparing the compounds of this application can be described in Schemes 1 and 1A herein. Unless otherwise stated, the examples presented herein are synthesized according to the general steps presented in Schemes 1 and 1A. Step 1 involves an SNAr reaction between an amine (i) and an aryl dichloride (ii) to provide the target chloroaryl intermediate (iii). Step 2 involves cross-coupling of the intermediate (iii) with the desired boric acid or borate (iv) to produce the desired compound of formula I. The amine (i), aryl dichloride (ii), and boric acid or borate (iv) are commercially available or known in the chemical literature unless otherwise stated. Bioassay

[0271] Compounds designed, selected, and / or optimized using the methods described above, once generated, can be used to determine whether they possess biological activity using a variety of assays known to those skilled in the art. For example, molecules can be determined to have predicted activity, binding activity, and / or binding specificity using conventional assays, including but not limited to those described below.

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

[0273] Various in vitro or in vivo bioassays may be used to detect the efficacy of the compounds disclosed herein. These in vitro or in vivo bioassays may include, but are not limited to, enzyme activity assays, electrophoretic mobility change assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

[0274] In some embodiments, the bioassay is the PBMC NLRP3 assay. In some embodiments, the PBMCs and cells are centrifuged and resuspended in culture medium. Cell counting is then performed and the cells are seeded in wells, followed by incubation. In some embodiments, assay medium can then be prepared and the PBMCs centrifuged, the 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 the control wells.

[0275] In some embodiments, cells for PBMC NLRP3 assay are initiated and a concentration-response curve can be prepared (e.g., 1000X test compound in 100% DMSO), followed by incubation. In some embodiments, cells can then be stimulated and the disc centrifuged, followed by transfer to a clean well storage disc for intercytokine measurement (e.g., using a mesoscale platform).

[0276] In some embodiments, the bioassay is a human whole blood assay. In some embodiments, blood may be collected and initiated. In some embodiments, NLRP3 activation may be performed and the disc may be centrifuged. In some embodiments, the IL-1β content in the supernatant may be analyzed (e.g., using the mesoscale discovery assay (MSD K151TUK) according to the manufacturer's instructions).

[0277] In some embodiments, the bioassays described in the examples herein are pharmaceutical compositions.

[0278] In some aspects, this disclosure provides a pharmaceutical composition comprising a compound of the disclosed herein as an active ingredient. In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound (each having the formula described herein), or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or diluents. In some embodiments, this disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1 or Table 2.

[0279] In some embodiments disclosed herein, the pharmaceutical composition comprises a compound of formula (I) as described herein and a pharmaceutically acceptable carrier.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0293] The compounds disclosed herein can be formulated into forms for oral administration, such as tablets, capsules (including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds disclosed herein can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or percutaneous (e.g., patch) administration, all using forms well known to those skilled in the art of pharmaceutical science.

[0294] The formulations disclosed herein may be in the form of an aqueous solution containing an aqueous mediator. The aqueous mediator component may contain water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from solubilizers, chelating agents, preservatives, tensioning agents, viscosity / suspending agents, buffers, and pH adjusters, and mixtures thereof.

[0295] Any suitable solubilizer may be used. Examples of solubilizers include cyclodextrins, such as those selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, atactic methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetylated-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonium)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltodextrin, β-cyclodextrin sulfonyl ether, branched-chain β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, atactic methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

[0296] Any suitable chelating agent may be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0297] Any suitable preservative may be used. Examples of preservatives include those selected from the group consisting of quaternary ammonium salts such as benzyl halides (preferably benzyl halides), chlorhexidine gluconate, benzenethonium chloride, hexadecylpyridinium chloride, bromotoluene, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropylbiguanide, and butylparaben, and mixtures thereof.

[0298] Aqueous mediators may also include tension agents to adjust tension (osmotic pressure). Tension agents may be selected from the group consisting of glycols (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride, and sodium chloride, and mixtures thereof.

[0299] Aqueous mediators may also contain viscosity / suspension agents. Suitable viscosity / suspension agents include those selected from cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropyl methylcellulose, and crosslinked acrylic polymers (carbomer), such as polymers crosslinked with acrylic acid and polyolefin ethers or divinyl glycol (carbopol, such as carbopol 934, carbopol 934P, carbopol 971, carbopol 974 and carbopol 974P), and mixtures thereof.

[0300] To adjust the formulation to an acceptable pH (typically from about 5.0 to about 9.0, more preferably from about 5.5 to about 8.5, particularly from about 6.0 to about 8.5, from about 7.0 to about 8.5, from about 7.2 to about 7.7, from about 7.1 to about 7.9, or from about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically a mineral acid or a metal hydroxide base, selected from the group consisting of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH adjusters are added to adjust the formulation to the target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base; depending on the formulation, adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

[0301] Aqueous mediators may also contain buffers to stabilize pH. When used, the buffers are selected from the group consisting of phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate), and ε-aminohexanoic acid, and mixtures thereof.

[0302] The formulation may further include a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamer), polyethoxylated ethers of castor oil, polyoxyethylene dehydrated sorbitan esters (polysorbate), oxyethylated octylphenol (Tyloxapol), polyoxyethylene 40 stearate, ethylene glycol esters of fatty acids, glycerol esters of fatty acids, sucrose fatty acid esters, and polyoxyethylene fatty acid esters, and mixtures thereof.

[0303] Oral formulations generally include inert diluents or pharmaceutically acceptable edible carriers. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be combined with excipients and administered in the form of tablets, lozenges, or capsules. Oral formulations may also be prepared using fluid carriers for use as mouthwashes, wherein the compound in the fluid carrier is administered orally and rinsed and spat out or swallowed. Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the formulation. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds of similar nature: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginate, Primogel, or corn starch; lubricants such as magnesium stearate or sterotes; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0304] According to a further aspect of this disclosure, a pharmaceutical composition is provided comprising the disclosed compound as defined above or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

[0305] The components disclosed herein may be in the form suitable for oral use (e.g., tablets, lozenges, hard capsules or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in the form suitable for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), in the form suitable for administration by inhalation (e.g., as fine powders or liquid aerosols), in the form suitable for administration by blowing (e.g., as fine powders), or in the form suitable for parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

[0306] The compositions disclosed herein can be obtained using conventional procedures for pharmaceutical excipients well known in the art. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavoring agents, and / or preservatives.

[0307] The effective amount of the disclosed compound used in the therapy is sufficient to treat or prevent the inflammasome-related conditions mentioned herein, slow their progression and / or reduce the symptoms associated with the condition.

[0308] The effective amount of the disclosed compound used in the therapy is sufficient to treat the inflammasome-related conditions mentioned herein, slow their progression and / or reduce the symptoms associated with the conditions.

[0309] Based on well-known medical principles, the dosage of compound (I) for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration. Method of Use

[0310] In some aspects, this disclosure provides a method for modulating NLRP3 activity (e.g., in vitro or in vivo), comprising contacting cells with an effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0311] In some aspects, this disclosure provides a method for modulating NLRP3 activity (e.g., in vitro or in vivo), which comprises contacting cells with the compound disclosed herein or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

[0318] In some implementations, the disease or ailment is one involving NLRP3.

[0319] In some embodiments, the disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, mental illness, graft-versus-host disease, abnormal pain, or NLRP3-related disease in subjects who have been identified as carrying germline or somatic non-silent mutations in NLRP3.

[0320] In some aspects, this disclosure provides a method for treating or preventing inflammation, autoimmune diseases, cancer, infections, central nervous system diseases or disorders, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, mental diseases, graft-versus-host disease, abnormal pain, or NLRP3-related diseases in subjects who have been identified as carrying germline or somatic non-silent mutations in NLRP3, comprising administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosed compound.

[0321] In some aspects, this disclosure provides a method for treating inflammation, autoimmune diseases, cancer, infections, central nervous system diseases or disorders, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, mental diseases, graft-versus-host disease, abnormal pain, or NLRP3-related diseases in subjects who have been identified as carrying germline or somatic non-silent mutations in NLRP3, comprising administering to the subject a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosed compound.

[0322] In some aspects, this disclosure provides a method for treating or preventing inflammation, autoimmune diseases, cancer, infections, central nervous system diseases or disorders, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, mental diseases, graft-versus-host disease, abnormal pain, or NLRP3-related diseases in subjects who have been identified as carrying germline or somatic non-silent mutations in NLRP3, comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

[0323] In some aspects, this disclosure provides a method for treating inflammation, autoimmune diseases, cancer, infections, central nervous system diseases or disorders, metabolic diseases, cardiovascular diseases, respiratory diseases, kidney diseases, liver diseases, eye diseases, skin diseases, lymphatic diseases, rheumatic diseases, mental diseases, graft-versus-host disease, abnormal pain, or NLRP3-related diseases in subjects who have been identified as carrying germline or somatic non-silent mutations in NLRP3, comprising administering to the subject a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

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

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

[0328] In some aspects, this disclosure provides a compound of the disclosed herein or a pharmaceutically acceptable salt thereof, which is used as an antagonist of NLRP3 (e.g., in vitro or in vivo).

[0329] In some respects, this disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for the treatment or prevention of the diseases or ailments disclosed herein.

[0330] In some respects, this disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for the treatment of the diseases or ailments disclosed herein.

[0331] In some aspects, this disclosure provides the use of the disclosed compound or a pharmaceutically acceptable salt thereof in the manufacture of an agent that modulates NLRP3 activity (e.g., in vitro or in vivo).

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

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

[0334] In some aspects, this disclosure provides the use of the disclosed compound or a pharmaceutically acceptable salt thereof in the manufacture of an agent that inhibits NLRP3 (e.g., in vitro or in vivo).

[0335] In some respects, this disclosure provides the use of the disclosed compounds or pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment or prevention of the diseases or ailments disclosed herein.

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

[0337] In some aspects, this disclosure provides the use of the disclosed compound or a pharmaceutically acceptable salt thereof for modulating NLRP3 activity (e.g., in vitro or in vivo).

[0338] In some aspects, this disclosure provides the use of the disclosed compound or a pharmaceutically acceptable salt thereof for inhibiting NLRP3 activity (e.g., in vitro or in vivo).

[0339] In some aspects, this disclosure provides the use of the disclosed compound or a pharmaceutically acceptable salt thereof in modulating NLRP3 (e.g., in vitro or in vivo).

[0340] In some aspects, this disclosure provides the use of the disclosed compound or a pharmaceutically acceptable salt thereof for the inhibition of NLRP3 (e.g., in vitro or in vivo).

[0341] In some respects, this disclosure provides the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof for the treatment or prevention of the disease or ailment disclosed herein.

[0342] In some respects, this disclosure provides the use of a compound of the disclosure or a pharmaceutically acceptable salt thereof for the treatment of the disease or ailment disclosed herein.

[0343] The effectiveness of the disclosed compounds can be determined by industrially accepted testing / disease models, which are based on standard practices as described in this technical field and found in current general knowledge.

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

[0345] In some embodiments, the disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, mental illness, graft-versus-host disease, abnormal pain, or NLRP3-related disease.

[0346] In some implementations, the disease or ailment is inflammation.

[0347] In some implementations, the disease or ailment is an autoimmune disease.

[0348] In some implementations, the disease or ailment is cancer.

[0349] In some implementations, the disease or illness is an infection.

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

[0351] In some implementations, the disease or ailment is a metabolic disease.

[0352] In some implementations, the disease or ailment is a cardiovascular disease.

[0353] In some implementations, the disease or ailment is a respiratory disease.

[0354] In some implementations, the disease or ailment is kidney disease.

[0355] In some implementations, the disease or ailment is liver disease.

[0356] In some implementations, the disease or ailment is an eye disease.

[0357] In some implementations, the disease or ailment is a skin disease.

[0358] In some implementations, the disease or ailment is a lymphatic disease.

[0359] In some implementations, the disease or ailment is a rheumatic disease.

[0360] In some implementations, the disease or disorder is a mental illness.

[0361] In some implementations, the disease or ailment is graft-versus-host disease.

[0362] In some implementations, the disease or ailment is abnormal pain.

[0363] In some implementations, the disease or ailment is an NLRP3-related disease.

[0364] In some embodiments, the disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, mental illness, graft-versus-host disease, abnormal pain, or NLRP3-related disease in subjects who have been identified as carrying germline or somatic non-silent mutations in NLRP3.

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

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

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

[0368] In some implementations, the kidney disease is acute kidney disease, chronic kidney disease, or rare kidney disease.

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

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

[0371] In some embodiments, the NLRP3-related disease in subjects who have been identified as carrying germline or somatic non-silent mutations in NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0372] In some implementations, the cryopyrin-associated autoinflammatory syndrome is familial cold-cause autoinflammatory syndrome, Muckle-Wells syndrome, or a neonatal multisystemic inflammatory disease. Administration pathway

[0373] The disclosed compounds or pharmaceutically acceptable salts thereof may be administered alone as a monotherapy, or may be administered in addition to the administration of one or more other substances and / or treatments. Such combination therapy may be achieved by administering individual components of the therapy simultaneously, sequentially, or separately.

[0374] For example, the effectiveness of treatment can be enhanced by administering an adjuvant (i.e., the adjuvant may have only minimal therapeutic benefit on its own, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by the individual can be increased by administering a compound of formula (I) together with another therapeutic agent (which also includes a treatment regimen) that also has therapeutic benefits.

[0375] When the disclosed compound is administered in combination with other therapeutic agents, the disclosed compound need not be administered via the same route as the other therapeutic agents, and can be administered via different routes (due to different physical and chemical properties). For example, the disclosed compound can be administered orally to produce and maintain its good blood levels, while another therapeutic agent can be administered intravenously. An initial administration can be made according to established protocols known in the art, and then a clinician with ordinary knowledge can modify the dosage, administration mode, and administration time based on the observed effects.

[0376] The specific selection of other therapeutic agents will depend on the attending physician's diagnosis and their judgment regarding the individual's condition and appropriate treatment plan. According to this aspect of the disclosure, a combination for treating diseases involving inflammasome activity is provided, comprising a compound of the present disclosure as defined above or a pharmaceutically acceptable salt thereof, and another suitable agent.

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

[0378] Any alternative embodiments of the macromolecules described herein also apply to any of the pharmaceutical compositions, procedures, methods, uses, pharmaceutical preparations, and manufacturing characteristics disclosed herein.

[0379] The compounds disclosed herein or pharmaceutical compositions comprising these compounds may be delivered to a subject via any convenient route of administration, whether systemic / peripheral or local (i.e., at the desired site of action).

[0380] Administration routes include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; percutaneous (including, for example, by patches, plasters, etc.); transmucosal (including, for example, by patches, plasters, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, via aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by pessaries); extragastric, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and by implantation of a reservoir or depository, for example, subcutaneously or intramuscularly. Exemplary embodiments

[0381] Exemplary Embodiment 1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X is N (Ra), O, S, or C (Rb)(Rc); Ra is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; or Ra is cyclized with R1 to form 3-to-8-membered heterocycloalkyl; Rb is hydrogen or C1-C6 alkyl; Rc is hydrogen or C1-C6 alkyl; or Rb and Rc together with the atoms to which they are attached form a C3-C8 cycloalkyl; Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl may be mediated by one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl groups as required. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, C3-C10 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O) t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl is substituted with one or more halogroups as needed, -R4OR5, substituted 3- to 8-membered heterocycloalkyl as needed, substituted C5-C10 aryl as needed, or substituted 5- to 9-membered heteroaryl as needed;R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R3) R5)2 or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is substituted with one or more C1-C6 alkyl, haloyl, or C1-C6 haloalkyl as required; or R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl is substituted with one or more R2a as required; R2a is hydrogen, C1-C6 alkyl, halogroup, or C1-C6 haloalkyl; R4 is absent, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; or R7 and R8 together with the atoms to which they are attached form a 3-to-8-membered heterocycloalkyl; and t is 1 or 2;The limiting condition is that R1 is not a C2 or C4 alkyl group substituted with a morpholino group.

[0382] Exemplary Embodiment 2. A compound of formula (I'), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X is N (Ra), O, S, or C (Rb)(Rc); Ra is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; or Ra is cyclized with R1 to form 3-to-8-membered heterocycloalkyl; Rb is hydrogen or C1-C6 alkyl; Rc is hydrogen or C1-C6 alkyl; or Rb and Rc together with the atoms to which they are attached form a C3-C8 cycloalkyl; Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heterocycloaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heterocycloaryl may be derived from one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, 5-to-9-membered heterocycloaryl, halo, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6. -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 are substituted; R1 can be C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), or -R4N(R7)S(O). t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl is substituted with one or more halogroups as needed, -R4OR5, substituted 3- to 8-membered heterocycloalkyl as needed, substituted C5-C10 aryl as needed, or substituted 5- to 9-membered heteroaryl as needed; R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl is substituted by one or more R2a as required;R2a is hydrogen, C1-C6 alkyl, halogroup or C1-C6 haloalkyl (R4 series not present), C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R8 is hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C3-C8 cycloalkyl, a 3- to 8-membered heterocycloalkyl, a C5-C10 aryl, or a 5- to 9-membered heteroaryl; or R7 and R8 together with the atoms to which they are attached form a 3- to 8-membered heterocycloalkyl; and t is 1 or 2; the restriction is that R1 is not a C2 or C4 alkyl group substituted with a morpholinoyl group.

[0383] Exemplary Embodiment 3. A compound of formula (I''), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X is N (Ra), O, S, or C (Rb)(Rc); Ra is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; or Ra cyclizes with R1 to form 3-to-8-membered heterocycloalkyl; Rb is hydrogen or C1-C6 alkyl; Rc is hydrogen or C1-C6 alkyl; or Rb and Rc together with the atoms to which they are attached form a C3-C8 cycloalkyl; Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl may be mediated by one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl groups as required. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 can be C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), or -R4N(R7)S(O). t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl is substituted with one or more halogroups as needed, -R4OR5, substituted 3- to 8-membered heterocycloalkyl as needed, substituted C5-C10 aryl as needed, or substituted 5- to 9-membered heteroaryl as needed;R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R4 is absent; it is C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl. R8 is hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C3-C8 cycloalkyl, a 3- to 8-membered heterocycloalkyl, a C5-C10 aryl, or a 5- to 9-membered heteroaryl; or R7 and R8 together with the atoms to which they are attached form a 3- to 8-membered heterocycloalkyl; and t is 1 or 2; the restriction is that R1 is not a C2 or C4 alkyl group substituted with a morpholinoyl group.

[0384] Exemplary Embodiment 4. A compound of any of the foregoing exemplary embodiments, wherein the compound is a compound of formula (II): or a pharmaceutically acceptable salt, solvate, inclusion complex, hydrate, stereoisomer, or tautomer thereof, wherein: Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl is optionally mediated by one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 can be C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), or -R4N(R7)S(O). t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl is substituted with one or more halogroups as needed, -R4OR5, substituted 3- to 8-membered heterocycloalkyl as needed, substituted C5-C10 aryl as needed, or substituted 5- to 9-membered heteroaryl as needed; R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required;R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R3) R5)2 or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is substituted with one or more C1-C6 alkyl, haloyl, or C1-C6 haloalkyl as required; or R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl is substituted with one or more R2a as required; R2a is hydrogen, C1-C6 alkyl, halogroup, or C1-C6 haloalkyl; R4 is absent, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl; R5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl; R8 is hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C3-C8 cycloalkyl, a 3- to 8-membered heterocycloalkyl, a C5-C10 aryl, or a 5- to 9-membered heteroaryl; or R7 and R8 together with the atoms to which they are attached form a 3- to 8-membered heterocycloalkyl; and t is 1 or 2; the restriction is that R1 is not a C2 or C4 alkyl group substituted with a morpholinoyl group.

[0385] Exemplary Embodiment 5. A compound as described in any of the foregoing exemplary embodiments, wherein X is N (Ra), O, S or C (Rb) (Rc).

[0386] Exemplary Embodiment 6. A compound as described in any of the foregoing exemplary embodiments, wherein X is N (Ra).

[0387] Exemplary Embodiment 7. A compound as described in any of the foregoing exemplary embodiments, wherein X is NH.

[0388] Exemplary Embodiment 8. A compound as described in any of the foregoing exemplary embodiments, wherein X is N (C1-C6 alkyl).

[0389] Exemplary Embodiment 9. A compound as described in any of the foregoing exemplary embodiments, wherein Ra is H.

[0390] Exemplary Embodiment 10. A compound as described in any of the foregoing exemplary embodiments, wherein Ra is a methyl group.

[0391] Exemplary Embodiment 11. A compound as described in any of the foregoing exemplary embodiments, wherein Y is a 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl is substituted as desired with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5.

[0392] Exemplary Embodiment 12. A compound as described in any of the foregoing exemplary embodiments, wherein Y is a 3- to 8-membered heterocyclic alkyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5.

[0393] Exemplary Embodiment 13. A compound as described in any of the foregoing exemplary embodiments, wherein Y is a piperidinyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5.

[0394] Exemplary Embodiment 14. A compound as described in any of the foregoing exemplary embodiments, wherein Y is a C5-C10 aryl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5.

[0395] Exemplary Embodiment 15. A compound as described in any of the foregoing exemplary embodiments, wherein Y is a phenyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5 groups.

[0396] Exemplary Embodiment 16. A compound as described in any of the foregoing exemplary embodiments, wherein Y is a phenyl substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5, wherein at least one substitution is a substitution at the para position of the phenyl ring.

[0397] Exemplary Embodiment 17. A compound as described in any of the foregoing exemplary embodiments, wherein Y is a phenyl group substituted at the para-position of the phenyl ring with a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C3-C8 cycloalkyl group, a halogen group, a cyano group, or a -R4OR5 group.

[0398] Exemplary Embodiment 18. A compound as described in any of the foregoing exemplary embodiments, wherein Y is a phenyl substituted with two C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5, wherein at least one substitution is a substitution at the para position of the phenyl ring.

[0399] Exemplary Embodiment 19. A compound as described in any of the foregoing exemplary embodiments, wherein Y is , , , , , , , , , , , , , , , , , , or.

[0400] Exemplary Embodiment 20. A compound as described in any of the foregoing exemplary embodiments, wherein Y is , , , , , , , , , , , , , , or.

[0401] Exemplary Embodiment 21. A compound as described in any of the foregoing exemplary embodiments, wherein Y is or.

[0402] Exemplary Embodiment 22. A compound as described in any of the foregoing exemplary embodiments, wherein Y is.

[0403] Exemplary Embodiment 23. A compound as described in any of the foregoing exemplary embodiments, wherein R2 is hydrogen or a C1-C6 alkyl group.

[0404] Exemplary Embodiment 24. A compound as described in any of the foregoing exemplary embodiments, wherein R2 is hydrogen.

[0405] Exemplary Embodiment 25. A compound as described in any of the foregoing exemplary embodiments, wherein R2 is a C1-C6 alkyl group.

[0406] Exemplary Embodiment 26. A compound as described in any of the foregoing exemplary embodiments, wherein R2 is a methyl group.

[0407] Exemplary Embodiment 27. A compound as described in any of the foregoing exemplary embodiments, wherein R3 is hydrogen or a C1-C6 alkyl group.

[0408] Exemplary Embodiment 28. A compound as described in any of the foregoing exemplary embodiments, wherein R3 is hydrogen.

[0409] Exemplary Embodiment 29. A compound as described in any of the foregoing exemplary embodiments, wherein R3 is a C1-C6 alkyl group.

[0410] Exemplary Embodiment 30. A compound as described in any of the foregoing exemplary embodiments, wherein R3 is a methyl group.

[0411] Exemplary Embodiment 31. A compound as described in any of the foregoing exemplary embodiments, wherein R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl, wherein the C3-C8 cycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl is substituted by one or more R2a as required.

[0412] Exemplary Embodiment 32. A compound as described in any of the foregoing exemplary embodiments, wherein R2a is hydrogen or a halogen group.

[0413] Exemplary Embodiment 33. A compound as described in any of the foregoing exemplary embodiments, wherein R2a is hydrogen.

[0414] Exemplary Embodiment 34. A compound as described in any of the foregoing exemplary embodiments, wherein R2a is a halogen group.

[0415] Exemplary Embodiment 35. A compound as described in any of the foregoing exemplary embodiments, wherein R2a is Cl.

[0416] Exemplary Embodiment 36. A compound as described in any of the foregoing exemplary embodiments, wherein R2 and R3 together with the atoms to which they are attached form , , , , , , , , , , , , , or.

[0417] Exemplary Embodiment 37. A compound as described in any of the foregoing exemplary embodiments, wherein R2 and R3 together with the atoms to which they are attached form , , , , , , , , , , , or.

[0418] Exemplary Embodiment 38. A compound as described in any of the foregoing exemplary embodiments, wherein R2 and R3 are formed together with the atoms to which they are attached, or

[0419] Exemplary Embodiment 39. A compound as described in any of the foregoing exemplary embodiments, wherein R2 and R3 together with the atoms to which they are attached form , , , , , , , or.

[0420] Exemplary Embodiment 40. A compound as described in any of the foregoing exemplary embodiments, wherein R2 and R3 are formed together with the atoms to which they are attached.

[0421] Exemplary Embodiment 41. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, 5- to 9-membered heteroaryl, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4S(O)tR5, -R4S(O)tN(R7)(R8) -R4P(O)(R5)2 or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl is substituted with one or more halogen groups as needed, -R4OR5, substituted with substituted 3- to 8-membered heterocycloalkyl, substituted with substituted C5-C10 aryl, or substituted with substituted 5- to 9-membered heteroaryl as needed.

[0422] Exemplary Embodiment 42. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is substituted with one or more halogen groups, -R4OR5, substituted with substituted 3- to 8-membered heterocyclic alkyl, substituted with substituted C5-C10 aryl, or substituted with substituted 5- to 9-membered heteroaryl as desired.

[0423] Exemplary Embodiment 43. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted with 3- to 8-membered heterocyclic alkyl groups, substituted with C5- to C10 aryl groups, or substituted with 5- to 9-membered heteroaryl groups as desired.

[0424] Exemplary Embodiment 44. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is a 3- to 8-membered heterocyclic alkyl group substituted as desired by one or more halogen groups, -R4OR5, a substituted 3- to 8-membered heterocyclic alkyl group substituted as desired by ...

[0425] Exemplary Embodiment 45. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is, as desired, a 5-to-9-membered heterocyclic alkyl group substituted with one or more halogen groups, -R4OR5, a 3-to-8-membered heterocyclic alkyl group substituted with one or more halogen groups, a C5-C10 aryl group substituted with one or more halogen groups, or a 5-to-9-membered heteroaryl group substituted with one or more halogen groups.

[0426] Exemplary Embodiment 46. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is a C1-C6 alkyl or a 3- to 8-membered heterocyclic alkyl, wherein the C1-C6 alkyl is substituted with one or more -R4OR5 as required.

[0427] Exemplary Embodiment 47. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is , ...

[0428] Exemplary Embodiment 48. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is , , , , , , , , , , , , , , , , , , or.

[0429] Exemplary Embodiment 49. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is.

[0430] Exemplary Embodiment 50. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is , , , , , , or.

[0431] Exemplary Embodiment 51. A compound of any of the aforementioned exemplary embodiments, wherein R4 is absent, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl.

[0432] Exemplary Embodiment 52. The compound of any of the aforementioned exemplary embodiments, wherein the R4 system is absent.

[0433] Exemplary Embodiment 53. A compound as described in any of the foregoing exemplary embodiments, wherein R5 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl.

[0434] Exemplary Embodiment 54. A compound as described in any of the foregoing exemplary embodiments, wherein R5 is hydrogen.

[0435] Exemplary Embodiment 55. A compound as described in any of the foregoing exemplary embodiments, wherein R5 is a C1-C6 alkyl group.

[0436] Exemplary Embodiment 56. A compound as described in any of the foregoing exemplary embodiments, wherein R5 is a methyl group.

[0437] Exemplary Embodiment 57. A compound as described in any of the foregoing exemplary embodiments, wherein R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl.

[0438] Exemplary Embodiment 58. A compound as described in any of the foregoing exemplary embodiments, wherein R7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl.

[0439] Exemplary Embodiment 59. A compound as described in any of the foregoing exemplary embodiments, wherein R8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C5-C10 aryl, or 5-to-9-membered heteroaryl.

[0440] Exemplary Embodiment 60. A compound as described in any of the foregoing exemplary embodiments, wherein R7 and R8 together with the atoms to which they are attached form a 3-to-8-membered heterocyclic alkyl group.

[0441] Exemplary Embodiment 61. A compound as described in any of the foregoing exemplary embodiments, wherein t is 1 or 2.

[0442] Exemplary Embodiment 62. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is not or

[0443] Exemplary Embodiment 63. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-a): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl group, a 3- to 8-membered heterocycloalkyl group, a C5-C10 aryl group, or a 5- to 9-membered heteroaryl group, wherein the C3-C8 cycloalkyl group, the 3- to 8-membered heterocycloalkyl group, the C5-C10 aryl group, or the 5- to 9-membered heteroaryl group is substituted with one or more R2a groups as desired.

[0444] Exemplary Embodiment 64. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-b): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocyclic alkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl group substituted with one or more R2a groups as desired.

[0445] Exemplary Embodiment 65. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-c): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocyclic alkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and R2 and R3 together with the atoms to which they are attached form 3- to 8-membered heterocyclic alkyl groups substituted with one or more R2a groups as desired.

[0446] Exemplary Embodiment 66. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-d): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, 3- to 8-membered heterocyclic alkyl, or 5- to 9-membered heteroaryl; and R2 and R3 together with the atoms to which they are attached form a C5-C10 aryl group substituted with one or more R2a as desired.

[0447] Exemplary Embodiment 67. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-d): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocyclic alkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and R2 and R3 together with the atoms to which they are attached form 5- to 9-membered heteroaryl groups substituted with one or more R2a groups as desired.

[0448] Exemplary Embodiment 68. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-e): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; R2 and R3, together with the atoms to which they are attached, form a C5-C10 aryl or a 5- to 9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl is substituted by one or more R2a as required; and Y is a 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl, C5-C10 aryl, or 5- to 9-membered heteroaryl is substituted by one, two, or three of the following as required: C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, or -R4OR5.

[0449] Exemplary Embodiment 69. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-f): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and Y is a 3- to 8-membered heterocycloalkyl group, C5-C10 aryl group, or 5- to 9-membered heteroaryl group, wherein the 3- to 8-membered heterocycloalkyl group, C5-C10 aryl group, or 5- to 9-membered heteroaryl group is substituted with one, two, or three of the following as desired: C1-C6 haloalkyl group, C3-C8 cycloalkyl group, halogen group, cyano group, or -R4OR5 group.

[0450] Exemplary Embodiment 70. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-g): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and Y is a 3- to 8-membered heterocycloalkyl group, C5-C10 aryl group, or 5- to 9-membered heteroaryl group, wherein the 3- to 8-membered heterocycloalkyl group, C5-C10 aryl group, or 5- to 9-membered heteroaryl group is substituted with one, two, or three of the following as desired: C1-C6 haloalkyl group, C3-C8 cycloalkyl group, halogen group, cyano group, or -R4OR5 group.

[0451] Exemplary Embodiment 71. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-h): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and Y is a 3- to 8-membered heterocycloalkyl group, C5-C10 aryl group, or 5- to 9-membered heteroaryl group, wherein the 3- to 8-membered heterocycloalkyl group, C5-C10 aryl group, or 5- to 9-membered heteroaryl group is substituted with one, two, or three of the following as desired: C1-C6 haloalkyl group, C3-C8 cycloalkyl group, halogen group, cyano group, or -R4OR5 group.

[0452] Exemplary Embodiment 72. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-i): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and Y is a 3- to 8-membered heterocycloalkyl group, C5-C10 aryl group, or 5- to 9-membered heteroaryl group, wherein the 3- to 8-membered heterocycloalkyl group, C5-C10 aryl group, or 5- to 9-membered heteroaryl group is substituted with one, two, or three of the following as desired: C1-C6 haloalkyl group, C3-C8 cycloalkyl group, halogen group, cyano group, or -R4OR5 group.

[0453] Exemplary Embodiment 73. The compound of Exemplary Embodiment 4, wherein the compound of Formula (II) is a compound of Formula (II-j): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: R1 is a C1-C6 alkyl group substituted with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocycloalkyl groups as desired, or substituted 5- to 9-membered heteroaryl groups as desired; and Y is a 3- to 8-membered heterocycloalkyl group, C5-C10 aryl group, or 5- to 9-membered heteroaryl group, wherein the 3- to 8-membered heterocycloalkyl group, C5-C10 aryl group, or 5- to 9-membered heteroaryl group is substituted with one, two, or three of the following as desired: C1-C6 haloalkyl group, C3-C8 cycloalkyl group, halogen group, cyano group, or -R4OR5 group.

[0454] Exemplary Embodiment 74. A compound of any of the foregoing exemplary embodiments, wherein the compound is selected from compounds 1-81 or their pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers or tautomers.

[0455] Exemplary Embodiment 75. A compound of any of the aforementioned exemplary embodiments, wherein the compound is selected from the compounds in Table 1 or their pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers.

[0456] Exemplary Embodiment 76. A compound of any of the aforementioned exemplary embodiments, wherein the compound is selected from the compounds in Table 2 or their pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers.

[0457] Exemplary embodiment 77. A compound of any one of exemplary embodiments 74-76, or a pharmaceutically acceptable salt or stereoisomer thereof.

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

[0459] Exemplary Embodiment 79. An isotopic derivative of a compound as described in any of the foregoing exemplary embodiments.

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

[0461] Exemplary Embodiment 81. A method of treating or preventing NLRP3-related diseases or disorders, the method comprising administering to a subject at least one therapeutically effective amount of a compound as described in any of the foregoing exemplary embodiments.

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

[0463] Exemplary Embodiment 83. The compound of any of the foregoing exemplary embodiments is used for the treatment or prevention of NLRP3-related diseases or disorders.

[0464] Exemplary Embodiment 84. Use of a compound as described in any of the foregoing exemplary embodiments in the manufacture of a medicament for the treatment or prevention of NLRP3-related diseases or disorders.

[0465] Exemplary Embodiment 85. A method, compound, or use as described in any of the foregoing exemplary embodiments, wherein the object is a person.

[0466] Exemplary Embodiment 86. The method, compound, or use of any of the foregoing exemplary embodiments, wherein the NLRP3-related disease or disorder is inflammation, autoimmune disease, cancer, infection, central nervous system disease or disorder, metabolic disease, cardiovascular disease, respiratory disease, kidney disease, liver disease, eye disease, skin disease, lymphatic disease, rheumatic disease, mental illness, graft-versus-host disease, abnormal pain, or NLRP3-related disease in a subject in which a germline or somatic non-silent mutation in NLRP3 has been identified.

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

[0468] Exemplary Embodiment 88. A method, compound, or use as described in any of the foregoing exemplary embodiments, wherein the kidney disease is acute kidney disease, chronic kidney disease, or rare kidney disease.

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

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

[0471] Exemplary Embodiment 91. The method, compound, or use of any of the foregoing exemplary embodiments, wherein the NLRP3-related disease in a subject that has been identified as carrying a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0472] Exemplary Embodiment 92. The method, compound, or use as described in any of the foregoing exemplary embodiments, wherein the cryopyrin-associated autoinflammatory syndrome is familial cold-cause autoinflammatory syndrome, Muckle-Wells syndrome, or a neonatal multisystemic inflammatory disease. Exemplary Embodiment A

[0473] Exemplary Embodiment 1A. A compound of formula (II-h), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: each R2a is hydrogen; R1 is a C1-C6 alkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(3-to-8-membered heterocycloalkyl), or -(CH2)n-(5-to-9-membered heteroaryl), wherein the alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl group is substituted with one or more halogen groups, CN, C1-C6 alkyl, C6-C10 aryl, -R4OR5, or -NR5R6 as required; and Y is a C6-C10 aryl group, wherein the aryl group is substituted with one or more halogen groups, C1-C6 alkyl, C1-C6 haloalkyl, or -R4OR5 as required; R4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl. R5 and R6 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the alkyl group is substituted with one or more D groups as required; and n is an integer from 0 to 4.

[0474] Exemplary Embodiment 2A. A compound as in Exemplary Embodiment 1A, wherein R1 is a C1-C6 alkyl group substituted with one or more halogen groups, CN, C1-C6 alkyl, C1-C6 haloalkyl, C6-C10 aryl, -NR4R5, or -R4OR5 as desired.

[0475] Exemplary embodiment 3A. A compound such as exemplary embodiment 2A, wherein R1 is a C1-C6 alkyl group substituted with one or more CN, C1-C6 alkyl, or -R4OR5 as desired.

[0476] Exemplary embodiment 4A. A compound such as exemplary embodiment 3A, wherein R4 is a bond.

[0477] Exemplary embodiment 5A. A compound such as exemplary embodiment 3A, wherein R5 is hydrogen or C1-C6 alkyl.

[0478] Exemplary embodiment 6A. A compound as in exemplary embodiment 1A, wherein R1 is -(CH2)n-(3- to 8-membered heterocyclic alkyl).

[0479] Exemplary embodiment 7A. A compound such as exemplary embodiment 6A, wherein the heterocyclic alkyl group is substituted with one or more halogen groups, C1-C6 alkyl groups, or -R4OR5.

[0480] Exemplary embodiment 8A. A compound such as exemplary embodiment 6A, wherein n is an integer selected from 0 or 1.

[0481] Exemplary embodiment 9A. A compound as in exemplary embodiment 1A, wherein R1 is -(CH2)n-(C3-C10 cycloalkyl).

[0482] Exemplary embodiment 10A. A compound such as exemplary embodiment 9A, wherein the cycloalkyl group is substituted with one or more halogen groups, C1-C6 alkyl groups, or -R4OR5.

[0483] Exemplary embodiment 11A. A compound as in exemplary embodiment 1A, wherein Y is a C6-C10 aryl group.

[0484] Exemplary embodiment 12A. A compound such as exemplary embodiment 11A, wherein Y is a phenyl group.

[0485] Exemplary embodiment 13A. A compound such as exemplary embodiment 12A, wherein the phenyl group is substituted with one or more halogen groups, C1-C6 alkyl groups, or -R4OR5.

[0486] Exemplary Embodiment 14A. The compound of Exemplary Embodiment 1A is selected from...

[0487] Exemplary Embodiment 15A. The compound of Exemplary Embodiment 14A is selected from 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 5-Chloro-2-(4-((4-fluorobenzyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol.

[0488] Exemplary Embodiment 16A. The compound of Exemplary Embodiment 15A is selected from 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 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 as described in Exemplary Embodiment 1A and a pharmaceutically acceptable carrier.

[0490] Exemplary embodiment 18A. A pharmaceutical composition comprising a compound as in exemplary embodiment 14A and a pharmaceutically acceptable carrier.

[0491] Exemplary embodiment 19A. A pharmaceutical composition comprising a compound as in exemplary embodiment 15A and a pharmaceutically acceptable carrier.

[0492] Exemplary Embodiment 20A. A pharmaceutical composition comprising a compound as described in Exemplary Embodiment 16A and a pharmaceutically acceptable carrier. Exemplary Embodiment B

[0493] Exemplary Embodiment 1B. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X is N (Ra), O, S, or C (Rb)(Rc); Ra 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; or Ra is cyclized with R1 to form 3- to 8-membered heterocycloalkyl; Rb is hydrogen or C1-C6 alkyl; Rc is hydrogen or C1-C6 alkyl; or Rb and Rc together with the atoms to which they are attached form a C3-C8 cycloalkyl; Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl may be derived from one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl groups as desired. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(3-to-8-membered heterocycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(5-to-9-membered heteroaryl), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), - R4N(R7)S(O)t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as required by one or more halogroups, CN, C1-C6 alkyl, -R4OR5, -NR5R6, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C10 aryl, or substituted 5- to 9-membered heteroaryl as required;R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R3) R5)2 or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogen, or C1-C6 haloalkyl groups as required; or R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group is substituted with one or more R2a groups as required; R2a is hydrogen, deuterium, C1-C6 alkyl, haloyl, or C1-C6 haloalkyl; R4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; R5 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, wherein the alkyl group is substituted with one or more D groups as required; R6 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; R7 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; R8 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; or R7 and R8 together with the atoms to which they are attached form 3-to-8-membered heterocycloalkyl;n is 0, 1, 2, 3, or 4; and t is 1 or 2; the constraint is that R1 is not a C2 or C4 alkyl group substituted with a morpholino group.

[0494] Exemplary Embodiment 2B. A compound of formula (I'), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X is N (Ra), O, S, or C (Rb)(Rc); Ra 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; or Ra is cyclized with R1 to form 3-to-8-membered heterocycloalkyl; Rb is hydrogen or C1-C6 alkyl; Rc is hydrogen or C1-C6 alkyl; or Rb and Rc together with the atoms to which they are attached form a C3-C8 cycloalkyl; Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl may be derived from one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl groups as desired. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(3- to 8-membered heterocycloalkyl), or -(CH2)n-(5- to 9-membered heteroaryl), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8). -R4N(R7)S(O)t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as required by one or more halogroups, CN, C1-C6 alkyl, -NR5R6, -R4OR5, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C10 aryl, or substituted 5- to 9-membered heteroaryl as required;R2 and R3, together with the atoms to which they are attached, form a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl is substituted with one or more R2a as required; R2a is hydrogen, deuterium, C1-C6 alkyl, haloyl, or C1-C6 haloalkyl; R4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; R5 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, wherein the alkyl group is substituted with one or more D as required; R6 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heterocycloalkyl; R7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heterocycloalkyl; R8 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heterocycloalkyl; or R7 and R8 together with the atoms to which they are attached form a 3-to-8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; and t is 1 or 2; the restriction is that R1 is not a C2 or C4 alkyl group substituted with a morpholinoyl group.

[0495] Exemplary Embodiment 3B. A compound of formula (I''), or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof, wherein: X is N (Ra), O, S, or C (Rb)(Rc); Ra 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; or Ra cyclizes with R1 to form 3-to-8-membered heterocycloalkyl; Rb is hydrogen or C1-C6 alkyl; Rc is hydrogen or C1-C6 alkyl; or Rb and Rc together with the atoms to which they are attached form a C3-C8 cycloalkyl; Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl may be derived from one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl groups as desired. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 is a C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(3- to 8-membered heterocycloalkyl), or -(CH2)n-(5- to 9-membered heteroaryl), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8). -R4N(R7)S(O)t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as required by one or more halogroups, CN, C1-C6 alkyl, -NR5R6, -R4OR5, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C10 aryl, or substituted 5- to 9-membered heteroaryl as required;R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl, wherein for -R4OR5, R4 can only be a bond; R5 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, wherein the alkyl group is substituted with one or more D groups as required; R6 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; R7 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; R8 is hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl, a C3-C8 cycloalkyl, a 3- to 8-membered heterocycloalkyl, a C6-C10 aryl, or a 5- to 9-membered heteroaryl; or R7 and R8 together with the atoms to which they are attached form a 3- to 8-membered heterocycloalkyl; n is 0, 1, 2, 3, or 4; and t is 1 or 2; the restriction is that R1 is not a C2 or C4 alkyl group substituted with a morpholinoyl group.

[0496] Exemplary Embodiment 4B. A compound of formula (II), or a pharmaceutically acceptable salt, solvate, inclusion complex, hydrate, stereoisomer, or tautomer thereof, wherein: Y is a C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl is optionally mediated by one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl. Halogenated, cyano, -R4OR5, -R4N(R5)(R6), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5 substituted; R1 can be C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(C6-C10 aryl), -(CH2)n-(3- to 8-membered heterocycloalkyl), or -(CH2)n-(5- to 9-membered heteroaryl), -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8). -R4N(R7)S(O)t(R8) or -R4P(O)(R5)2, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as required by one or more halogroups, CN, C1-C6 alkyl, -NR5R6, -R4OR5, substituted 3- to 8-membered heterocycloalkyl, substituted C6-C10 aryl, or substituted 5- to 9-membered heteroaryl as required;R2 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R5)2, or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl is substituted with one or more C1-C6 alkyl, halogroup, or C1-C6 haloalkyl groups as required; R3 is hydrogen, halogroup, cyanogroup, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, 5- to 9-membered heteroaryl, -R4OR5, -R4SR6, -R4C(O)OR6, -R4C(O)N(R7)(R8), -R4N(R7)C(O)R8, -R4S(O)tR5, -R4S(O)tN(R7)(R8), -R4N(R7)S(O)t(R8), -R4P(O)(R3) R5)2 or -R4SF5, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is substituted with one or more C1-C6 alkyl, halogen, or C1-C6 haloalkyl groups as required; or R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group is substituted with one or more R2a groups as required; R2a is hydrogen, deuterium, C1-C6 alkyl, haloyl, or C1-C6 haloalkyl; R4 is a bond, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl; R5 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, wherein the alkyl group is substituted with one or more D groups as required; R6 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; R7 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; R8 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; or R7 and R8 together with the atoms to which they are attached form 3-to-8-membered heterocycloalkyl;n is 0, 1, 2, 3, or 4; and t is 1 or 2; the constraint is that R1 is not a C2 or C4 alkyl group substituted with a morpholino group.

[0497] Exemplary Embodiment 5B. A compound as in Exemplary Embodiment 1B, wherein: X is N (Ra) or O; Ra is hydrogen or C1-C6 alkyl; Y is 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is substituted as desired with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halo, cyano, -R4OR5, -R4SR6, or -R4SF5; R1 is a C1-C6 alkyl, C1-C6 haloalkyl, -(CH2)n-(C3-C10 cycloalkyl), -(CH2)n-(3-to-8-membered heterocycloalkyl), -(CH2)n-(C6-C10 aryl), or -(CH2)n-(5-to-9-membered heteroaryl), wherein the C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, 3-to-8-membered heterocycloalkyl, C6-C10 aryl, or 5-to-9-membered heteroaryl is substituted with one or more halogen groups, CN, C1-C6 alkyl, or -R4OR5 as required; R2 is hydrogen or a C1-C6 alkyl group substituted with one or more halogen groups as required; R3 is hydrogen or a C1-C6 alkyl group substituted with one or more halogen groups as desired; or R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group, wherein the C3-C8 cycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl group is substituted with one or more R2a groups as desired; R2a is a halogen group; R4 is a bond or a C1-C6 alkyl group; R5 is hydrogen, a C1-C6 alkyl group, or a C1-C6 haloalkyl group, wherein the alkyl group is substituted with one or more D groups as desired; and n is 0, 1, 2, 3, or 4; the limitation is that R1 is not a C2 or C4 alkyl group substituted with a morpholino group.

[0498] Exemplary embodiment 6B. A compound as described in any of the foregoing exemplary embodiments, wherein X is N (Ra) or O.

[0499] Exemplary Embodiment 7B. A compound as described in any of the foregoing exemplary embodiments, wherein X is NH.

[0500] Exemplary Embodiment 8B. A compound as in any of the foregoing exemplary embodiments, wherein Y is a 3- to 8-member heterocycloalkyl, a C5-C10 aryl, or a 5- to 9-member heteroaryl, and the 3- to 8-member heterocycloalkyl, C5-C10 aryl, or 5- to 9-member heteroaryl is optionally substituted by one or more C1-C6 alkyls, C1-C6 haloalkyls, C3-C8 cycloalkyls, halogens, cyanos, or -R4OR5.

[0501] Exemplary Embodiment 9B. A compound as in any of the foregoing exemplary embodiments, wherein Y is a piperidinyl or a phenyl, and the piperidinyl or phenyl is substituted by one or more C1-C6 alkyls, C1-C6 haloalkyls, C3-C8 cycloalkyls, halogens, cyanos, or -R4OR5.

[0502] Exemplary Embodiment 10B. A compound as in any of the foregoing exemplary embodiments, wherein Y is, , , , , , , , , , , , , , , , , , or .

[0503] Exemplary Embodiment 11B. A compound as in any of the foregoing exemplary embodiments, wherein R2 is hydrogen or a C1-C6 alkyl.

[0504] Exemplary Embodiment 12B. A compound as in any of the foregoing exemplary embodiments, wherein R3 is hydrogen or a C1-C6 alkyl.

[0505] Exemplary Embodiment 13B. A compound as in any of the foregoing exemplary embodiments, wherein R2 and R3 together with the atoms to which they are attached form a C3-C8 cycloalkyl, a C5-C10 aryl, or a 5- to 9-member heteroaryl, and the C3-C8 cycloalkyl, C5-C10 aryl, or 5- to 9-member heteroaryl is optionally substituted by one or more R2as.

[0506] Exemplary Embodiment 14B. A compound as in any of the foregoing exemplary embodiments, wherein R2a is hydrogen or a halogen.

[0507] Exemplary Embodiment 15B. A compound as in any of the foregoing exemplary embodiments, wherein R2 and R3 together with the atoms to which they are attached form

[0508] , , , , , , , , , , , or .

[0509] Exemplary Embodiment 16B. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is a C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl is substituted as desired by one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocyclic alkyl, substituted C5-C10 aryl, or substituted 5- to 9-membered heteroaryl as desired.

[0510] Exemplary Embodiment 17B. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is a 3- to 8-membered heterocyclic alkyl group substituted as desired with one or more halogen groups, -R4OR5, substituted 3- to 8-membered heterocyclic alkyl group substituted as desired with one or more halogen groups, -R4OR5, substituted C5- to C10 aryl group substituted as desired with one or more substituted C5- to C10 aryl group substituted as desired with one or more substituted 5- to 9-membered heterocyclic alkyl group substituted as desired with one or more halogen groups.

[0511] Exemplary Embodiment 18B. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is, as desired, a 5-to-9-membered heterocyclic alkyl group substituted with one or more halogen groups, -R4OR5, a 3-to-8-membered heterocyclic alkyl group substituted with one or more halogen groups, a C5-C10 aryl group substituted with one or more halogen groups, or a 5-to-9-membered heteroaryl group substituted with one or more halogen groups.

[0512] Exemplary Embodiment 19B. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is , ...

[0513] Exemplary Embodiment 20B. A compound as described in any of the foregoing exemplary embodiments, wherein R4 is a bond, a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group.

[0514] Exemplary embodiment 21B. A compound as described in any of the foregoing exemplary embodiments, wherein R5 is hydrogen or a C1-C6 alkyl group.

[0515] Exemplary Embodiment 22B. A compound as described in any of the foregoing exemplary embodiments, wherein R6 is hydrogen or a C1-C6 alkyl group.

[0516] Exemplary embodiment 23B. A compound as described in any of the foregoing exemplary embodiments, wherein n is 0, 1, or 2.

[0517] Exemplary Embodiment 24B. A compound as described in any of the foregoing exemplary embodiments, wherein R1 is not or

[0518] Exemplary Embodiment 25B. A compound of any of the foregoing exemplary embodiments, wherein the compound is a compound of formula (II-f), (II-g), (II-h), (II-i), or (II-j): or a pharmaceutically acceptable salt, solvate, inclusion compound, hydrate, stereoisomer, or tautomer thereof.

[0519] Exemplary Embodiment 26B. A compound as described in any of the aforementioned exemplary embodiments, wherein the compound is selected from the compounds in Table 1 or Table 2, or pharmaceutically acceptable salts, solvates, inclusion compounds, hydrates, stereoisomers, or tautomers thereof.

[0520] Exemplary Embodiment 27B. A pharmaceutical composition comprising a compound as described in any of the aforementioned exemplary embodiments and one or more pharmaceutically acceptable carriers.

[0521] Exemplary embodiment 28B. A method of modulating NLRP3, the method comprising delivering to a subject a compound as in any one of exemplary embodiments 1B-26B or a pharmaceutical composition as in exemplary embodiment 27B.

[0522] Exemplary embodiment 29B. A method of treating or preventing a disease or ailment, the method comprising administering to a subject a compound as in any one of exemplary embodiments 1B-26B or a pharmaceutical composition as in exemplary embodiment 27B.

[0523] Exemplary embodiment 30B. A compound of any one of exemplary embodiments 1B-26B or a pharmaceutical composition of exemplary embodiment 27B is used for the treatment or prevention of diseases or ailments.

[0524] Exemplary Embodiment 31B. Use of a compound as described in any one of Exemplary Embodiments 1B-26B in the manufacture of a medicament for the treatment or prevention of a disease or ailment.

[0525] Exemplary embodiment 32B. Use of a compound as described in any one of exemplary embodiments 1B-26B for the treatment or prevention of a disease or ailment.

[0526] Exemplary embodiment 33B. A method, compound, or use as described in any of exemplary embodiments 28B-32B, wherein the disease or ailment is an NLRP3-related disease or ailment.

[0527] Exemplary embodiment 34B. A method, compound, or use as described in any of Exemplary embodiments 28B-33B, wherein the object is a person.

[0528] Exemplary embodiment 35B. A method, compound, or use as described in any of Exemplary embodiments 28B-34B, wherein the disease or ailment is inflammation, an autoimmune disease, cancer, an infection, a central nervous system disease or ailment, a metabolic disease, a cardiovascular disease, a respiratory disease, a kidney disease, a liver disease, an eye disease, a skin disease, a lymphatic disease, a rheumatic disease, a mental illness, graft-versus-host disease, abnormal pain, or an NLRP3-related disease.

[0529] Exemplary embodiment 36B. The method, compound, or use of exemplary embodiment 35B, wherein the central nervous system disease or disorder is Parkinson's disease, Alzheimer's disease, traumatic brain injury, spinal cord injury, amyotrophic lateral sclerosis, or multiple sclerosis.

[0530] Exemplary embodiment 37B. A method, compound, or use as in exemplary embodiment 35B, wherein the kidney disease is acute kidney disease, chronic kidney disease, or rare kidney disease.

[0531] Exemplary embodiment 38B. A method, compound, or use as in exemplary embodiment 35B, wherein the skin condition is psoriasis, hidradenitis suppurativa (HS), or atopic dermatitis.

[0532] Exemplary embodiment 39B. The method, compound, or use of exemplary embodiment 35B, wherein the rheumatic disease is dermatomyositis, Stell's disease, or juvenile idiopathic arthritis.

[0533] Exemplary embodiment 40B. Methods, compounds, or uses as in exemplary embodiment 35B, wherein the NLRP3-related disease is present in a subject in which a germline or somatic non-silent mutation in NLRP3 has been identified.

[0534] Exemplary embodiment 41B. The method, compound, or use of exemplary embodiment 40B, wherein the NLRP3-related disease in a subject that has been identified as carrying a germline or somatic non-silent mutation in NLRP3 is cryopyrin-associated autoinflammatory syndrome.

[0535] Exemplary Embodiment 42B. A method, compound, or use as in Exemplary Embodiment 35B, wherein the cryopyrin-associated autoinflammatory syndrome is familial cold-cause autoinflammatory syndrome, Muckle-Wells syndrome, or a multisystemic inflammatory disease with neonatal onset. Examples

[0536] For illustrative purposes, the neutral compound of formula (I) was synthesized and tested in the examples. It should be understood that the neutral compound of formula (I) can be converted into a pharmaceutically acceptable salt of the compound using routine techniques in the art (e.g., by saponifying an ester to a carboxylate, or by hydrolyzing a amide to form the corresponding carboxylic acid, and then converting the carboxylic acid to a carboxylate).

[0537] Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz and 300.3 K as stated, unless otherwise stated; chemical shifts (δ) were reported in parts per million (ppm). Spectra were recorded using a Bruker Avance 400 instrument, with 8, 6, or 32 scans.

[0538] LC-MS chromatograms and spectra were recorded using a Shimadzu LCMS-2020. Injection volumes were 0.7–8.0 µl, while flow rates were typically 0.8 or 1.2 ml / min. Detection methods included diode array (DAD) or evaporative light scattering (ELSD) and positive ion electrospraying. The MS range was 100–1000 Da. Solvents were gradients of water and acetonitrile, both containing modifiers (typically 0.01–0.04%), such as trifluoroacetic acid or ammonium carbonate.

[0539] Abbreviations: DMF: N,N-Dimethylformamide; DMSO: Dimethyl sulfoxide; dppf: 1,1'-bis(diphenylphosphino)ferrocene; ESI: Electrolytic free; EtOAc or EA: Ethyl acetate; EtOH: Ethanol; h: hour; HPLC: High performance liquid chromatography; LCMS: Liquid chromatography-mass spectrometry; MeCN or ACN: Acetonitrile; min: minutes; mw: Microwave; m / z: Mass / charge; PE: Petroleum ether; prep-HPLC: Preparative high performance liquid chromatography; rt: Room temperature; Y: Yield

[0540] A suitable general route for preparing the compound of this application can be described using Plan A in Scheme 2 of this document.

[0541] Step 1 involves an SNAr reaction between an amine (i) and an aryl dichloride (ii) to provide the target chloroaryl intermediate (iii). Step 2 involves a cross-coupling between the intermediate (iii) and the desired boric acid or borate (iv) to produce the desired compound (I). The amine (i), aryl dichloride (ii), and boric acid or borate (iv) are commercially available or known in the chemical literature unless otherwise stated.

[0542] A suitable general route for preparing the compound of this application is also described using Plan B in Scheme 3 of this document.

[0543] Step 1 involves opening a commercially available 3,4-pyridinedicarboxylic anhydride (vi) with Grignard reagent to obtain a carboxylic acid (vii). Step 2 is characterized by chlorination followed by condensation with hydrazine to provide pyridazine alcohol (viii). Step 3 then involves another chlorination to provide a key intermediate (ix), which can then participate in step 4 via an SNAr reaction with an amine (i) to form an aziridine (x). Step 5 then involves deprotection with a methyl ether to provide a compound of formula (I). Example 1. Synthesis of (S)-1-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazine-4-amine (compound 1) and (S)-4-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazine-1-amine (compound 2).

[0544] Step 1. Synthesis of (S)-1-chloro-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazine-4-amine and (S)-4-chloro-N-((tetrahydrofuran-2-yl)methyl)pyrido[4,3-d]pyridazine-1-amine

[0545] To an 8 mL microwave tube, add 1,4-dichloropyrido[3,4-d]pyridazine (250 mg, 1.25 mmol, 1.00 equivalent), 1-[(2S)-tetrahydrofuran-2-yl]methylamine (152 mg, 1.50 mmol, 1.20 equivalent), Na₂CO₃ (397 mg, 3.75 mmol, 3.00 equivalent), and DMF (2 mL). The final reaction mixture was irradiated with microwaves at 130 °C for 30 min. The reaction progress 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 under vacuum. 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%, a mixture of the two isomers) as a yellow oil. LCMS (ES, m / z): RT = 0.54 min, m / z = 265.0 [M+1]+.

[0546] Step 2. Synthesis of (S)-1-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazine-4-amine (Compound 1) and (S)-4-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[3,4-d]pyridazine-1-amine (Compound 2)

[0547] To an 8 mL microwave tube purged and maintained under an inert nitrogen atmosphere, add a mixture 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 (150 mg, 0.56 mmol, 1.00 equivalent), p-chloro-phenylboronic acid (106 mg, 0.68 mmol, 1.20 equivalent), Pd(dppf)Cl2 (82.9 mg, 0.11 mmol, 0.20 equivalent), Na2CO3 (180 mg, 1.70 mmol, 3.00 equivalent), dioxane (2.0 mL, 23.61 mmol, 41.7 equivalent), and H2O (0.4 mL, 22.20 equivalent). (mmol, 39.2 equivalents). The resulting solution was stirred in an oil bath at 80 °C for 2 h. The reaction progress was monitored by LCMS. The resulting solution was extracted with 3 × 5 mL of ethyl acetate, and the resulting mixture was concentrated under vacuum. 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]pyridazine-4-amine and (S)-4-(4-chlorophenyl)-N-((tetrahydrofuran-2-yl)methyl)pyrido[4,3-d]pyridazine-1-amine (160 mg, a mixture of the two isomers) as yellow solids. The crude product (160 mg, purity = 83.23%) was purified by prep-HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep 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, at 8 min; wavelength, 254 / 220 nm. This yielded compound 1 (53.3 mg, 27%) and compound 2 (5.6 mg, 7.3%) as a grayish-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]+. 1H 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). Example 2. Synthesis of (R)-1-(4-chlorophenyl)-4-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d] darazine (compound 3) and (R)-4-(4-chlorophenyl)-1-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d] darazine (compound 4).

[0548] Step 1: Synthesis of (R)-1-chloro-4-((tetrahydrofuran-2-yl)methoxy)pyrido[3,4-d] darazine and (R)-4-chloro-1-((tetrahydrofuran-2-yl)methoxy)pyrido[4,3-d] darazine

[0549] To a 50 mL three-necked round-bottom flask, add (R)-(tetrahydrofuran-2-yl)methanol (61.3 mg, 0.60 mmol, 0.80 equivalent), DMF (1.5 mL, 19.38 mmol, 25.9 equivalent), and NaH (36.0 mg, 1.50 mmol, 2.00 equivalent, 60% in mineral oil). The resulting mixture was stirred at 0 °C for 1 h. Subsequently, 1,4-dichloropyridinium[3,4-d]pyridazine (150 mg, 0.75 mmol, 1.00 equivalent) was added in portions at 0 °C. The resulting solution was stirred at 25 °C for 2 h. The reaction progress 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 under vacuum. 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%, a mixture of the two isomers) as a pale yellow oil. LCMS (ES, m / z): RT = 0.60 min, m / z = 266[M+1]+.

[0550] 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)

[0551] At 25°C, (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 equivalent), p-chloro-phenylboronic acid (106 mg, 0.67 mmol, 1.20 equivalent), Pd(dppf)Cl2 (82.6 mg, 0.11 mmol, 0.20 equivalent), Na2CO3 (119 mg, 1.13 mmol, 2.00 equivalent), dioxane (1.5 mL, 17.7 mmol, 31.4 equivalent), and H2O (0.3 mL, 16.7 mmol, 29.5 equivalent) were added to a 10 mL sealed tube. The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction progress was monitored by LCMS. The resulting solution was extracted with 3 × 5 mL of ethyl acetate. The resulting mixture was concentrated under vacuum. 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%, a mixture of two isomers) as a pale yellow oil. The crude product (150 mg, purity = 78.30%) was purified by Prep-HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD, 30*150 mm, 5 µm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (35% ACN, for 12 min); detector, UV 254 / 220 nm. This yielded compound 3 (3.3 mg, 12%) 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]+. 1H 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). Example 3. 5-Chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d] darazin-1-yl)phenol (Compound 82) Step 1: Synthesis of 1-({1-chloropyrido[3,4-d] darazin-4-yl}amino)-2-methylprop-2-ol.

[0552] At room temperature, 1,4-dichloropyridinol[3,4-d]pyridazine (1.00 g, 5.00 mmol, 1.00 equivalent), 1-amino-2-methylprop-2-ol (0.42 g, 4.75 mmol, 0.95 equivalent), DMF (10.00 mL), and Na2CO3 (1.59 g, 15.00 mmol, 3.00 equivalent) were added to a 20 mL sealed tube. The final reaction mixture was microwaved at 130 °C for 30 min. The reaction was repeated two hundred times in parallel. All reaction solutions were then collected and filtered to remove inorganic salts. The filtrate was then concentrated to 160–200 mL under reduced pressure. The residue was diluted in DCM (200 mL) and shaken in an ultrasonic bath for 10 min (a dark brown solid precipitated in the solution), and then petroleum ether (200 mL) was added. After stirring for 20 min, 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 re-dissolved in DMF and the above post-processing procedure was repeated). This yielded 1-({1-chloropyridino[3,4-d]pyridazin-4-yl}amino)-2-methylprop-2-ol (103.0 g, yield: 40%) as a yellow solid. LCMS (LCMS, ESI): RT = 0.83 min, m / z = 253.0 [M + H]+. ¹H 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). Step 2: Synthesis of 5-chloro-2-(4-((2-hydroxy-2-methylpropyl)amino)pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 82)

[0553] Pd(dppf)Cl2 (275 mg, 0.376 mmol, 0.19 equivalent) and Na2CO3 (426 mg, 4.019 mmol, 2.03 equivalent) were added fractionally to a stirred solution of 1-({1-chloropyridino[3,4-d]pyridazin-4-yl}amino)-2-methylprop-2-ol (500 mg, 1.98 mmol, 1.00 equivalent) and 4-chloro-2-hydroxyphenylboronic acid (375 mg, 2.176 mmol, 1.10 equivalent) in dioxane and H2O (5:1, 8 mL). The resulting mixture was stirred at 80 °C for 1 h under a nitrogen atmosphere. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18 silica gel; mobile phase, MeOH aqueous solution, 30% gradient, for 10 min; detector, UV 254 nm, to obtain the crude product. The crude product was then purified by Prep-HPLC under the following conditions (column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: DCM:EtOH = 9:1; flow rate: 25 mL / min; gradient: 55% B to 55% B, at 13 min, 55% B; wavelength: 254 nm; RT1 (min): 11.5); yielding a yellow solid of 5-chloro-2-{4-[(2-hydroxy-2-methylpropyl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (118.7 mg, 17.38%). LCMS (ES, m / z): m / z = 345.10 [M+H]+. 1H 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).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.

[0554] To an 8 mL microwave-safe tube, add 1,4-dichloropyrido[3,4-d]pyridazine (200 mg, 1.00 mmol, 1.00 equivalent), 2-methoxy-2-methylpropyl-1-amine (103 mg, 1.00 mmol, 1.00 equivalent), Na₂CO₃ (318 mg, 3.00 mmol, 3.00 equivalent), and DMF (3.00 mL). The final reaction mixture was irradiated with microwaves at 130 °C for 0.5 h. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted 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 yellow solids. LCMS (ES, m / z): RT = 0.61 min, m / z = 267[M+1]+. Step 2: Synthesis of 5-chloro-2-{4-[(2-methoxy-2-methylpropyl)amino]pyrido[3,4-d]pyridazin-1-yl}phenol (compound 83)

[0555] To an 8 mL sealed tube, add 1-chloro-N-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyridazine-4-amine (140 mg, 0.52 mmol, 1.00 equivalent), 4-chloro-2-hydroxyphenylboronic acid (181 mg, 1.05 mmol, 2.00 equivalent), Pd(dppf)Cl2 (76.8 mg, 0.10 mmol, 0.20 equivalent), Na2CO3 (167 mg, 1.57 mmol, 3.00 equivalent), dioxane (2.00 mL), and H2O (0.30 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The desired product was detectable by LCMS. The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with water (3 x 5 mL) and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. 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%, a mixture of two isomers). The crude product (68.0 mg, purity = 85.00%, a mixture of two isomers) was purified by Prep-HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD Column, 30*150 mm, 5µm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (35% ACN rising to 45% in 8 min); detector, UV 254nm. This yielded 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]+.¹H NMR (400 MHz, DMSO-d6) δ 10.23 (s, 1H), 9.82 (s, 1H), 8.85 (d, J = 2.4 Hz, 1H), 7.68–7.65 (m, 1H), 7.36–7.29 (m, 2H), 7.04–7.02 (m, 2H), 3.80 (d, J = 6 Hz, 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]+. 1H 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). 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.

[0556] To a 20 mL pressure vessel reactor, add 1-(3,3-difluorocyclopentyl)methylamine (300 mg, 2.22 mmol, 1.00 equivalent), 1,4-dichloropyrido[3,4-d]pyridazine (444 mg, 2.22 mmol, 1.00 equivalent), Na₂CO₃ (707 mg, 6.66 mmol, 3.00 equivalent), and DMF (6.00 mL). The resulting mixture was irradiated with microwave at 130 °C for 30 min. The reaction progress was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3 x 5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC under the following conditions: column: XBridge Prep 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, at 10 min, 55% B; wavelength: 254 nm; RT1 (min): 9. This yielded 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]+. 1H NMR (400 MHz, DMSO-d 6) 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). Step 2: 5-Chloro-2-[4-({[(1S)-3,3-difluorocyclopentyl]methyl}amino)pyrido[3,4-d]pyridazin-1-yl]phenol (Compound 91)

[0557] To an 8 mL tube, add 1-chloro-N-[(3,3-difluorocyclopentyl)methyl]pyrido[3,4-d]pyridazin-4-amine (100 mg, 0.33 mmol, 1.00 equivalent), 4-chloro-2-hydroxyphenylboronic acid (69.2 mg, 0.40 mmol, 1.20 equivalent), Pd(dppf)Cl2 (73.5 mg, 0.10 mmol, 0.30 equivalent), dioxane (0.50 mL), Na2CO3 (106.44 mg, 1.00 mmol, 3.00 equivalent), and H2O (0.10 mL). The resulting mixture was stirred at 80 °C for 2 h under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to give 1-chloro-N-((3,3-difluorocyclopentyl)methyl)pyrido[3,4-d]pyridazine-4-amine (150 mg, purity = 92%, a mixture of two isomers). The mixture product (105 mg) was purified by Chiral-Prep-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, at 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; number of runs: 4. This yielded 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 elution 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 elution peak: LCMS (ES, m / z): RT = 1.09 min, m / z = 391.1 [M+1]⁺. ¹H 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). Similarly, the stereochemistry of compounds 94, 97, 100, and 105 is arbitrarily specified. Example 6. Synthesis of 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)cyclopentyl-1-ol.

[0558] At -78°C under a nitrogen atmosphere, magnesium bromide (0.5 M in THF) (241 mL, 120 mmol, 0.60 equivalent) was added dropwise to a stirred solution of furano[3,4-c]pyridine-1,3-dione (30.0 g, 201.20 mmol, 1.00 equivalent) and tetrahydrofuran (300 mL). The resulting mixture was stirred at 25°C for 2 h under a nitrogen atmosphere. The reaction progress 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 x 50 mL). This gave 20 g of 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid (yield = 34.08%) as a light brown solid. LCMS (ES, m / z): RT = 0.662 min, m / z = 292.0 [M+1]+. Step 2: Synthesis of 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol

[0559] To a 250 mL round-bottom flask, add 5.00 g (17.1 mmol, 1.00 equivalent) of 4-(4-chloro-2-methoxybenzoyl)pyridine-3-carboxylic acid and 50 mL of SOCl2. The resulting mixture was stirred at 70 °C for 2 h. The reaction was monitored by TLC. After the reaction was complete, the resulting mixture was concentrated under vacuum. The residue was dissolved in DCM (50 mL) and added at 0 °C to a solution of NH2NH2.H2O (3.43 g, 68.6 mmol, 4.00 equivalent) and MeOH (50 mL). The resulting mixture was stirred in an oil bath at 70 °C for 3 h. The reaction progress was monitored by LCMS. The precipitated solid was collected by filtration. The crude product (4 g, purity = 90%) was purified by Prep-HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Shield RP18 OBD column, 19*250 mm, 10 µm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (39% ACN, for 17 min); detector, UV 254 / 220 nm. This yielded 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-ol (2.0 g, yield = 40.6%) as a grayish-white solid. LCMS: (ES, m / z): RT = 0.723 min, m / z = 288.0 [M+H]+. ¹H 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). Step 3: Synthesis of 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine.

[0560] To a 250 mL round-bottom flask, add 1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine-4-ol (2.5 g, 8.69 mmol, 1.00 equivalent) and POCl3 (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 at 0 °C with 500 mL sodium bicarbonate (aq.) and 500 mL EtOAc. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This gave 1.5 g of 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (yield = 56.38%) as a brown solid. LCMS (ES, m / z): RT=0.845 min, m / z=306.0[M+1]+. 1H NMR (400 MHz, DMSO-d 6) 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). Step 4: Synthesis of (1S,2S)-2-((1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazin-4-yl)amino)cyclopentan-1-ol

[0561] At room temperature, 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (90 mg, 0.29 mmol, 1.00 equivalent), (1S,2S)-2-aminocyclopentan-1-ol (44.6 mg, 0.44 mmol, 1.50 equivalent), Na2CO3 (93.5 mg, 0.88 mmol, 3.00 equivalent), and 2 mL of NMP were added to an 8 mL microwave tube. The final reaction mixture was stirred at 60 °C for 2 h. The reaction progress was monitored by LCMS. The reaction mixture was used for the next step without further purification. LCMS (ES, m / z): RT = 0.629 min, m / z = 371 [M+1]+. Step 5: Synthesis of 5-chloro-2-(4-{[(1S,2S)-2-hydroxycyclopentyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol)(Compound 95)

[0562] Sodium ethanethiol (371.80 mg, 4.43 mmol, 15.00 equivalents) was added to the reaction mixture from VTT-2772-1 at room temperature. The final reaction mixture was stirred at 120 °C for 2 h. The reaction progress was monitored by LCMS. The reaction was quenched with 20 mL of water, extracted with DCM (3 x 20 mL), concentrated, and the residue was purified by Prep-HPLC under the following conditions: column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 46% B, at 8 min, 46% B; wavelength: 254 nm; RT1 (min): 6.5; yielding a grayish-white solid of 5-chloro-2-(4-{[(1S,2S)-2-hydroxycyclopentyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (44.2 mg, yield = 42%). LCMS (ES, m / z): RT = 0.598 min, m / z = 357 [M+1]+. 1H NMR (400 MHz, methanol-d 4) 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). 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-methylprop-2-ol

[0563] At room temperature, 1-amino-2-methylprop-2-ol (2.00 g, 22.43 mmol, 1.00 equivalent), PMBCl (17.57 g, 112.18 mmol, 5.00 equivalent), TEA (11.35 g, 112.18 mmol, 5.00 equivalent), and DMF (20 mL) were added to a 40 mL vial. The resulting mixture was stirred at room temperature for 2 h. The reaction progress was monitored by LCMS. The mixture was quenched with 30 mL of water and extracted with DCM (30 mL x 3). The organic layer was concentrated under vacuum, and the residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18; mobile phase, MeCN aqueous solution, 0% to 100% gradient, for 30 min; detector, UV 254 nm. This yielded 1-{bis[(4-methoxyphenyl)methyl]amino}-2-methylprop-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). Step 2: Synthesis of [2-(d3)methoxy-2-methylpropyl]bis[(4-methoxyphenyl)methyl]amine

[0564] In a 100 mL three-necked round-bottom flask at 0 °C, 1-{bis[(4-methoxyphenyl)methyl]amino}-2-methylprop-2-ol (500 mg, 1.51 mmol, 1.00 equivalent), THF (15 mL), and KH (30%) (1.00 g, 7.55 mmol, 5.00 equivalent) were added. The resulting mixture was stirred at 0 °C for 30 min. Then, a solution of CD3I (660 mg, 4.55 mmol, 3.00 equivalent) in THF (15 mL) was added at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction progress was monitored by LCMS. The reaction was quenched with 50 mL of NH4Cl(aq), and the resulting mixture was extracted with EtOEt (3 x 50 mL). The combined organic layers were washed with NaCl(aq) (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase rapid chromatography under the following conditions: column, C18; mobile phase, MeCN aqueous solution, 0% to 100% gradient, at 30 min; detector, UV 254 nm. This yielded [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). Step 3: Synthesis of 2-(d³)methoxy-2-methylpropyl-1-amine

[0565] At room temperature, [2-(d3)methoxy-2-methylpropyl]bis[(4-methoxyphenyl)methyl]amine (1.00 g, 2.88 mmol, 1.00 equivalent), Pd / C (154 mg, 1.44 mmol, 0.50 equivalent), and MeOH (100 mL) were added to a 250 mL round-bottom flask. The resulting mixture was stirred overnight at room temperature under a hydrogen atmosphere. The reaction progress was monitored by LCMS. 5 mL of HCl (2 M) was added to this solution, and the reaction mixture was stirred at room temperature for 30 min. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. This gave 2-(d3)methoxy-2-methylpropyl-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]+. Step 4: Synthesis of 1-(4-chloro-2-methoxyphenyl)-N-(2-(methoxy-d3)-2-methylpropyl)pyrido[3,4-d]pyridazine-4-amine

[0566] At room temperature, 2-(d3)methoxy-2-methylprop-1-amine hydrochloride (104 mg, 0.98 mmol, 2.00 equivalent), 4-chloro-1-(4-chloro-2-methoxyphenyl)pyrido[3,4-d]pyridazine (150 mg, 0.49 mmol, 1.00 equivalent), Na2CO3 (259 mg, 2.45 mmol, 5.00 equivalent), and DMSO (3 mL) were added to a 20 mL vial. The resulting mixture was stirred at 80 °C for 2 h. The reaction progress 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]+. Step 5: Synthesis of 5-chloro-2-(4-{[2-(d3)methoxy-2-methylpropyl]amino}pyrido[3,4-d]pyridazin-1-yl)phenol (Compound 99)

[0567] At room temperature, sodium ethanethiol (179 mg, 2.13 mmol, 10.00 equivalent) and DMSO (4 mL) were added to a 50 mL round-bottom flask containing the reaction mixture from VTT-2628-4. The resulting mixture was stirred at 120 °C for 1 h. The reaction progress was monitored by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The crude product (80 mg, purity = 60%) was purified by Prep-HPLC under the following conditions (2#SHIMADZU (HPLC-01)): column, XBridge Prep OBD C18 Column, 30*150 mm, 5 µm; mobile phase, water (10 mmol / L NH4HCO3) and ACN (20% ACN rising to 70%, in 8 min); detector, UV 254 nm. This yielded 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). Compound Synthesis

[0568] Synthesize compound 1-82 according to plan A.

[0569] Synthesize compound 82-105 according to plan A or B.

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

[0571] Compounds 117-126, 128, and 131 were synthesized according to Project B. Example 8. 1H NMR data. Example 9. Bioactivity of the disclosed compounds.

[0572] The bioactivity of the disclosed compounds was determined using the assays described herein. Human PBMC NLRP3 assay

[0573] Reagents: Human PBMC (normal): iXCells Cat # 10HU-003; RPMI 1640 medium with GlutaMAX: ThermoFisher Cat # 61870127 (complete medium: 4.5 g / L D-glucose, 10% FBS, 100 mM NaPyr, 1% penicillin / streptomycin (Pen / Strep), 10 mM HEPES and 0.05 mM β-mercaptoethanol; assay medium: 4.5 g / L D-glucose, 100 mM NaPyr, 1% Pen / Strep, 10 mM HEPES and 0.05 mM β-mercaptoethanol; 96-well V-disc: Costar Cat # 3894; LPS (E. coli O26:B6): Sigma Cat # L2654, 5 mg / mL stock solution in PBS; ATP: Sigma Cat # A6419, prepared in 1 M 250 mM stock solution in HEPES (adjusted to pH 7.4).

[0574] Human PBMC NLRP3 assay: Frozen PBMCs were rapidly thawed in a 37°C water bath for 2 min. Cells were then centrifuged at 1200 RPM for 5 min and resuspended in ~50 mL of fresh RPMI 1640 complete medium. Cells were counted using a hemocytometer and adjusted to 2.5 x 10⁵ cells / mL. 200 µL of PMBCs (5 x 10⁴) were seeded per well in a V-shaped 96-well dish and incubated overnight at 37°C and 5% CO₂. Assay medium containing 100 ng / mL LPS was then prepared. PBMCs were centrifuged at 1200 RPM for 5 min, the serum-containing medium was aspirated, and 150 µL of assay medium + LPS was immediately added to each well. Assay medium without LPS was added to untreated control wells. Cells were then started with LPS at 37°C and 5% CO₂ for 4 h. A concentration-response curve (CRC) of the 1000X test compound in 100% DMSO was prepared. The CRC was then diluted 1:50 in test medium, followed by a further 1:5X dilution in test medium to obtain the final 4X CRC in 0.4% DMSO / test medium. 50 µL / well of the 4X test compound CRC or medium (0.4% DMSO / test medium) was then transferred to each well and incubated at 37°C and 5% CO2 for 30 min. Cells were then stimulated for 1 h at 37°C and 5% CO2 by adding 4 µL of 250 mM ATP (using the 250 mM stock solution prepared in 1 M Hepes without further dilution) (for a final concentration of 5 mM). The plates were then centrifuged at 1200 RPM for 5 min; 50 µl of the culture medium was transferred to a clean 96-well storage plate for interleukin measurement using the mesoscale platform and stored at -80°C until analysis. When it is necessary to quantify TNFα in interleukin plates to confirm selectivity, the compound was added 30 minutes before starting cells with LPS.

[0575] Table A lists the potency assignment codes for each compound in the human PBMC NLRP3 assay: A, B, C, or D. According to the codes, A indicates an IC50 value < 0.3 µM; B indicates an IC50 value ≥ 0.3 µM and < 0.5 µM; C indicates an IC50 value ≥ 0.5 µM and < 1.0 µM; and D indicates an IC50 value ≥ 1.0 µM. Human whole blood - NLRP3

[0576] Heparin lithium coated tubes were used to collect blood from volunteers. Blood samples were distributed onto 96-well plates using 90 µl per well. Activation (priming) was performed for 4.5 h in a humidified incubator at 37 °C and 5% CO2 with the addition of 5 µl of LPS (O26:B6; Sigma L-2654) to a final concentration of 1 µg / ml. 30 min before NLRP3 activation, 5 µl of 20X compound solution or mordant (2% DMSO) was added to each well, and the plates were incubated in a humidified incubator at 37 °C and 5% CO2 on a shaker (450 rpm). Activation was then performed by adding 3.3 µl of 31X ATP solution to each well. At the end of the 30-minute stimulation, the plates were centrifuged (800 g, 10 min, room temperature), and the plasma from each well was frozen at -80 °C. Following the manufacturer's instructions, the IL-1β levels in the supernatant were analyzed using the mesoscale discovery assay (MSD K151TUK). Whole blood was drawn from healthy volunteers after obtaining written informed consent.

[0577] Table B lists the potency assignment codes for each compound in the human whole blood (hWB) NLRP3 assay: A or B. According to the codes, A indicates an IC50 value ≤ 1.0 µM; B indicates an IC50 value > 1.0 µM. Example 10. Potency of the Compounds

[0578] The table below shows the observed improved potency. This disclosure notes that fused bicyclic pyridine analogs exhibited superior activity compared to monocyclic pyridazines, as illustrated by the potency assay in the PBMC test:

[0579] Furthermore, it has been noted that the specific pyridopyridazine regioisomer disclosed herein exhibits improved potency relative to other regioisomers. The introduction of a nitrogen atom into this bicyclic structure also allows binding to proteins associated with improved whole blood potency: homogeneous

[0580] Details of one or more embodiments of this disclosure are set forth in the accompanying description above. Although any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, preferred methods and materials are described herein. Other features, objectives, and advantages of this disclosure will become apparent from the implementation and from the claims. In the specification and the appended claims, the singular form includes the plural indicator unless the context clearly requires 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 pertains. All patents and publications cited in this specification are incorporated herein by reference.

[0581] The foregoing description is presented for illustrative purposes only and is not intended to limit this disclosure to the exact form disclosed, but is limited by the scope of the claims attached thereto.

Claims

1. A pharmaceutical composition comprising a compound of formula (II-h) or (II-i) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, or tautomer thereof, wherein (II-h) or (II-i) contains: Each R2a is hydrogen; R1 is a C1-C6 alkyl group substituted with one or more halogen groups or -R4OR5; Y is a phenyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5, wherein at least one substitution is at the para position of the phenyl ring; R4 is a bond or C1-C6 alkyl group; and R5 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

2. The pharmaceutical composition of claim 1, wherein the compound is a compound of formula (II-h): (II-h).

3. As in claim 1, the pharmaceutical composition, wherein: Each R2a is hydrogen; R1 is a C1-C6 alkyl group substituted with one or more halogen groups or -R4OR5; Y is a phenyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5, wherein at least one substitution is at the para position of the phenyl ring; R4 is a bond; and R5 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

4. The pharmaceutical composition of claim 3, wherein the compound is a compound of formula (II-h): (II-h); wherein: Each R2a is hydrogen; R1 is a C1-C6 alkyl group substituted with one or more halogen groups or -R4OR5; Y is a phenyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, halogen, cyano, or -R4OR5, wherein at least one substitution is at the para position of the phenyl ring; R4 is a bond; and R5 is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl.

5. A pharmaceutical composition as claimed in any of claims 1 to 4, wherein Y is a phenyl group substituted with one, two, or three C1-C6 haloalkyl, halogen, cyano, or -R4OR5 groups.

6. The pharmaceutical composition of claim 5, wherein Y is a phenyl group substituted with one or two of the following C1-C6 haloalkyl, halogen, cyano or -R4OR5 groups.

7. A pharmaceutical composition as claimed in any of claims 1 to 4, wherein Y is a phenyl group substituted with two C1-C6 alkyl groups, C1-C6 haloalkyl groups, C3-C8 cycloalkyl groups, halogen groups, cyano groups, or -R4OR5 groups.

8. A pharmaceutical composition as claimed in any of claims 1 to 4, wherein Y is a phenyl group substituted with one or more halogen groups or -R4OR5.

9. A pharmaceutical composition as claimed in any of claims 1 to 4, wherein Y is a phenyl group substituted with a chloro group at the para position.

10. A pharmaceutical composition as claimed in any of items 1 to 4, wherein R1 is , , , , , or.

11. A pharmaceutical composition as claimed in any of claims 1 to 4, wherein R1 is.

12. A pharmaceutical composition as claimed in any of claims 1 to 4, wherein R5 is hydrogen.

13. The pharmaceutical composition of claim 3, wherein the compound is a compound of formula (II-h): (II-h); wherein: Each R2a is hydrogen; R1 is , , , , , , or; Y is a phenyl group substituted with one or more C1-C6 alkyl, C1-C6 haloalkyl, halogroup or -R4OR5, wherein at least one substitution is at the para position of the phenyl ring; R4 is a bond; and R5 is hydrogen.

14. A pharmaceutical composition as claimed in claim 13, wherein the compound is a compound of formula (II-h): (II-h); wherein: Each R2a is hydrogen; R1 is , , , , , , or; Y is a phenyl group substituted with one, two, or three C1-C6 haloalkyl, halogen, cyano, or -R4OR5, wherein at least one substitution is at the para position of the phenyl ring; R4 is a bond; and R5 is hydrogen.

15. A pharmaceutical composition as claimed in claim 13 or 14, wherein Y is a phenyl group substituted with one or two of the following C1-C6 haloalkyl, halogen, cyano or -R4OR5 groups.

16. A pharmaceutical composition as claimed in claim 13 or 14, wherein Y is a phenyl group substituted with two substituents.

17. The pharmaceutical composition of claim 16, wherein each substituent is selected from halogen groups or -R4OR5.

18. The pharmaceutical composition as claimed in claim 13 or 14, wherein R1 is.

19. A pharmaceutical composition as claimed in claim 17, wherein the halogen group is a chlorine group.