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WO2024240153A1 - Inhibiteurs de l'inflammasome nlrp3 et leurs utilisations - Google Patents

Inhibiteurs de l'inflammasome nlrp3 et leurs utilisations Download PDF

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Publication number
WO2024240153A1
WO2024240153A1 PCT/CN2024/094491 CN2024094491W WO2024240153A1 WO 2024240153 A1 WO2024240153 A1 WO 2024240153A1 CN 2024094491 W CN2024094491 W CN 2024094491W WO 2024240153 A1 WO2024240153 A1 WO 2024240153A1
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cycloalkyl
alkyl
haloalkyl
hydroxyalkyl
aminoalkyl
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Jianping Wu
Luoheng QIN
Xiaoyu Ding
Chaopeng LI
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InSilico Medicine IP Ltd
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InSilico Medicine IP Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present disclosure relates to novel compounds and compositions that are useful as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome pathway.
  • NLRP3 NOD-like receptor protein 3
  • NLRP3 is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1 ⁇ and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways, and a regulatory mitochondrial hub. The aberrant activation of the NLRP3 inflammasome has been linked with several inflammatory disorders, which include cryopyrin-associated periodic syndromes, Alzheimer’s disease, diabetes, and atherosclerosis.
  • the disclosure provides for a compound represented by Formula (I) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • B is C or N:
  • D is C or N
  • E is CR CE or N
  • R CE is hydrogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • ring C is phenyl, 5 to 7-membered heteroaryl, C 5 -C 8 cycloalkyl, or 5 to 8 membered heterocycloalkyl;
  • R 1 on the same atom or different atoms are taken together to form a C 3 -C 8 cycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more R e ;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, 4-6 membered heterocycloalkyl, or C 3 -C 6 cycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 2 taken together to form a C 3 -C 6 cycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 3 is C 6 -C 10 aryl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, 4, 5, or 6;
  • q 0, 1, 2, or 3;
  • w 0, 1, 2, 3, or 4.
  • the disclosure provides for a compound represented by Formula (II) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is C 6 -C 10 aryl, 4-12 membered heteroaryl, C 3 -C 12 cycloalkyl, or 4-12 membered heterocycloalkyl;
  • B, D, or E are each independently C or N;
  • G is O, S, N, NR G ’ , or CR G ;
  • F is O, S, N, NR F ’ , or CR F ; wherein G and F are not both O or S at the same time;
  • each R G and R F is independently hydrogen, halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • each R G ’ and R F ’ is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • R 3 is phenyl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, 4, or 5;
  • w 0, 1, 2, or 3.
  • the compound of Formula (II) has the structure of Formula (IIa) , or a pharmaceutically acceptable salt thereof:
  • G is CR G or N; and F is CR F or N.
  • the compound of Formula (II) has the structure of Formula (IIb) , or a pharmaceutically acceptable salt thereof:
  • G is CR G or N; and F is CR F or N.
  • the compound of Formula (II) has the structure of Formula (IIc) , or a pharmaceutically acceptable salt thereof:
  • G is CR G or N; and F is CR F or N.
  • the compound of Formula (II) has the structure of Formula (IId) , or a pharmaceutically acceptable salt thereof:
  • G is CR G , NR G ’ , O, or S;
  • F is CR F , NR F ’ , N, O, or S, wherein G and F are not both O or S at the same time.
  • the disclosure provides for a compound represented by Formula (III) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is C 6 -C 10 aryl, 4-12 membered heteroaryl, C 3 -C 12 cycloalkyl, or 4-12 membered heterocycloalkyl; H, J, and K are each independently N or CR 1 ;
  • each R 1 is independently hydrogen, halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • R 3 is phenyl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, 4, or 5;
  • w 0, 1, 2, or 3.
  • the disclosure provides for a compound represented by Formula (IV) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is C 6 -C 10 aryl, 4-12 membered heteroaryl, C 3 -C 12 cycloalkyl, or 4-12 membered heterocycloalkyl;
  • Y is CR CE or N;
  • R CE is hydrogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • Z is absent, NR 1 , S, O, or CR 1 R 1 ;
  • each R 1 is independently hydrogen, halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • R 1 on the same atom or different atoms are taken together to form a C 3 -C 8 cycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more R e ;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • R 3 is phenyl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, or 3;
  • w 0, 1, 2, or 3.
  • the disclosure provides for a compound represented by Formula (V) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • E is CR VE or N
  • R 1 is hydrogen, halogen, -OH, -CN, -NO 2 , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, 4-6 membered heterocycloalkyl, or C 3 -C 6 cycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 2 taken together to form a C 3 -C 6 cycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 3 is C 6 -C 10 aryl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 1, 2, or 3;
  • p 0, 1, 2, 3, 4, 5, or 6;
  • w 0, 1, 2, 3, or 4.
  • composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Also disclosed herein is a method of modulating NLRP3 inflammasome in a subject, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • Also disclosed herein is a method of inhibiting NLRP3 in a subject, the method comprising administering to the subject the compound disclosed herein, or a pharmaceutically acceptable salt thereof
  • Also disclosed herein is a method of treating an auto-immune or auto-inflammatory disease or condition in a subject in need thereof, the method comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt thereof.
  • the disease or disorder is selected from inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndrome) , liver related diseases/disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH) , alcoholic steatohepatitis, and alcoholic liver disease) , inflammatory arthritis related disorders (e.g.
  • autoinflammatory fever syndromes e.g., cryopyrin-associated periodic syndrome
  • liver related diseases/disorders e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH) , alcoholic steatohepatitis, and alcoholic liver disease
  • inflammatory arthritis related disorders e.g.
  • gout gout, pseudogout (chondrocalcinosis) , osteoarthritis, rheumatoid arthritis, arthropathy e.g., acute, chronic) , kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I/Type II diabetes and related complications (e.g. nephropathy, retinopathy) , hypertensive nephropathy, hemodialysis related inflammation) , neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer’s disease) , cardiovascular/metabolic diseases/disorders (e.g.
  • CvRR cardiovascular risk reduction
  • POD peripheral artery disease
  • PED peripheral artery disease
  • inflammatory skin diseases e.g. hidradenitis suppurativa, acne
  • wound healing and scar formation e.g. asthma, sarcoidosis, age-related macular degeneration, and cancer related diseases/disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS) , myelofibrosis) .
  • MDS myelodysplastic syndromes
  • Carboxyl refers to -COOH.
  • Cyano refers to -CN.
  • Alkyl refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2, 2-dimethyl-1-butyl, 3, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopent
  • a numerical range such as “C 1 -C 6 alkyl” or “C 1-6 alkyl” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1-10 alkyl.
  • the alkyl is a C 1-6 alkyl.
  • the alkyl is a C 1-5 alkyl.
  • the alkyl is a C 1-4 alkyl.
  • the alkyl is a C 1-3 alkyl.
  • an alkyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkyl is optionally substituted with halogen.
  • Alkenyl refers to a straight-chain, or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms.
  • a numerical range such as “C 2 -C 6 alkenyl” or “C 2-6 alkenyl” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated.
  • an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkenyl is optionally substituted with halogen.
  • Alkynyl refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • a numerical range such as “C 2 -C 6 alkynyl” or “C 2-6 alkynyl” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated.
  • an alkynyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 .
  • the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe.
  • the alkynyl is optionally substituted with halogen.
  • Alkylene refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH 2 , or -NO 2 . In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.
  • Aryl refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom.
  • the aromatic monocyclic or aromatic multicyclic hydrocarbon ring system can contain only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ⁇ –electron system in accordance with the Hückel theory.
  • the ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.
  • the aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems.
  • the aryl is a 6-to 10-membered aryl.
  • the aryl is a 6-membered aryl (phenyl) .
  • Aryl radicals include, but are not limited to, aryl radicals derived from the hydrocarbon ring systems of anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.
  • Carbocycle refers to a saturated, unsaturated, or aromatic rings in which each atom of the ring is carbon. Carbocycle may include 3-to 10-membered monocyclic rings, 6-to 12-membered bicyclic rings, and 6-to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as valence permits, are included in the definition of carbocyclic.
  • Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Unless stated otherwise specifically in the specification, a carbocycle may be optionally substituted.
  • Cycloalkyl refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated.
  • Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to fifteen carbon atoms (e.g., C 3 -C 15 fully saturated cycloalkyl or C 3 -C 15 cycloalkenyl) , from three to ten carbon atoms (e.g., C 3 -C 10 fully saturated cycloalkyl or C 3 -C 10 cycloalkenyl) , from three to eight carbon atoms (e.g., C 3 -C 8 fully saturated cycloalkyl or C 3 -C 8 cycloalkenyl) , from three to six carbon atoms (e.g., C 3 -C 6 fully saturated cycloalkyl or C 3 -C 6 cycloalkenyl) , from three to five carbon atoms (e.g., C 3 -C 5 fully saturated cycloalkyl or C 3 -C 5 cycloalkenyl) , or three to four
  • the cycloalkyl is a 3-to 10-membered fully saturated cycloalkyl or a 3-to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3-to 6-membered fully saturated cycloalkyl or a 3-to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5-to 6-membered fully saturated cycloalkyl or a 5-to 6-membered cycloalkenyl.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0] octane, bicyclo [4.3.0] nonane, cis-decalin, trans-decalin, bicyclo [2.1.1] hexane, bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, bicyclo [3.2.2] nonane, and bicyclo [3.3.2] decane, and 7, 7-dimethyl-bicyclo [2.2.1] heptanyl.
  • Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • a cycloalkyl is optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe.
  • the cycloalkyl is optionally substituted with halogen.
  • Cycloalkenyl refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, preferably having from three to twelve carbon atoms and comprising at least one double bond.
  • a cycloalkenyl comprises three to ten carbon atoms.
  • a cycloalkenyl comprises five to seven carbon atoms.
  • the cycloalkenyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkenyls includes, e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.
  • Halo or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.
  • haloalkyl or “haloalkane” refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • the alkyl part of the fluoroalkyl radical is optionally further substituted.
  • halogen substituted alkanes examples include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane) , di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane) , 1-haloethane, 2-haloethane, 1, 2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1, 2-dihalopropane, 1, 3-dihalopropane, 2, 3-dihalopropane, 1, 2, 3-trihalopropane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc. ) .
  • halogen substituted alkanes e.g., Cl, Br, F, I, etc.
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2, 2, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
  • “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.
  • Aminoalkyl refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.
  • Heteroalkyl refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -) , sulfur, phosphorus, or combinations thereof.
  • a heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • a heteroalkyl is a C 1 -C 6 heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g.
  • heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl.
  • heteroalkyl are, for example, -CH 2 OCH 3 , -CH 2 CH 2 OCH 3 , -CH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH (CH 3 ) OCH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 ) 2 , -CH 2 CH 2 NHCH 3 , or -CH 2 CH 2 N (CH 3 ) 2 .
  • a heteroalkyl is optionally substituted for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.
  • Heterocycloalkyl refers to a 3-to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens.
  • the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen.
  • the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) , spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C 2 -C 15 fully saturated heterocycloalkyl or C 2 -C 15 heterocycloalkenyl) , from two to ten carbon atoms (e.g., C 2 -C 10 fully saturated heterocycloalkyl or C 2 -C 10 heterocycloalkenyl) , from two to eight carbon atoms (e.g., C 2 - C 8 fully saturated heterocycloalkyl or C 2 -C 8 heterocycloalkenyl) , from two to seven carbon atoms (e.g., C 2 -C 7 fully saturated heterocycloalkyl or C 2 -C 7 heterocycloalkenyl) , from two to six carbon atoms (e.g., C 2 -C 6 fully saturated heterocycloalkyl or C 2 -C 6 heterocycloalkenyl) , from two to five carbon
  • heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl
  • heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides.
  • heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring) .
  • the heterocycloalkyl is a 3-to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 7-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered fully saturated heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl.
  • the heterocycloalkyl is a 3-to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkenyl.
  • a heterocycloalkyl may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.
  • Heteroaryl refers to a 5-to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur.
  • the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen.
  • the heteroaryl comprises one to three nitrogens.
  • the heteroaryl comprises one or two nitrogens.
  • the heteroaryl comprises one nitrogen.
  • the heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized.
  • the heteroaryl is a 5-to 10-membered heteroaryl.
  • the heteroaryl is a 5-to 6-membered heteroaryl.
  • the heteroaryl is a 6-membered heteroaryl.
  • the heteroaryl is a 5-membered heteroaryl.
  • examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [b] [1, 4] dioxepinyl, 1, 4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl) , benzotriazolyl, benzo [4, 6] imidazo [1, 2-a] pyridinyl, carbazolyl, cinnolinyl,
  • a heteroaryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF 3 , -OH, -OMe, -NH 2 , or -NO 2 .
  • the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF 3 , -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic, and heterocyclic, aromatic, and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • one or more when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents.
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide;
  • an “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.
  • treat, ” “treating” or “treatment, ” as used herein, include alleviating, abating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition.
  • a “disease or disorder associated with NLRP3 inflammasome” or, alternatively, “a NLRP3 inflammasome-mediated disease or disorder” means any disease or other deleterious condition in which the NLRP3 inflammasome is known or suspected to play a role.
  • Described herein are compounds, or a pharmaceutically acceptable salt thereof useful in the treatment of a disease or disorder associated with NLRP3 inflammasome.
  • the disclosure provides a compound represented by Formula (I) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • B is C or N:
  • D is C or N
  • E is C, CR CE or N
  • R CE is hydrogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • ring C is phenyl, 5 to 7-membered heteroaryl, C 5 -C 8 cycloalkyl, or 5 to 8 membered heterocycloalkyl;
  • R 1 on the same atom or different atoms are taken together to form a C 3 -C 8 cycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more R e ;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, 4-6 membered heterocycloalkyl, or C 3 -C 6 cycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 2 taken together to form a C 3 -C 6 cycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 3 is C 6 -C 10 aryl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, 4, 5, or 6;
  • q 0, 1, 2, or 3;
  • w 0, 1, 2, 3, or 4.
  • the disclosure provides a compound represented by Formula (I) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is C 6 -C 10 aryl, 4-12 membered heteroaryl, C 3 -C 12 cycloalkyl, or 4-12 membered heterocycloalkyl;
  • B is C or N:
  • D is C or N
  • E is C, CR CE or N
  • R CE is hydrogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • ring C is phenyl, 5 to 7-membered heteroaryl, C 5 -C 8 cycloalkyl, or 5 to 8 membered heterocycloalkyl;
  • each R 1 is independently hydrogen, halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • R 3 is phenyl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, or C 1 -C 6 alkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 1 or 2;
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, or 3;
  • w 0, 1, 2, or 3.
  • ring C is phenyl or 5 to 6 membered heteroaryl. In some embodiments of Formula (I) , ring C is phenyl. In some embodiments of Formula (I) , ring C is 6 membered heteroaryl. In some embodiments of Formula (I) , ring C is 5 membered heteroaryl. In some embodiments of Formula (I) , ring C is phenyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, pyrrole, imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or triazinyl.
  • ring C is phenyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or triazinyl. In some embodiments of Formula (I) , ring C is furanyl, oxazolyl, isoxazolyl, pyrrole, imidazolyl, or triazolyl.
  • ring C is:
  • R 1 ’ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • ring C is C 5 -C 8 cycloalkyl or 5 to 8 membered heterocycloalkyl. In some embodiments of Formula (I) , ring C is C 5 -C 6 cycloalkyl or 5 to 6 membered heterocycloalkyl. In some embodiments of Formula (I) , ring C is cyclopentyl, cyclohexyl, pyrrolidinyl, or piperidinyl. In some embodiments of Formula (I) , ring C is cyclopentyl or cyclohexyl. In some embodiments of Formula (I) , ring C is pyrrolidinyl or piperidinyl.
  • ring C is:
  • Y is CR CE or N
  • R CE is hydrogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • Z is absent, NR 1’ , S, O, or CR 1 R 1 ;
  • R 1 ’ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl;
  • R 1 ’ and one of R 1 are taken together to form a 4 to 6 membered heterocycloalkyl, which is optionally substituted with one or more R e ;
  • p 0, 1, 2, 3, 4, or 5.
  • ring C is:
  • R 1 ’ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl; or
  • R 1 ’ and one of R 1 are taken together to form a 4 to 6 membered heterocycloalkyl, which is optionally substituted with one or more R e .
  • ring C is:
  • R 1 ’ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl; or
  • R 1 ’ and one of R 1 are taken together to form a 4 to 6 membered heterocycloalkyl, which is optionally substituted with one or more R e .
  • a compound of Formula (II) or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is C 6 -C 10 aryl, 4-12 membered heteroaryl, C 3 -C 12 cycloalkyl, or 4-12 membered heterocycloalkyl;
  • B, D, or E are each independently C or N;
  • G is O, S, N, NR G ’ , or CR G ;
  • F is O, S, N, NR F ’ , or CR F ; wherein G and F are not both O or S at the same time;
  • each R G and R F is independently hydrogen, halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • each R G ’ and R F ’ is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • R 3 is phenyl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, 4, or 5;
  • w 0, 1, 2, or 3.
  • B is C. In some embodiments of Formula (I) or (II) , B is N. In some embodiments of Formula (I) or (II) , D is C. In some embodiments of Formula (I) or (II) , D is N. In some embodiments of Formula (I) or (II) , E is C. In some embodiments of Formula (I) or (II) , E is N. In some embodiments of Formula (I) , E is CR CE . In some embodiments of Formula (II) , G is O. In some embodiments of Formula (II) , G is S. In some embodiments of Formula (II) , G is N.
  • G is NR G . In some embodiments of Formula (II) , G is CR G . In some embodiments of Formula (II) , F is O. In some embodiments of Formula (II) , F is S. In some embodiments of Formula (II) , F is N. In some embodiments of Formula (II) , F is NR F . In some embodiments of Formula (II) , F is CR F .
  • B and D are each C; and E is N.
  • B is N; and D and E are each C.
  • D is N; and B and E are each C.
  • B, D, and E are each C.
  • the compound of Formula (II) has the structure of Formula (IIa) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • G is CR G or N; and F is CR F or N.
  • G is CR G ; and F is N. In some embodiments of Formula (IIa) , G is N; and F is CR F . In some embodiments of Formula (IIa) , G is N and F is N.
  • the compound of Formula (II) has the structure of Formula (IIb) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • G is CR G or N; and F is CR F or N.
  • G is CR G . In some embodiments of Formula (IIb) , G is N. In some embodiments of Formula (IIb) , F is CR F . In some embodiments of Formula (IIb) , F is N.
  • the compound of Formula (II) has the structure of Formula (IIc) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • G is CR G or N; and F is CR F or N
  • G is N. In some embodiments of Formula (IIc) , G is CR G . In some embodiments of Formula (IIc) , F is N. In some embodiments of Formula (IIc) , F is CR F . In some embodiments of Formula (IIc) , G is N and F is N.
  • the compound of Formula (II) has the structure of Formula (IId) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • G is CR G , NR G ’ , O, or S;
  • F is CR F , NR F ’ , N, O, or S, wherein G and F are not both O or S at the same time.
  • G is O or S; and F is CR F . In some embodiments of Formula (IId) , G is O; and F is CR F . In some embodiments of Formula (IId) , G is S; and F is CR F .
  • G is CR G ; and F is O or S. In some embodiments of Formula (IId) , G is CR G ; and F is O. In some embodiments of Formula (IId) , G is CR G ; and F is S. In some embodiments of Formula (IId) , G is NR G ’ ; and F is CR G . In some embodiments of Formula (IId) , G is CR G ; and F is NR G ’ . In some embodiments of Formula (IId) , G is O; and F is N. In some embodiments of Formula (IId) , G is N; and F is O.
  • a compound of Formula (III) or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is C 6 -C 10 aryl, 4-12 membered heteroaryl, C 3 -C 12 cycloalkyl, or 4-12 membered heterocycloalkyl; H, J, and K are each independently N or CR 1 ;
  • each R 1 is independently hydrogen, halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • R 3 is phenyl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, 4, or 5;
  • w 0, 1, 2, or 3.
  • H is N; and J and K are each CR 1 .
  • J is N; and H and K are each CR 1 .
  • H and J are each CR 1 ; and K is N.
  • H and J are each N; and K is CR 1 .
  • H and K are each N; and J is CR 1 .
  • H and K are each N; and J is CR 1 .
  • H and K are each N; and J is CR 1 .
  • H, J are each N.
  • H, J, and K are each N.
  • a compound of Formula (IV) or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is C 6 -C 10 aryl, 4-12 membered heteroaryl, C 3 -C 12 cycloalkyl, or 4-12 membered heterocycloalkyl;
  • Y is CR CE or N
  • R CE is hydrogen, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • Z is absent, NR 1 , S, O, or CR 1 R 1 ;
  • each R 1 is independently hydrogen, halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • R 1 on the same atom or different atoms are taken together to form a C 3 -C 8 cycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more R e ;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl;
  • R 3 is phenyl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 0, 1, 2, or 3;
  • p 0, 1, 2, 3, 4, or 5;
  • q 0, 1, 2, or 3;
  • w 0, 1, 2, or 3.
  • the disclosure provides for a compound represented by Formula (V) , or a pharmaceutically acceptable salt or a stereoisomer thereof:
  • ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
  • E is CR VE or N
  • R 1 is hydrogen, halogen, -OH, -CN, -NO 2 , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl;
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, 4-6 membered heterocycloalkyl, or C 3 -C 6 cycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 2 taken together to form a C 3 -C 6 cycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R 3 is C 6 -C 10 aryl, 5 to 12 membered heteroaryl, C 3 -C 12 cycloalkyl, 4 to 12 membered heterocycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl; each of which is optionally substituted with one or more R 5 ;
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e ;
  • n 1, 2, or 3;
  • p 0, 1, 2, 3, 4, 5, or 6;
  • w 0, 1, 2, 3, or 4.
  • Y is N. In some embodiments of Formula (IV) , Y is CR CE . In some embodiments of Formula (IV) , Y is CH.
  • Z is NR 1 or O. In some embodiments of Formula (IV) , Z is NR 1 . In some embodiments of Formula (IV) , Z is O. In some embodiments of Formula (IV) , Z is S. In some embodiments of Formula (IV) , Z is CR 1 R 1 . In some embodiments of Formula (IV) , Z is absent.
  • each R G and R F is independently hydrogen, halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl.
  • each R G and R F is independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl. In some embodiments, each R G and R F is independently C 1 -C 6 alkyl. In some embodiments, each R G and R F is independently methyl or ethyl. In some embodiments, each R G and R F is independently C 3 -C 6 cycloalkyl. In some embodiments, each R G and R F is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R G and R F is hydrogen.
  • R G is hydrogen, halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl.
  • R G is hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl.
  • R G is C 1 -C 6 alkyl. In some embodiments, R G is methyl or ethyl. In some embodiments, R G is C 3 -C 6 cycloalkyl. In some embodiments, R G is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R G is hydrogen.
  • R F is hydrogen, halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl.
  • R F is hydrogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl.
  • R F is C 1 -C 6 alkyl. In some embodiments, R F is methyl or ethyl. In some embodiments, R F is C 3 -C 6 cycloalkyl. In some embodiments, R F is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R F is hydrogen.
  • each R G ’ and R F ’ is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • each R G ’ and R F ’ is independently hydrogen or C 1 -C 6 alkyl.
  • each R G ’ and R F ’ is independently C 1 -C 6 alkyl.
  • each R G ’ and R F ’ is independently hydrogen.
  • R G ’ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • R G ’ is hydrogen or C 1 -C 6 alkyl.
  • R G ’ is C 1 -C 6 alkyl.
  • R G ’ is hydrogen.
  • R F ’ is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments, R F ’ is hydrogen or C 1 -C 6 alkyl. In some embodiments, R F ’ is C 1 -C 6 alkyl. In some embodiments, R F ’ is hydrogen.
  • R CE is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl. In some embodiments, R CE is hydrogen.
  • R VE is hydrogen.
  • R VE is halogen.
  • R VE is -OH.
  • R VE is -CN.
  • R VE is -OR a .
  • R VE is -O-C 1 -C 6 alkyl, wherein the alkyl is optionally substituted with one or more halogen.
  • R VE is C 1 -C 6 alkoxy.
  • R VE is C 1 -C 6 haloalkoxy.
  • R VE is C 1 -C 6 alkyl.
  • R VE is C 1 -C 6 haloalkyl.
  • R VE is C 1 -C 6 hydroxyalkyl.
  • R VE is C 1 -C 6 aminoalkyl. In some embodiments, R VE is or C 1 -C 6 heteroalkyl. In some embodiments, R VE is alkylamino or dialkylamino. In some embodiments, R VE is -NR c R d .
  • R VE is -NR c R d , wherein R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl; or R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • R c and R d are each independently hydrogen or C 1 -C 6 alkyl.
  • R c and R d are taken together with the nitrogen to which they are attached to form a 4-6 membered heterocycloalkyl (e.g., 5-membered lactam ring, piperidine ring) , wherein the heterocycloalkyl is optionally substituted with 1 to 4 -OH.
  • 4-6 membered heterocycloalkyl e.g., 5-membered lactam ring, piperidine ring
  • ring A is C 6 -C 10 aryl. In some embodiments, ring A is C 6 -C 8 aryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is phenyl fused with a heterocycloalkyl. In some embodiments, ring A is phenyl fused with a cycloalkyl.
  • ring A is
  • ring A is 5 or 6 membered heteroaryl. In some embodiments, ring A is a 6 membered heteroaryl. In some embodiments, ring A is pyridine.
  • ring A is bicyclic heteroaryl. In some embodiments, ring A is fused heteroaryl. In some embodiments, ring A is 5-6 or 6-5 fused heteroaryl. In some embodiments o, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is bicyclic heteroaryl. In some embodiments, ring A is fused heteroaryl. In some embodiments, ring A is 5-6 or 6-5 fused heteroaryl. In some embodiments o, ring A is In some embodiments, ring A is In some embodiments, ring A is In some embodiments, ring A is
  • R 4 ’ is R 4 , or two R 4 ’ are taken together with the atoms to which they are attached to form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R 6 ;and
  • X is CH, CR 4 or N.
  • Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) is In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , is In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , is
  • ring A is C 3 -C 12 cycloalkyl. In some embodiments, ring A is C 3 -C 6 cycloalkyl. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , ring A is 4-12 membered heterocycloalkyl. In some embodiments, ring A is 4-6 membered heterocycloalkyl.
  • X is CR 4 .
  • X is CH.
  • X is N.
  • two R 4 ' are taken together to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R 6 .
  • two R 4 ’ are taken together to form a cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R 6 .
  • each R 4 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, or C 1 -C 6 alkoxyl, which is optionally substituted with one or more halogen.
  • each R 4 is independently methyl -OH, -CF 3 , -CF 2 H, -OCF 3 , or -OCF 2 H.
  • each R 4 is independently methyl CN, -OH, -CF 3 , -CF 2 H, -OCF 3 , or -OCF 2 H.
  • each R 4 is independently -OH or -CF 3 .
  • each R 4 is independently -OH. In some embodiments, each R 4 is independently -CF 3 . In some embodiments, at least one R 4 is -OH. In some embodiments, at least one R 4 is -CF 3 . In some embodiments, at least one R 4 is -CH 3 . In some embodiments, at least one R 4 is -CN.
  • each R 6 is independently halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • each R 6 is independently halogen or C 1 -C 6 alkyl.
  • R 6 is C 1 -C 6 alkyl.
  • R 6 is halogen.
  • each R 1 is independently hydrogen, halogen, -CN, -NO 2 , -OH, -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl.
  • each R 1 is independently hydrogen, halogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl.
  • each R 1 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • each R 1 is each independently halogen or C 1 -C 6 haloalkyl. In some embodiments, each R 1 is each independently fluoro, chloro, bromo, CF 3 , or CHF 2 . In some embodiments, each R 1 is independently C 1 -C 6 alkyl. In some embodiments, each R 1 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl. In some embodiments, each R 1 is methyl. In some embodiments, each R 1 is independently C 3 -C 6 cycloalkyl. In some embodiments, each R 1 is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R 1 is hydrogen.
  • R 1 is hydrogen, halogen, -OH, -CN, -NO 2 , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 1 -C 6 heteroalkyl.
  • R 1 is hydrogen, halogen, or C 1 -C 6 alkyl.
  • two R 1 on the same atom or different atoms are taken together to form a C 3 -C 8 cycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more R e .
  • two R 1 on the same atom or different atoms are taken together to form a C 3 -C 8 cycloalkyl.
  • two R 1 on the same atom or different atoms are taken together to form a cyclopropyl, cyclobutyl, cyclopentyl, or cycloheptyl.
  • two R 1 on the same atom or different atoms are taken together to form a 4 to 8 membered heterocycloalkyl. In some embodiments, two R 1 on the same atom or different atoms are taken together to form a 4 membered, 5 membered, or 6 membered heterocycloalkyl.
  • R 1 ’ is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl.
  • R 1 ’ is hydrogen or C 1 -C 6 alkyl.
  • R 1 ’ is C 1 -C 6 alkyl.
  • R 1 ’ is methyl, ethyl, isopropyl, or tert-butyl.
  • R 1 ’ is hydrogen.
  • R 1 ’ and one of R 1 are taken together to form a 4 to 6 membered heterocycloalkyl, which is optionally substituted with one or more R e . In some embodiments, R 1 ’ and one of R 1 are taken together to form a 4 membered, 5 membered, or 6 membered heterocycloalkyl.
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, 4-6 membered heterocycloalkyl, or C 3 -C 6 cycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R 2 is independently halogen, -OH, -CN, -NO 2 , -OR a , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, or C 3 -C 6 cycloalkyl.
  • two R 2 are taken together to form a C 3 -C 6 cycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from R e .
  • two R 2 are taken together to form a C 3 -C 6 cycloalkyl.
  • two R 2 are taken together to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • two R 2 are taken together to form a 4-6 membered heterocycloalkyl. In some embodiments, two R 2 are taken together to form a 4 membered, 5 membered, or 6 membered heterocycloalkyl.
  • two R 2 are taken together to form an oxo.
  • R 3 is a C 3 -C 12 cycloalkyl or 4 to 12 membered heterocycloalkyl; each of which is optionally substituted with one or more R 5 .
  • R 3 is a C 3 -C 6 cycloalkyl, which is optionally substituted with 1, 2, or 3 R 5 .
  • R 3 is a 4 to 6 membered heterocycloalkyl, which is optionally substituted with 1, 2, or 3 R 5 .
  • R 3 is each of which is optionally substituted with 1, 2, or 3 R 5 .
  • R 5 is each independently selected from -OH, -OR a , -SH, -SR a , SF 5 , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, and C 3 -C 6 cycloalkyl.
  • R 3 is a C 3 -C 12 cycloalkyl which is optionally substituted with one or more R 5 .
  • R 3 is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • R 3 is monocyclic. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , R 3 is bicyclic. In some embodiments, R 3 is
  • R 3 is a 4 to 12 membered heterocycloalkyl which is optionally substituted with one or more R 5 .
  • R 3 is a 4 to 8 membered optionally substituted heterocycloalkyl.
  • R 3 is a 5 to 6 membered optionally substituted heterocycloalkyl.
  • R 3 is a 6 membered optionally substituted heterocycloalkyl.
  • R 3 is optionally substituted monocyclic heterocycloalkyl.
  • R 3 is optionally substituted bicyclic heterocycloalkyl.
  • R 3 is cyclohexyl or piperidine, each of which is optionally substituted. In some embodiments, R 3 is optionally substituted piperidine. In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is cyclohexyl. In some embodiments, R 3 is optionally substituted cyclohexyl. In some embodiments, R 3 is In some embodiments, R 3 is cyclopentyl. In some embodiments, R 3 is optionally substituted cyclopentyl. In some embodiments, R 3 is
  • R 3 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 aminoalkyl, each of which is optionally substituted with one or more R 5 .
  • R 3 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 3 is C 1 -C 6 hydroxyalkyl. In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is optionally substituted C 1 -C 6 alkyl. In some embodiments, R 3 is C 1 -C 6 hydroxyalkyl. In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is In some embodiments, R 3 is optionally substituted C 1 -C 6 alkyl. In
  • R 3 is C 6 -C 10 aryl or 5 to 12 membered heteroaryl, each of which is optionally substituted with one or more R 5 .
  • R 3 is C 6 -C 10 aryl, which is optionally substituted with one or more R 5 .
  • R 3 is optionally substituted phenyl.
  • R 3 is 5 to 12 membered heteroaryl, which is optionally substituted with one or more R 5 .
  • R 3 is 5 to 6 membered heteroaryl. In some embodiments, R 3 is phenyl or 5 to 6 membered heteroaryl. In some embodiments, R 3 is phenyl or 5 to 6 membered heteroaryl, each of which is optionally substituted with one or more R 5 .
  • R 3 is
  • each R 5 is independently halogen, -OH, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4 to 6 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R 5 is independently halogen. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , each R 5 is independently fluoro, bromo or chloro.
  • each R 5 is independently -OH. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , each R 5 is independently C 1 -C 6 alkyl.
  • each R 5 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.
  • each R 5 is independently C 3 -C 6 cycloalkyl or 4 to 6 membered heterocycloalkyl. In some embodiments, each R 5 is independently C 3 -C 6 cycloalkyl. In some embodiments, each R 5 is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R 5 is independently a 4 to 6 membered heterocycloalkyl.
  • each R 5 is independently a 4 membered heterocycloalkyl. In some embodiments, each R 5 is independently a 5 membered heterocycloalkyl. In some embodiments, each R 5 is independently a 6 membered heterocycloalkyl. In some embodiments, each R 5 is independently selected from -OH, -OR a , -SH, -SR a , SF 5 , -NR c R d , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 aminoalkyl, and C 3 -C 6 cycloalkyl.
  • n is 3. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , n is 1 or 2.
  • n is 2. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , n is 1. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , n is 1. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , or (IV) , n is 0.
  • p is 6. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , p is 5. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , p is 5.
  • p is 3 In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , p is at least 3.
  • p is 1, 2, or 3. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , p is 2 or 3.
  • p is 1 or 2. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , p is 2.
  • p is 1. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , p is 0.
  • q is 3. In some embodiments of Formula (I) , (III) , or (IV) , q is 2. In some embodiments of Formula (I) , (III) , or (IV) , q is 1. In some embodiments of Formula (I) , (III) , or (IV) , q is 0.
  • w is 4. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , w is 3.
  • w is 2. In some embodiments of Formula (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) , or (V) , w is 1.
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R a is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R a is independently C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • each R a is independently C 1 -C 6 alkyl.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R b is independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • each R b is independently hydrogen or C 1 -C 6 alkyl.
  • each R b is hydrogen.
  • each R b is independently C 1 -C 6 alkyl.
  • R c and R d are each independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R c and R d are independently hydrogen, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl.
  • each R c and R d are independently hydrogen or C 1 -C 6 alkyl.
  • each R c and R d are hydrogen.
  • each R c and R d are independently C 1 -C 6 alkyl.
  • R c and R d are taken together with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R e .
  • each R e is independently halogen, -CN, -OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 - C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalkyl, C 1 -C 6 heteroalkyl, or C 3 -C 6 cycloalkyl.
  • each R e is independently halogen, -CN, -OH, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl.
  • each R e is independently halogen, C 1 -C 6 alkyl, or C 3 -C 6 cycloalkyl. In some embodiments of a compound disclosed herein, each R e is independently C 1 -C 6 alkyl. In some embodiments of a compound disclosed herein, each R e is independently C 3 -C 6 cycloalkyl. In some embodiments of a compound disclosed herein, each R e is independently halogen.
  • one or more of R 1 , R 1 ’ , R 2 , R 3 , R 4 , R 5 , R 6 , R CE , R G , R G ’ , R F , R F ’ , R a , R b , R c , and R d , and R e groups comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the following groups R 1 , R 1 ’ , R 2 , R 3 , R 4 , R 5 , R 6 , R CE , R G , R G ’ , R F , R F ’, R a , R b , R c , and R d , and R e .
  • the abundance of deuterium in each of R 1 , R 1 ’ , R 2 , R 3 , R 4 , R 5 , R 6 , R CE , R G , R G ’ , R F , R F ’ , R a , R b , R c , and R d , and R e is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • the compound disclosed herein, or a pharmaceutically acceptable salt or a stereoisomer thereof is one of the compounds in Table 1 or Table 2.
  • the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center exists in the R configuration, or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc. ) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography.
  • the compounds described herein exist in their isotopically-labeled forms.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds.
  • the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions.
  • the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes examples include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2 H (D) , 3 H, 13 C, 14 C, l5 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • isotopically-labeled compounds for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100%by molar.
  • one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium.
  • one or more 1 H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.
  • the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
  • the compounds described herein exist as their pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts.
  • the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
  • the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-1, 4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1, 6-dioate, hydroxybenzoate,
  • the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedis
  • other acids such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.
  • those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • a suitable base such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine.
  • Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like.
  • bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl) 4 , and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.
  • the compounds described herein exist as solvates.
  • the disclosure provides for methods of treating diseases by administering the compounds in the form of such solvates.
  • the disclosure provides for methods of treating diseases by administering a composition comprising the compounds in the form of such solvates.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed during the process of crystallization with pharmaceutically acceptable solvents.
  • Tautomers are compounds that are interconvertible by migration of a hydrogen atom, accompanied by a switch of a single bond and adjacent double bond. In bonding arrangements where tautomerization is possible, a chemical equilibrium of the tautomers will exist. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH.
  • Disclosed herein is a method of modulating NLRP3 inflammasome in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.
  • a method of inhibiting NLRP3 inflammasome in a subject the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, disclosed herein
  • Disclosed herein is a method of treating an auto-immune or auto-inflammatory disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.
  • the disease or condition is an auto-immune disease.
  • the disease or condition is an auto-inflammatory disease.
  • the disease or disorder is selected from inflammasome-related diseases/disorders, immune diseases, inflammatory diseases, auto-immune diseases, or auto-inflammatory diseases, for example, autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndrome) , liver related diseases/disorders (e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH) , alcoholic steatohepatitis, and alcoholic liver disease) , inflammatory arthritis related disorders (e.g.
  • autoinflammatory fever syndromes e.g., cryopyrin-associated periodic syndrome
  • liver related diseases/disorders e.g. chronic liver disease, viral hepatitis, non-alcoholic steatohepatitis (NASH) , alcoholic steatohepatitis, and alcoholic liver disease
  • inflammatory arthritis related disorders e.g.
  • gout gout, pseudogout (chondrocalcinosis) , osteoarthritis, rheumatoid arthritis, arthropathy e.g., acute, chronic) , kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I/Type II diabetes and related complications (e.g. nephropathy, retinopathy) , hypertensive nephropathy, hemodialysis related inflammation) , neuroinflammation-related diseases (e.g. multiple sclerosis, brain infection, acute injury, neurodegenerative diseases, Alzheimer's disease) , cardiovascular/metabolic diseases/disorders (e.g.
  • CvRR cardiovascular risk reduction
  • POD peripheral artery disease
  • PED peripheral artery disease
  • inflammatory skin diseases e.g. hidradenitis suppurativa, acne
  • wound healing and scar formation e.g. asthma, sarcoidosis, age-related macular degeneration, and cancer related diseases/disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS) , myelofibrosis) .
  • MDS myelodysplastic syndromes
  • compositions containing the compound (s) described herein are administered for therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • the administration of the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.
  • a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms.
  • the amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.
  • doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day.
  • the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof are from about 0.01 to about 50 mg/kg per body weight.
  • the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.
  • Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.
  • the compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In some embodiments, the compounds described herein are administered to animals.
  • compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995) ; Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A.
  • the compounds and salts of Formulas (I) , (II) , (IIa) , (IIb) , (IIc) , (IId) , (III) , (IV) and (V) can be synthesized according to one or more illustrative schemes herein and/or techniques known in the art. Materials used herein are either commercially available or prepared by synthetic methods generally known in the art. These schemes are not limited to the compounds listed in the examples or by any particular substituents, which are employed for illustrative purposes. Although various steps are described and depicted in the synthesis schemes below, the steps in some cases may be performed in a different order than the order shown below. Numberings or R groups in each scheme do not necessarily correspond to that of the claims or other schemes or tables herein.
  • Step 1 3- (dimethylamino) -1- (2-methoxy-4- (trifluoromethyl) phenyl) prop-2-en-1-one
  • Step 2 Ethyl-4- (dimethylamino) -3- (2-methoxy-4- (trifluoromethyl) benzoyl) -2-oxobut-3-enoate
  • Step 3 ethyl 4- (2-methoxy-4- (trifluoromethyl) benzoyl) -1H-pyrazole-5-carboxylate
  • Step 4 ethyl 1- (3- ( (tert-butyldimethylsilyl) oxy) propyl) -4- (2-methoxy-4-(trifluoromethyl) benzoyl) -1H-pyrazole-5-carboxylate
  • Step 5 1- (3-hydroxypropyl) -4- (2-methoxy-4- (trifluoromethyl) phenyl) -1H-pyrazolo [3, 4-d]pyridazin-7-ol
  • Step 6 7-chloro-1- (3-chloropropyl) -4- (2-methoxy-4- (trifluoromethyl) phenyl) -1H-pyrazolo [3, 4-d] pyridazine
  • Step 7 (R) -tert-butyl 3- (3- (2-methoxy-4- (trifluoromethyl) phenyl) -8, 9-dihydro-1, 4, 5, 6, 9a-pentaazabenzo [cd] azulen-6 (7H) -yl) piperidine-1-carboxylate
  • Step 8 (R) -2- (6- (piperidin-3-yl) -6, 7, 8, 9-tetrahydro-1, 4, 5, 6, 9a-pentaazabenzo [cd] azulen-3-yl)-5- (trifluoromethyl) phenol
  • Step 9 (R) -2- (6- (1-methylpiperidin-3-yl) -6, 7, 8, 9-tetrahydro-1, 4, 5, 6, 9a-pentaazabenzo [cd] azulen-3-yl) -5- (trifluoromethyl) phenol
  • Step 1 4- (2-methoxy-4- (trifluoromethyl) phenyl) -1H-pyrazolo [3, 4-d] pyridazin-7-ol
  • Step 2 7-chloro-4- (2-methoxy-4- (trifluoromethyl) phenyl) -1H-pyrazolo [3, 4-d] pyridazine
  • Step 3 1- (2- ( (tert-butyldimethylsilyl) oxy) ethyl) -7-chloro-4- (2-methoxy-4-(trifluoromethyl) phenyl) -1H-pyrazolo [3, 4-d] pyridazine
  • Step 4 2- (7-chloro-4- (2-methoxy-4- (trifluoromethyl) phenyl) -1H-pyrazolo [3, 4-d] pyridazin-1-yl)ethan-1-ol
  • Step 5 2- (7-chloro-4- (2-methoxy-4- (trifluoromethyl) phenyl) -1H-pyrazolo [3, 4-d] pyridazin-1-yl)acetaldehyde
  • Step 6 (R) -N- (2- (7-chloro-4- (2-methoxy-4- (trifluoromethyl) phenyl) -1H-pyrazolo [3, 4-d]pyridazin-1-yl) ethyl) -1-methylpiperidin-3-amine
  • Step 7 (R) -8- (2-methoxy-4- (trifluoromethyl) phenyl) -5- (1-methylpiperidin-3-yl) -4, 5-dihydro-3H-2, 2a, 5, 6, 7-pentaazaacenaphthylene
  • Step 8 (R) -2- (5- (1-methylpiperidin-3-yl) -4, 5-dihydro-3H-2, 2a, 5, 6, 7-pentaazaacenaphthylen-8-yl) -5- (trifluoromethyl) phenol
  • Step 1 (R) -1- (3- (2-methoxy-4- (trifluoromethyl) phenyl) -8, 9-dihydro-1, 4, 5, 6, 9a-pentaazabenzo [cd] azulen-6 (7H) -yl) propan-2-ol
  • Step 2 (R) -2- (6- (2-hydroxypropyl) -6, 7, 8, 9-tetrahydro-1, 4, 5, 6, 9a-pentaazabenzo [cd] azul-en-3-yl) -5- (trifluoromethyl) phenol
  • the mixture was purified by Prep-HPLC (Column: Phenomenex C18 80*30mm*5um, Mobile Phase: water (NH 3 ⁇ H 2 O +NH 4 HCO 3 ) -ACN, Mobile Phase B: acetonitrile Flow rate: 25 mL/min, gradient condition from 50%B to 80%) and lyophilized to give title compound.
  • Step 1 (3R, 5R) -N- (2- (7-chloro-4- (2-methoxy-4- (trifluoromethyl) phenyl) -1H-pyrazolo [3, 4-d]pyridazine-1-yl) ethyl) -5-fluoro-1-methylpiperidin-3-amine
  • Step 2 (3R, 5R) -5- (5-fluoro-1-methylpiperidin-3-yl) -8- (2-methoxy-4- (trifluoromethyl) phenyl) -4, 5-dihydro-3H-2, 2a, 5, 6, 7-pentaazaacenaphthylene
  • Step 3 (3R, 5R) -2- (5- (5-fluoro-1-methylpiperidin-3-yl) -4, 5-dihydro-3H-2, 2a, 5, 6, 7-pentaazaacenaphthylen-8-yl) -5- (trifluoromethyl) phenol
  • intermediate 18-3 (2.6 g, 13.74 mmol) in diethyl ether (40 mL) was added methylmagnesium bromide (6.9 mL, 20.7 mmol, 3M in 2-methyltetrahydrofuran) dropwise at 0 °C under N 2 .
  • the resulting mixture was stirred at 0 °C for 1 h.
  • the mixture was quenched with saturated NH 4 Cl aqueous solution (20 mL) and extracted with Et 2 O (50 mL x 2) .
  • the combined organic layers were washed with brine (80 mL) , dried over Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to give intermediate 18-4 (2.0 g, crude) as colorless oil, which was used for next step directly.
  • stereoismoer 1 of intermediate 18-5 LC-MS (ESI+) : m/z 236.1 (M+H) + .
  • stereoismoer 2 of intermediate 18-5 LC-MS (ESI+) : m/z 236.1 (M+H) + .
  • intermediate 12-1 was similar to that for intermediate 1-8 by replacing (R) -tert-butyl 3-aminopiperidine-1-carboxylate with (4-methoxyphenyl) methanamine.
  • the compounds below were prepared using a synthesis method similar to that described in Compound 1 or Compound 12 by substituting the appropriate starting materials, reagents and reaction conditions.
  • the reaction temperatures varied from -78 °C to 0 °C for last step under the condition of BBr 3 .
  • the compounds below were prepared using a synthesis method similar to that described in Compound 2 or Compound 4 by substituting the appropriate starting materials, reagents and reaction conditions.
  • the reaction temperatures varied from -78 °C to 0 °C for last step under the condition of BBr 3 .
  • intermediate 17-6 (4.00 g, 22.83 mmol) in EtOH (15 mL) was bubbled HCl gas at 0 °C. The mixture was stirred at 0 °C for 4 h. The mixture was concentrated to give intermediate 17-7 (4.80 g, 81.6%yield) as yellow oil, which was used for next step directly.
  • intermediate 17-11 (2.00 g, 5.88 mmol) in ACN (15 mL) were added intermediate 17-8 (5.66 g, 29.41 mmol) and K 2 CO 3 (2.44 g, 17.65 mmol) .
  • the mixture was stirred at 80 °C for 1 h.
  • water (30 mL) and extracted with EtOAc (30 mL x 3) .
  • intermediate 17-12 (1.20 g, 2.97 mmol) in 1, 3, 5-trimethylbenzene (40 mL) were added intermediate 17-4 (5.13 g, 17.80 mmol) and 4-methylbenzenesulfonic acid (102.0 mg, 0.59 mmol) .
  • the reaction was stirred at 160 °C for 3 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0 ⁇ 45%ethyl acetate in petroleum ether to give intermediate 17-13 (830.0 mg, 44.5%yield) as yellow oil.
  • LC-MS (ESI+) m/z 627.2 (M+H) + .
  • intermediate 101-3 700.0 mg, 2.53 mmol
  • dioxane 10.0 mL
  • intermediate 17-1 657.8 mg, 3.28 mmol
  • the reaction mixture was concentrated under reduced pressure to afford a residue.
  • the residue was purified by flash column chromatography on silica gel eluted with 0 ⁇ 50%ethyl acetate in petroleum ether to give intermediate 101-4 (318.0 mg, 84%purity, 26.6%yield) as white solid.
  • LC-MS (ESI+) m/z: 397.0 (M+H) + .
  • Example B-1 NLRP3 inflammasome assay
  • Radioligand dilution working concentration was 25nM [ 3 H] -MCC950.1 ⁇ L [ 3 H] -MCC950 (23 ⁇ M stock) was added to 919 ⁇ L assay buffer.
  • Example B-2 NLRP3 inflammasome Activation Assay on human monocytes
  • Example B-3 IL-1 ⁇ release THP-1 assay
  • THP-1 cells Culture RPMI1640 medium, 10%FBS, 1%PS, 55uM ⁇ -Mer at 37°C &5%CO 2 incubator.
  • H Ave (DMSO)
  • CV% (H) 100* (SD_H/Ave_H)
  • logIC50 same log units as X
  • Example B-4 NLRP3 Enzymatic Activity ADP-Glo Assay
  • NLRP3 activity test experiment measuring the hydrolysis of NLRP3 on the substrate ATP using the ADP-Glo assay.
  • NLRP3 ICE, YM2306T-H06MHS
  • ATP Promega, V915A
  • substrate solution 5 ⁇ L
  • NLRP3 and ATP were prepared in 50 mM HEPES, 10 mM MgCl2, 0.01%Brij-35, 1 mM EGTA, and 2 mM DTT buffers at final concentrations of 15 nM and 1 ⁇ M, respectively.
  • 10 ⁇ L ADP-Glo reagent solution (Promega, V9102) was added into each assay well, centrifuged at 1000 rpm for 1 min, and then incubated at room temperature for 45 min.
  • ADP-Glo detection solution Promega, V9102
  • 20uL ADP-Glo detection solution Promega, V9102
  • the luminescence signal values were read using a BMG instrument and the IC50 values were determined by fitting the data to an S-shaped dose-response curve using nonlinear regression.
  • the Enzymatic ADP-Glo Assay data for select compounds are shown in Table 3.
  • NLRP3 Inflammasome IC 50 (nM) example B-1: 0 ⁇ A ⁇ 10; 10 ⁇ B ⁇ 100; 100 ⁇ C ⁇ 1000; 1000 ⁇ D.
  • THP-1 IL-1 ⁇ IC 50 (nM) example B-3: 0 ⁇ A ⁇ 10; 10 ⁇ B ⁇ 100; 100 ⁇ C ⁇ 1000; 1000 ⁇ D.
  • Enzymatic Activity ADP-Glo IC 50 (nM) example B-4: 0 ⁇ A ⁇ 10; 10 ⁇ B ⁇ 100; 100 ⁇ C ⁇ 1000; 1000 ⁇ D.

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Abstract

L'invention concerne des inhibiteurs de l'inflammasome protéine NLRP3 (NOD-like receptor protein 3) et des compositions pharmaceutiques comprenant lesdits inhibiteurs. Les composés et compositions de l'invention sont utiles pour le traitement d'une maladie ou d'un trouble associé à la voie biologique de l'inflammasome NLRP3.
PCT/CN2024/094491 2023-05-22 2024-05-21 Inhibiteurs de l'inflammasome nlrp3 et leurs utilisations Pending WO2024240153A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115461345A (zh) * 2020-04-23 2022-12-09 詹森药业有限公司 作为nlrp3抑制剂的三环化合物
WO2023036330A1 (fr) * 2021-09-13 2023-03-16 先声再明医药有限公司 Composé tricyclique utile en tant qu'inhibiteur de cbl-b

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115461345A (zh) * 2020-04-23 2022-12-09 詹森药业有限公司 作为nlrp3抑制剂的三环化合物
WO2023036330A1 (fr) * 2021-09-13 2023-03-16 先声再明医药有限公司 Composé tricyclique utile en tant qu'inhibiteur de cbl-b

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025153532A1 (fr) 2024-01-16 2025-07-24 NodThera Limited Polythérapies faisant intervenir des inhibiteurs de nlrp3 et des agonistes de glp-1

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