Nlrp3 inflammasome inhibitors and uses thereof

Abstract

Described herein are NOD-like receptor protein 3 (NLRP3) inflammasome inhibitors and pharmaceutical compositions comprising the inhibitors. The subject compounds and compositions are useful for the treatment of diseases or disorders associated with the NLRP3 inflammasome pathway.

Description

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date 28 November 2024 (28.11.2024) WIPO I PCT lllllllllllllllllllllllllllllll^ (10) International Publication Number WO 2024 / 240153 Al 22 May 2023 (22.05.2023) CN (51) International Patent Classification: RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, ME, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). C07D 487 / 16 (2006.01) C07D 498 / 16 (2006.01) A61K31 / 395 (2006.01) A61P 29 / 00 (2006.01) A61P35 / 00 (2006.01) A61P9 / 00 (2006.01) A61P 3 / 70(2006.01) (21) International Application Number: PCT / CN2024 / 094491 Declarations under Rule 4.17: — of inventorship (Rule 4.17 (iv)) (22) International Filing Date: 21 May 2024 (21.05.2024) Published: — with international searchreport (Art. 21(3)) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: PCT / CN2023 / 095515 w o 20 24 / 2 40 15 3 A l IIII III III III III III III III III III IN (71) Applicant: INSILICO MEDICINE IP LIMITED [CN / CN]; 26thFloor, Three Exchange Square, 8 Connaught Place Central, Hong Kong (CN). (72) Inventors: WU, Jianping; Suite 901, Tower C, Chang- tai Plaza, 2889 Jinke Road, Pudong New Area, Shanghai 201203 (CN). QIN, Luoheng; Suite 901, Tower C, Chang- tai Plaza, 2889 Jinke Road, Pudong New Area, Shanghai 201203 (CN). DING, Xiaoyu; Suite 901, Tower C, Chang- tai Plaza, 2889 Jinke Road, Pudong New Area, Shanghai 201203 (CN). LI, Chaopeng; Suite 901, Tower C, Chang- tai Plaza, 2889 Jinke Road, Pudong New Area, Shanghai 201203 (CN). (74) Agent: AFD CHINA INTELLECTUAL PROPERTY LAW OFFICE; Tower B, 21st Fl. Suite 2108, 38 Xueqing Road, Haidian District, Beijing 100083 (CN). (81) Designated States (unless otherwise indicated, for every kind of nationalprotection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CV, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, MG, MK, MN, MU, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, CV, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SC, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, (54) Title: NLRP3 INFLAMMASOME INHIBITORS AND USES THEREOF (57) Abstract: Described herein are NOD-like receptor protein 3 (NLRP3) inflammasome inhibitors and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions areuseful for the treatment of a disease or disorder associated withNLRP3 inflammasome pathway. WO 2024 / 240153 PCT / CN2024 / 094491 NLRP3 INFLAMMASOME INHIBITORS AND USES THEREOF CROSS-REFERENCE

[0001] This patent application claims the benefit of International Application No. PCT / CN2023 / 095515, filed May 22, 2023, which is incorporated herein by reference in its entirety. BACKGROUND

[0002] The present disclosure relates to novel compounds and compositions that are useful as inhibitors of NOD-like receptor protein 3 (NLRP3) inflammasome pathway.

[0003] 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 β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Studies have revealed new regulators of the NLRP3inflammasome, 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.

[0004] Based on the foregoing, there is a need to identify inhibitors of NLRP3 inflammasome. SUMMARY

[0005] In one aspect, the disclosure provides for a compound represented by Formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof: Formula (I), wherein; ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; B is C or N: D is C or N; E is CRCE or N; RCE is hydrogen, -OH, Ci-CTalkyl, Cj-C.alkoxy, Ci-Cehaloalky 1, Ci-Cfihydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb,-C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-Cqalkyl, Ci-Cehaloalkyl, Ci-Cqhydroxyalkyl, Ci-C6aminoalkyl, -1- WO 2024 / 240153 PCT / CN2024 / 094491 Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Cealkyl, Ci-Cgalkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, C1- Ceheteroalkyl, Cs-Cecycloalkyl, or 4 to 6 membered heterocycloalkyl; ring C is phenyl, 5 to 7-membered heteroaryl, Cs-Gcycloalkyl. or 5 to 8 membered heterocycloalkyl; each R1 isindependently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, - S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, - S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, Ci-GhctciOalkyl. C2-Coalkenyl, C2-C6alkynyl, C3-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; or two R1 on the same atom or different atoms are taken together to form a C3-Cscycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more Re; or two R1 on the same atom are taken together to form an oxo; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-C<,alkyl, Ci-G,alkoxy,Ci- G,haloalkyl, Ci-Cqhydroxyalkyl, Ci -Cqaminoalkyl, 4-6 membered heterocycloalkyl, or C3- G,cycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; or two R2 are taken together to form an oxo; or two R2 are taken together to form a Cs-Cqcycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from Re; R3 is C6-Cioaryl, 5 to 12 membered heteroaryl, C3-Ci2cycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-Cf,alkyl, C1-C6haloalkyl, Ci-Cfhydroxyalkyl, G-Galkoxy, or G-Gaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P / =O)R4U, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo,Ci-Cqalkyl, G-Ghaloalkyl. G-Ghydroxyalkyl. G-G,heteroalkyl, Ci-Ceaminoalkyl, C3-C6cycloalkyf 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 Re; -2- WO 2024 / 240153 PCT / CN2024 / 094491 each Ra is independently Ci-Cealkyl, Ci-Cfihaloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci- Ceheteroalkyl, C2-C6alkenyl, Cx-G.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 Re; each Rb is independently hydrogen, Ci-Cealkyl, Ci-CTshaloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci -Cohctcroalkyk C2-C6alkenyl, C2-Cealkynyl, 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 Re; Rc and Rd are each independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-C6alkynyl, 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 Re; or Rc and Rd 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 Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3,-C(=O)OH, -C(=O)OCH3, Ci-C(,alkyl, Ci-C6alkoxy, Ci-C<,haloalkyl, Ci-Cthydroxyalkyl, Ci-C6aminoalkyl, Ci-G,heteroalkyl, or Cs-Cscycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, or 3; and w is 0, 1, 2, 3, or 4.

[0006] In some embodiments, the disclosure provides for a compound represented by Formula (II), or a pharmaceutically acceptable salt or a stereoisomer thereof: Formula (II), wherein, ring A is Ce-Cioaryl, 4-12 membered heteroaryl, C3-Ci2cycloalkyl, or 4-12 membered heterocycloalkyl; B, D, or E are each independently C or N; G is O, S, N, NRG’, or CRG; F is O, S, N, NRF’, or CRF; wherein G and F are not both O or S at the same time; -3- WO 2024 / 240153 PCT / CN2024 / 094491 each RG and RF is independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-C6alkyl, Ci- Cealkoxy, Ci-Cehaloalkyl, Ci-Cghydroxyalkyl, Ci-C6aminoalkyl, or Ca-Cficycloalkyl; each RG’ and RF’ is independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ca-Cecycloalkyl, or 4 to 6 memberedheterocycloalkyl; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Cj-C,alkoxy, Ci- Gshaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ca-Cecycloalkyl; R3 is phenyl, 5 to 12 membered heteroaryl, C3-Ci2cycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Cgalkoxy, or Ci-Ceaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo (=0), Ci-Cealkyl, Ci-Ckhaloalkyl, Ci-Cehydroxyalkyl, Cj-C,heteroalkyl. Ci-Gaminoalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with 1 to 4substituents independently selected from Rc; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=O)Ra, -NRbC(=0)0Rb, -C(=O)Ra, -C(=O)ORb, - C(=0)NRcRd, -0C(=0)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-G.alkyl, Ci-G>haloalkyl, Ci-G,hydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cftheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Cj-Cscycloalkyl. or4-12 memberedheterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Coalkyl, Ci-Cealkoxy, Ci-Cqhaloalkyl, Ci-G.hydroxyalkyl, Ci -C6aminoalkyl, Ci- Gheleroalkyl.Cs-Cicycloalkyl, or 4 to 6 membered heterocycloalkyl; each Ra is independently Ci-Cealkyl, Ci-G,haloalkyl, G-G,hydroxyalkyl, Ci-Cf,aminoalkyl, Ci- Coheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; each Rb is independently hydrogen, Ci-Cf,alkyl, G-G,haloalkyl, Ci-Cehydroxyalkyl, Ci-Cf,aminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, G-Galkynyl, 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 Re; -4- WO 2024 / 240153 PCT / CN2024 / 094491 Rc and Rd are each independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl,Ci-Cfihydroxyalkyl, Ci- Ceaminoalkyl, Ci-Cgheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; or Rc and Rd 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 Rc; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci -Cealkyl, Ci -Cealkoxy, Ci -G, haloalky I, Ci -C&hy dr oxy alkyl, Ci -G.ami noalkyl, Ci -Ghctcroalkyl, or C3-Cecycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, or 5; and w is 0, 1, 2, or 3.

[0007] In some embodiments, the compound of Formula (II)has the structure of Formula (Ila), or a pharmaceutically acceptable salt thereof: wherein, G is CRG or N; and F is CRF or N.

[0008] In some embodiments, the compound of Formula (II) has the structure of Formula (Ilb), or a pharmaceutically acceptable salt thereof: wherein, G is CRG or N; and F is CRF or N.

[0009] In some embodiments, the compound of Formula (II) has the structure of Formula (lie), or a pharmaceutically acceptable salt thereof: -5- WO 2024 / 240153 PCT / CN2024 / 094491 Formula (He), wherein, G is CRG or N; and F is CRF or N.

[0010] In some embodiments, the compound of Formula (II) has the structure of Formula (lid), or a pharmaceutically acceptable salt thereof: Formula (lid), wherein, G is CRG, NRG’, O, or S; and F is CRF, NRF’, N, O, or S, wherein G and F are not both O or S at the same time.

[0011] In some embodiments, the disclosure provides for a compound represented by Formula (III), or a pharmaceutically acceptable salt or a stereoisomer thereof: Formula (III),wherein, ring A is Ce-Cioaryl, 4-12 membered heteroaryl, Cj-Ci2cycloalkyl, or 4-12 membered heterocycloalkyl; H, J, and K are each independently N or CR1; each R1 is independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cialkyl, Ci-C6alkoxy, Ci-Cehaloalkyl, Ci-Cghydroxyalkyl, Ci-Ceaminoalkyl, or Ca-Cficycloalkyl; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cgalkoxy, C1- Cshaloalkyl, Ci-Ci hydroxyalkyl, Ci-Cxaminoalkyl, or Cs-Cicycloalkyl; R3 is phenyl, 5 to 12 membered heteroaryl, Cs-Cucycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Cj-Qalkoxy, or Ci-CTaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo (=0), Ci-Cealkyl, Ci-Qhaloalkyl, Ci-G, hydroxy alkyl, Ci-Cxheteroalkyl, Ci-Cxaminoalkyl, C3-G,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 Re; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, - -6- WO 2024 / 240153 PCT / CN2024 / 094491 C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)R% -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-Cealkyl, Ci-Cfihaloalkyl, Ci-Cihydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, G-Galkynyl, G-Gcycloalkyl. or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, G-GJiydroxyalkyl, Ci-Ceaminoalkyl, Ci- Cftheteroalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; each Ra is independently Ci-Cfialkyl, G-Ghaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, C1- Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; each Rb is independently hydrogen, Ci-C / ,alkyl, Ci-GJialoalkyl, G-GJiydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cftheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; Rc and Rd are each independently hydrogen, G-G,alkyl, Ci-C&haloalkyl, Ci-C6hydroxyalkyl, Ci- Gaminoalkyk Ci -Cftheteroalkyl, C2-C6alkenyl, G-Cealkynyl, 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 Re; or Rc and Rd 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 Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2,-NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-Csalkyl, Ci-Cealkoxy, G-Ghaloalkyl, Ci-CGydroxyalkyl, G-G,ami noalky I, Ci-Ccheteroalkyl, or G-G,cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, or 5; and w is 0, 1, 2, or 3.

[0012] In some embodiments, the disclosure provides for a compound represented by Formula (IV), or a pharmaceutically acceptable salt or a stereoisomer thereof: -7- WO 2024 / 240153 PCT / CN2024 / 094491 Formula (IV), wherein, ring A is C&-Cioaryl, 4-12 membered heteroaryl, Cs-Cncycloalkyl. or 4-12 membered heterocycloalkyl; Y is CRCE or N; RCE is hydrogen, -OH, Ci-C6,alkyl, Ci-Calkoxy, Cj-C(,haloalkyl, Ci -G, hydroxyalkyl, Cj -Chaminoalkyl, or Ci -Ceheteroalkyl; Z is absent, NR1, S, O, or CR'R1; each R1 is independently hydrogen, halogen, -OH, -CN, -NO?, -ORa, -NRcRd, Ci-C,alkyk Cj-Gmlkoxy, Ci-Cehaloalkyl, Ci-Cshydroxyalkyl, Ci-C6aminoalkyl, or Ci-C,cycloalkyl: or two R1 on the same atom or different atoms are taken together to form a Cs-Cscycloalkyl or 4 to 8membered heterocycloalkyl, each of which is optionally substituted with one or more Re; or two R1 on the same atom are taken together to form an oxo; each R2 is independently halogen, -OH, -CN, -NO?, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cealkoxy, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or CVCfiCycloalkyl; R3 is phenyl, 5 to 12 membered heteroaryl, C3-Ci2cycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, G-Cgalkoxy, or Ci-Ceaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo (=0), Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceheteroalkyl, Ci-Ceaminoalkyl, Ci-CecycloalkyL or 4 to 6 membered heterocycloalkyl, wherein each of thealkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=0)Ra, -NRbC(=0)0Rh, -C(=O)Ra, -C(=O)ORb, - C(=0)NRcRd, -0C(=0)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C6alkyl, Ci-CThaloalkyl, Ci-Cihydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, Ci-G.alkynyl, Cs-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2,-C(=O)CH3, -C(=0)0H, - -8- WO 2024 / 240153 PCT / CN2024 / 094491 C(=O)OCH3, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cghaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci- Ceheteroalkyl, Ca-Cgcycloalkyl, or 4 to 6 membered heterocycloalkyl; each Ra is independently G-Galkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, G- Ceheteroalkyl, CT-Cealkenyf C2-C6alkynyl, 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 Rc; each Rb is independently hydrogen, G-Galkyl. Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, G-Garni noalkyl. Ci-Ceheteroalkyl, C2-Cealkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1to 4 substituents independently selected from Re; Rc and Rd are each independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Gaminoalkyl, Ci -Ciheteroalkyl, G-Galkcnyl. C2-C6alkynyl, 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 Re; or Rc and Rd 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 Rc; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ct -Csalkyl, Ci-Ce alkoxy, Ci -G, haloalky I, Ci -C&hy dr oxy alkyl, Ci-Garni noalkyl, Ci -Ghctcroalkyl, or G-G>cycloalkyl; n is 0, 1,2, or 3; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, or 3; and w is 0, 1, 2, or 3.

[0013] In one aspect, the disclosure provides for a compound represented by Formula (V), or a pharmaceutically acceptable salt or a stereoisomer thereof: Formula (V), wherein; ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; E is CRVE or N; -9- WO 2024 / 240153 PCT / CN2024 / 094491 RVE is hydrogen, halogen, -OH, -NRcRd, -CN, -ORa, -C(=O)Ra, Ci-C6alkyl, Ci-Cialkoxy, Ci-Cfihaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Cfiheteroalkyl; R1 is hydrogen, halogen, -OH, -CN, -NO2, -NRcRd, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, C1- Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Cgheteroalkyl; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-Cealkyl, Ci-Cehaloalkyl,Ci-Cihydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Cs-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Cealkyl, Ci-G.alkoxy, Ci-G,haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, C1- Cftheteroalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-C&alkyl, Ci-Cealkoxy, Ci- G.haloalkyl, Ct-Cehydroxy alkyl, Ci -Ceaminoalkyl, 4-6 membered heterocycloalkyl, or C3- G,cycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selectedfrom Re; or two R2 are taken together to form an oxo; or two R2 are taken together to form a C3-C6cycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from Re; R3 is C6-Cioaryl, 5 to 12 membered heteroaryl, C3-Ci2cycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-C&alkyl, Ci-C&haloalkyl, Ci-Cohydroxyalkyl, Ci-C&alkoxy, or Ci-Coaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo, Ci -Coalkyd, Ci-Cbhaloalkyl, Ci-C&hydroxyalkyl, Ci-Coheteroalkyl, Ci-Csaminoalkyl, C3-C6cycloalkyl, 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 Re; each Ra is independently Ci-Cealkyl, Ci-Cshaloalkyl, Ci-Cehydroxyalkyl, Ci-Cf,aminoalkyl, Ci- Ceheteroalkyl, C2-Cealkenyf C2-C6alkynyl, 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 Re; -10- WO 2024 / 240153 PCT / CN2024 / 094491 each Rb is independently hydrogen, Ci-C6alkyl, Ci-Cfihaloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; Rc and Rd are eachindependently hydrogen, Ci-Galkyl, Ci-Cehaloalkyl, Ci-Cfihydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, Ci-Cealkenyl, C2-Cealkynyl, 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 Re; or Rc and Rd 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 Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci -G,alkyl, Ci-Ce alkoxy, Ci -Ghaloalkyl, Ci -Cthy dr oxy alkyl, Ci -Cxaminoalkyl, Ci -Gheteroalkyl, or Ca-Cftcycloalkyl; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, or 6; and w is 0, 1, 2, 3, or 4.

[0014] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0015] 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.

[0016] 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

[0017] 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.

[0018] In some embodiments, 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. gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g., acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupus nephritis, Type I / Type -11- WO 2024 / 240153 PCT / CN2024 / 094491 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. cardiovascular risk reduction (CvRR), hypertension,atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g. hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer related diseases / disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis).

[0019] Additional aspects and advantages of the present disclosure will become readily apparent to those skilled in this art from the following detailed description, wherein only illustrative embodiments of the present disclosure are shown and described. As will be realized, the present disclosure is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, all without departing from the disclosure. Accordingly, the drawings and description are to be regarded as illustrative innature, and not as restrictive. INCORPORATION BY REFERENCE

[0020] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. DETAILED DESCRIPTION

[0021] While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to theembodiments of the invention described herein may be employed. Definitions

[0022] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0023] Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention. -12- WO 2024 / 240153 PCT / CN2024 / 094491

[0024] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at leastone embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents rmless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0025] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0026] “oxo” refers to =O.

[0027] “Carboxyl” refers to -COOH.

[0028] “Cyano” refers to -CN.

[0029] “Alkyl” refers to a straight-chain, or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably oneto six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2- methyl-1-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2,2-dimethyl-l-propyl, 2-methyl-1-pentyl, 3-methyl- l-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l- butyl, 3,3-dimethyl-l-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-C& alkyl” or “Ci-6alkyl”, 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 ofthe term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-ioalkyl. In some embodiments, the alkyl is a Ci-ealkyl. In someembodiments, the alkyl is a Ci-salkyl. In some embodiments, the alkyl is a Ci-4alkyl. In some embodiments, the alkyl is a Ci-3alkyl. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NHz, or -NOz. In some embodiments, the alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0030] “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. The group may be in either the cis or trans conformation about the double bond(s),and should be understood to include both isomers. Examples include, but are not limited to ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-C6 alkenyl” or “C2-6alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon -13- WO 2024 / 240153 PCT / CN2024 / 094491 atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, - COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, thealkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0031] “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. Whenever it appears herein, a numerical range such as “C2-C6 alkynyl” or “C2-6alkynyl”, 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, - CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0032] “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, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionallysubstituted with halogen.

[0033] “Alkoxy” refers to a radical of the formula -ORa where Ra 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, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0034] “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 -14- WO 2024 / 240153 PCT / CN2024 / 094491 contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hixkel 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. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0035] “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, andaromatic 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.

[0036] “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., C3-C15 fully saturated cycloalkyl or C3-C15cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-Cs fully saturated cycloalkyl or Cs-Cs cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, 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. -15- WO 2024 / 240153 PCT / CN2024 / 094491 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. Unless stated otherwise specifically in the specification, 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. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH,or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0037] “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. In certain embodiments, a cycloalkenyl comprises three to ten carbon atoms. In other embodiments, 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.

[0038] ‘‘Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0039] As used herein, the term “haloalkyl” or “haloalkane” refers to an alkyl radical, as defined above, that issubstituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally further substituted. Examples of halogen substituted alkanes (“haloalkanes”) 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.). When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected e.g., 1-chloro,2-fluoroethane.

[0040] “Fluoroalkyl” refers to an alkyl radical, as definedabove, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like.

[0041] “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, -16- WO 2024 / 240153 PCT / CN2024 / 094491 hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0042] “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. Insome embodiments, the aminoalkyl is aminomethyl.

[0043] “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. In one aspect, a heteroalkyl is a Ci-Ce 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. - NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, - CH2OCH3, -CH2CH2OCH3,-CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, - CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, withoxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or-OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0044] “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 tothree 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. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, 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. Representative heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fullysaturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2- -17- WO 2024 / 240153 PCT / CN2024 / 094491 Cg fully saturated heterocycloalkyl or C2-G heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-Ce heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such 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, thiomorpholinyl, thiamorpholinyl, 1 -oxo- thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3- dihydroisobenzofuran-1-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, 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).In some embodiments, the heterocycloalkyl is a 3 - to 8-membered fully saturated heterocycloalkyl. In some embodiments, the heterocyclo alkyl 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. In some embodiments, 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. Unless stated otherwise specifically in the specification, a heterocycloalkyl may beoptionally 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. In some embodiments, the heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.

[0045] “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. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some -18- WO2024 / 240153 PCT / CN2024 / 094491 embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, 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. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6-membered heteroaryl. In some embodiments, the heteroaryl is a5-membered heteroaryl. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzo furanyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphtho furanyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzo furanyl, benzo furanonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, 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. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, - OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0046] The term “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. In certain embodiments, 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. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched, and unbranched, carbocyclic, -19- WO 2024 / 240153 PCT / CN2024 / 094491 and heterocyclic, aromatic, and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same ordifferent for appropriate organic compounds. For purposes of this disclosure, 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.

[0047] The term “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.

[0048] The term “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 acidaddition 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, / >-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, substitutedamines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0049] The phrases “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.

[0050] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / ordosage 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. -20- WO 2024 / 240153 PCT / CN2024 / 094491

[0051] The phrase “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. Some examples of 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 sodiumcarboxymethyl 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; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0052] 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 toproduce a desired therapeutic effect.

[0053] The terms “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.

[0054] As used herein, 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. Compounds of the disclosure

[0055] Described herein are compounds, or a pharmaceutically acceptable salt thereof useful in the treatment of a disease or disorder associated with NLRP3 inflammasome.

[0056] In one aspect, the disclosure provides a compound represented by Formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof: Formula (I), wherein, ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; -21- WO 2024 / 240153 PCT / CN2024 / 094491 B is C or N: D is C or N; E is C, CRCE or N; RCE is hydrogen, -OH, Ci-Cealkyl, Ci-Galkoxy, Ci-Ghaloalkyl, Ci-Cihydroxyalkyl, Ci-Gaminoalkyl, or Ci -Gheteroalkyl; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, G-Galkyl, C-Ghaloalkyl, Ci-Cihydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cxheteroalkyl, C2-C6alkenyl, C2-G,alkynyl, G-Gcycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, orcycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Cealkyl, Ci-Cxalkoxy, Ci-Ghaloalkyl, Ci-Cxhydroxyalkyl, G-Gaminoalkyl, C1- Gheteroalkyl. C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; ring C is phenyl, 5 to 7-membered heteroaryl, G-Cscycloalkyl, or 5 to 8 membered heterocycloalkyl; each R1 is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, - S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, - S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C6alkyl, G-Ghaloalkyl, Ci-C6hydroxyalkyl, Ct-Cxaminoalkyl, G-Gheteroalkyl, G-Galkcnyl, G-Galkynyl, Cs-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein eachof the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; or two R1 on the same atom or different atoms are taken together to form a C3-Cscycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more Re; or two R1 on the same atom are taken together to form an oxo; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Galkyl, G-G,alkoxy, Ci- Ghaloalkyl, Ci-Ghydroxyalkyl, Ci-Gaminoalkyl, 4-6 membered heterocycloalkyl, or C3- Gcycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; or two R2 are taken together to form an oxo; or two R2 are taken together to form a G-Gcycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from Re; -22- WO2024 / 240153 PCT / CN2024 / 094491 R3 is Ce-Cioaryl, 5 to 12 membered heteroaryl, Ca-Cncycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cfihydroxyalkyl, Ci-Cealkoxy, or Ci-Ceaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo, Ci-Cealkyl, Ci-Cihaloalkyl, Ci-Cghydroxyalkyl, Ci-Ceheteroalkyl, Ci-Ceaminoalkyl, Cs-Cecycloalkyl, 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 Re; each Ra is independently Ci-Cealkyl, Ci-GJialoalkyl, Ci-Cshydroxy alkyl, Ci-Ceaminoalkyl. Ci- Ceheteroalkyl,C2-C6alkenyl, C2-C6alkynyl, 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 Re; each Rb is independently hydrogen, G-G.alkyl, Ci-Ghaloalkyl, Ci-Cshydroxy alkyl, Ci-Ceaminoalkyl, Ci-Cqheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; Rc and Rd are each independently hydrogen, Ci-C^alkyl, Ci-C&haloalkyl, Ci-C6hydroxyalkyl, Ci- G,am i noalky I, Ci -Ghctci'oalkyL C2-C6alkenyl, G-G,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 Re; or Rc and Rd 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 Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=0)0H, -C(=O)OCH3, Ci-Cqalkyl, Ci-G>alkoxy. Ci-C<,haloalkyl, G-Gfiydroxyalkyl, G-G,ami noalky I, Ci -G.hctcroalkyl, or C3-C6 cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, or 3; and w is 0, 1, 2, 3, or 4.

[0057] In another aspect, the disclosure provides a compound represented by Formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof: -23- WO 2024 / 240153 PCT / CN2024 / 094491 Formula (I), wherein, ring A is C&-Cioaryl,4-12 membered heteroaryl, C3-Ci2cycloalkyl, or 4-12 membered heterocycloalkyl; B is C or N: D is C or N; E is C, CRCE or N; RCE is hydrogen, -OH, Ci-C6,alkyl, Ci-Cf,alkoxy, Ci-Qhaloalkyk Ci-C6hydroxyalkyl, Ci-Ckaminoalkyl, or Ci -Cdieteroalkyl; ring C is phenyl, 5 to 7-membered heteroaryl, Cs-Cscycloalkyl, or 5 to 8 membered heterocycloalkyl; each R1 is independently hydrogen, halogen, -OH, -CN, -NO?, -ORa, -NRcRd, Ci-Cealkyl, Ci-C6alkoxy, Ci-Cehaloalkyl, Ci-C / hydroxyalkyl, Ci-C6aminoalkyl, or C3-Cf,cycloalkyl; each R2 is independently halogen, -OH, -CN, -NO?, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cealkoxy, Ci- Cehaloalkyl, Cj-Cj, hydroxyalkyl, Ci-Ceaminoalkyl, or C3-C6cycloalkyl; R3 is phenyl, 5 to 12 membered heteroaryl, C3-Ci2cycloalkyl, 4 to 12 membered heterocycloalkyl, or Ci-Cealkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2,-ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra,-S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo, Ci-Cealkyl, Ci-Cihaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceheteroalkyl, Ci-Ciaminoalkyl, C3-C6cycloalkyl, 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 Re; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, Cb-Cealkcnyl, Ck-Cealkynyl, C3-Cscycloalkyl, or4-12 memberedheterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl,aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cshaloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci- Cehctcioalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; -24- WO 2024 / 240153 PCT / CN2024 / 094491 each Ra is independently Ci-Cealkyl, Ci-Cfihaloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci- Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; each Rb is independently hydrogen, Ci-Cealkyl,Ci-CTshaloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci -Ceheteroalkyl, G-Cealkenyl, C2-Cealkynyl, 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 Re; Rc and Rd are each independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Cfihetcroalkyl, C2-C6alkcnyk Ch-G, 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 Re; or Rc and Rd 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 substituentsindependently selected from Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, G-G>alkyl, Ci-C6alkoxy, G-Ghaloalkyl, Ci-C&hydroxyalkyl, Ci-C6aminoalkyl, Ci-Ghctcroalkyl, or C3-C6cycloalkyl; n is 1 or 2; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, or 3; and w is 0, 1, 2, or 3.

[0058] In some embodiments of Formula (I), 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. In some embodiments of Formula (I), ring C is phenyl, thiophenyl, pyridinyl, pyridazinyl, pyrimidinyl, or triazinyl. In some embodiments ofFormula (I), ring C is furanyl, oxazolyl, isoxazolyl, pyrrole, imidazolyl, or triazolyl.

[0059] In some embodiments of Formula (I), ring C is: -25- WO 2024 / 240153 PCT / CN2024 / 094491 r1 , r1 , or R1 , wherein R1’is hydrogen, Ci-Cealkyl, Ci-Galkoxy, Ci- Cfihaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Cs-Cecycloalkyl, or 4 to 6 membered heterocycloalkyl.

[0060] In some embodiments of Formula (I), ring C is Cs-Cscycloalkyl or 5 to 8 membered heterocycloalkyl. In some embodiments of Formula (I), ring C is Cs-Cecycloalkyl 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.

[0061] In some embodiments of Formula (I), ring C is: wherein, Y is CRCE or N; RCE is hydrogen, -OH, Ci-C&alkyl, Ci-Cealkoxy, G-Ghaloalkyl, Ci-C6hydroxyalkyl, Ci -Gaminoalkyl. or Ci-Ceheteroalkyl; Z is absent, NR1’, S, O, or CR'R1; each R1 is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, - S(=O)2Ra, -S(=O)2NRaRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, - S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-G,aminoalkyl, G-Gheleroalkyl. C2-G,alkenyl, G-Galkynyl, G’.-Gcycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, -26- WO 2024 / 240153 PCT / CN2024 / 094491 alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; or two R1 on the same atom or different atoms are taken together to form a Cs-Cscycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more Re; or two R1 on the same atom are taken together to forman oxo; R1’ is hydrogen, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, Ci-Cfihydroxyalkyl, Ci-CTaminoalkyl, C3- Cecycloalkyl, or 4 to 6 membered heterocycloalkyl; or R1 ’ and one of R1 are taken together to form a 4 to 6 membered heterocycloalkyl, which is optionally substituted with one or more Re; and p is 0, 1, 2, 3, 4, or 5.

[0062] In some embodiments of Formula (I), ring C is: R1’ is hydrogen, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, C3- Cecycloalkyl, or 4 to 6 membered heterocycloalkyl; or -27- WO 2024 / 240153 PCT / CN2024 / 094491 R1’ and one of R1 are taken together to form a 4 to 6 membered heterocycloalkyl, which is optionally substituted with one or more Re.

[0063] In some embodiments of Formula (I), ring C is: R1’ is hydrogen, Ci-Cealkyl, G-G,alkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, G-Gaminoalkyl, C3- C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; or R1 ’ and one of R1 are taken together to form a 4 to 6 membered heterocycloalkyl, which isoptionally substituted with one or more Re.

[0064] In some embodiments, provided herein is a compound of Formula (II), or a pharmaceutically acceptable salt or a stereoisomer thereof: Formula (II), wherein, ring A is Ce-Cioaryl, 4-12 membered heteroaryl, Ca-Cncycloalkyl, or 4-12 membered heterocycloalkyl; B, D, or E are each independently C or N; G is O, S, N, NRG’, or CRG; F is O, S, N, NRF’, or CRF; wherein G and F are not both O or S at the same time; each RG and RF is independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Ci- Galkoxy, Ci-Cehaloalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, or C3-C6cycloalkyl; each RG’ and RF’ is independently hydrogen, Ci-Cealkyl, G-Ghaloalkyl, Cs-Cecycloalkyl, or 4 to 6 membered heterocycloalkyl; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-C&alkyl, G-G,alkoxy, C1- Ghaloalkyl, Ci-Cehydroxy alkyl, Ci-Ceaminoalkyl, or G-Gcycloalkyl; -28- WO 2024 / 240153 PCT / CN2024 / 094491 R3 is phenyl, 5 to 12 membered heteroaryl,C3-Ci2cycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cghydroxyalkyl, Ci-Cealkoxy, or Ci-Ceaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo (=0), Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceheteroalkyl, Ci-Ceaminoalkyl, Cs-Cecycloalkyl, 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 Re; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb,- C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(O)(NRb)Rh, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-Cealkyl, Ci-GJialoalkyl, Ci-C6hydroxyalkyl, Ct-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Cs-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Coalkyl, Ci-Cqalkoxy, Ci-G,haloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci- Ghcteroalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; each Ra is independently Ci-Cqalkyl, G-Ghaloalkyl, Ct-Cshydroxyalkyl, Ci-Cqaminoalkyl, Ci- Qheteroalkyl. G-G,alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl, 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 Re; each Rb is independently hydrogen, Ci-Cf,alkyl, G-G,haloalkyl, Ci-Cehydroxyalkyl, Ci-Gaminoalkyl, Ci-Gheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; Rc and Rd are each independently hydrogen, Ci-Qalkyl, Ci-Ghaloalkyl, G-G,hydroxyalkyl, Ci- G,aminoalkyl, Ci-G, heteroalkyl. C2-C6alkenyl, C2-Cf,alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl is optionally substituted with 1 to 4 substituents independently selected from Re; -29- WO 2024 / 240153 PCT / CN2024 / 094491 or Rc and Rd 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 Rc; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cshaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, or Cs-Cecycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, or 5; and w is 0, 1, 2, or 3.

[0065] In some embodiments of Formula (I) or (II), B is C. In some embodiments of Formula (I) or (II), B isN. In some embodiments of Formula (I) or (Π), 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 isN. In some embodiments of Formula (I), E is CRCE. In some embodiments of Formula (II), G is O. In some embodiments of Formula (II), G is S. In some embodiments of Formula (Π), G is N. In some embodiments of Formula (II), G isNRG. In some embodiments of Formula (II), G is CRG. 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 NRF. In some embodiments of Formula (II), F is CRE.

[0066] In some embodiments of Formula (I) or (II), B and D are each C; and E is N.

[0067] In some embodiments of Formula (I) or (II), B is N; and D and E are each C.

[0068] In some embodiments of Formula (I) or (II), D is N; and B and E are each C.

[0069] In some embodiments of Formula (I) or (II), B, D, and E are each C.

[0070] In some embodiments, the compound of Formula (II) has the structure of Formula (Ila), or a pharmaceutically acceptable salt or a stereoisomer thereof:Formula (Ila), wherein, G is CRG or N; and F is CRF or N.

[0071] In some embodiment of Formula (Ila), G is CRG; and F is N. In some embodiments of Formula (Ila), G is N; and F is CRE In some embodiments of Formula (Ila), G is N and F is N.

[0072] In some embodiments, the compound of Formula (II) has the structure of Formula (lib), or a pharmaceutically acceptable salt or a stereoisomer thereof: -30- WO 2024 / 240153 PCT / CN2024 / 094491 wherein, G is CRG or N; and F is CRF or N.

[0073] In some embodiments of Formula (lib), G isCRG. In some embodiments of Formula (lib), G is N. In some embodiments of Formula (lib), F is CRF. In some embodiments of Formula (lib), F is N.

[0074] In some embodiments, the compound of Formula (II) has the structure of Formula (lie), or a pharmaceutically acceptable salt or a stereoisomer thereof: Formula (He), wherein, G is CRG or N; and F is CRF or N

[0075] In some embodiments of Formula (lie), G is N. In some embodiments of Formula (lie), G is CRG. In someembodiments of Formula (lie), F is N. In some embodiments of Formula (lie), F is CRF. In some embodiments of Formula (lie), G is N and F is N.

[0076] In some embodiments, the compound of Formula (II) has the structure of Formula (lid), or a pharmaceutically acceptable salt or a stereoisomer thereof: wherein, G is CRG, NRG’, O, or S; and F is CRF, NRF’, N, O, or S, wherein G and F are not both O or S at the same time.

[0077] In some embodiments of Formula (lid), G is O or S; and F is CRF. In some embodiments of Formula (lid), G is O; and F is CRF. In some embodiments of Formula (lid), G is S; and F is CRF.

[0078] In some embodiments of Formula (lid), G is CRG; and F is O or S. In some embodiments of Formula (lid), G is CRG; and F is O. In some embodiments of Formula (lid), G is CRG; and F is S. In some embodiments of Formula (lid), G is NRG’; and F is CRG. In some embodiments of Formula (lid), G is CRG; and F is NRG’. In some embodiments of Formula (lid), G is O; and F isN. In someembodiments of Formula (lid), G is N; and F is O. -31- WO 2024 / 240153 PCT / CN2024 / 094491

[0079] In some embodiments, provided herein is a compound of Formula (HI), or a pharmaceutically acceptable salt or a stereoisomer thereof: Formula (III), wherein, ring A is C6-Cioaryl, 4-12 membered heteroaryl, C3-Ci2cycloalkyl, or 4-12 membered heterocycloalkyl; H, J, and K are each independently N or CR1; each R1 is independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-C+alkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, Ci-Cshydroxyalkyl, Ci-C6aminoalkyl, or Ci-Cxcycloalkyl; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-C&alkyl, Ci-Cealkoxy, Ci- G,haloalkyl, Ct-Cbhydroxyalkyl, Ci-G.aminoalkyl, or Ci-Cxcycloalkyl; R3 is phenyl, 5 to 12 membered heteroaryl, Cs-Cucycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-Cealkyl, Ci-Cshaloalkyl, Ci-Crhydroxyalkyl, G-Galkoxy, or Ci-C6aminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen,-OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RaRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo (=0), Ci-Cxalkyl, Ci-C&haloalkyl, Ci-G,hydroxyalkyl, G-G, heteroalkyl. Ci-C6aminoalkyl, C3-G,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 Re; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRhC(=O)NR Rd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-Gsalkyl, G-G,haloalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, G-G,heteroalkyl, C2-Cf,alkenyl, C2-C6alkynyfC;-Cscycloalkyl. or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Cealkyl, Ci-C,alkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, G-G,aminoalkyl, Ci- Ceheteroalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; each Ra is independently G-C,alkyl, G-G,haloalkyl, Ci-C,hydroxyalkyl, G-G,aminoalkyl. Ci- Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein -32- WO 2024 / 240153 PCT / CN2024 / 094491 each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with1 to 4 substituents independently selected from Rc; each Rb is independently hydrogen, G-Galkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Cj-G.aminoalkyk Ci-Cgheteroalkyl, C2-C6alkenyl, G-Cealkynyl, 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 Rc; Rc and Rd are each independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Cj-C6hydroxyalky 1, Ci- Gaminoalkyl, Ci -Ceheteroalkyl, G-Galkcnyl. C2-Cealkynyl, 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 Re; or Rc and Rd 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 Rc; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci -G.alkyl, Ci -C6 alkoxy, Ci -Ghaloalkyl, Ci -C&hy dr oxy alkyl, Ci-Gaminoalkyl, Ci -Ghctcroalkyl, or Ca-Cecycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, or 5; and w is 0, 1, 2, or 3.

[0080] In some embodiments of Formula (III), H is N; and J and K are each CR1. In some embodiments of Formula (III), J is N; and H and K are each CR1. In some embodiments of Formula (III), H and J are each CR1; and K is N. In some embodiments of Formula (III), H and J are each N; and K is CR1. In some embodiments of Formula (III), H and K are eachN; and J is CR1. In some embodiments of Formula (III); H is CR1; and J and K are each N. In some embodiments of Formula (III), H, J, and K are each N.

[0081] In someembodiments, provided herein is a compound of Formula (IV), or a pharmaceutically acceptable salt or a stereoisomer thereof: Formula (IV), wherein, ringAis Ce-Cioaryl,4-12memberedheteroaryl, C3-Ci2cycloalkyl, or 4-12 membered heterocycloalkyl; -33- WO 2024 / 240153 PCT / CN2024 / 094491 Y is CRCE or N; RCE is hydrogen, -OH, Ci-Csalkyl, Ci-Cealkoxy, Ci-Cihaloalkyl, Ci-Cihydroxyalkyl, Ci-Ceaminoalkyl, or Ci -Ceheteroalkyl; Z is absent, NR1, S, O, or CR1^; each R1 is independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Ci-Galkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ca-Cficycloalkyl; or two R1 on the same atom or different atoms are taken together to form a Cs-Cscycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more Re; or two R1 on the same atom are taken together to form an oxo; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Chalky 1, G-G,alkoxy, C1- G.haloalkyl, Ci-G,hydroxyalkyl,Ci-Ceaminoalkyl, or Cs-Cccycloalkyl; R3 is phenyl, 5 to 12 membered heteroaryl, C3-Ci2cycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-Cealkyl, Ci-Cehaloalkyl, G-GJiydroxyalkyl, G-Galkoxy, or Ci-Ceaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=0)Ra, -NRbC(=0)0Rb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=0)R4U, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo (=0), Ci-C6alkyl, G-G,haloalkyl, Ct-Cshydroxyalkyl, G-G,hctcroalkyl, Ci-Ceaminoalkyl, C3-C6cycloalkyl, 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 Re; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRaRd, -NRbC(=0)Ra, -NRbC(=0)0Rb, -C(=O)Ra, -C(=O)ORb, - C(=0)NRaRd, -0C(=0)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C^alkyk Ci-G.haloalkyf Ci-Cbhydroxyalkyl, Ci-Cbaminoalkyl, Ci-Cftheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, G-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=0)0H, - C(=O)OCHa, Ci-C6,alkyl, G-G,alkoxy, G-G,haloalkyl, G-G,hydroxyalkyl, Ci-C6aminoalkyl, Ci- G,heteroalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; each Ra is independently G-G,alkyl, G-G,haloalkyl, G-G,hydroxyalkyl, Ci-Cf,aminoalkyl, Ci-G,heleroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; -34- WO 2024 / 240153 PCT / CN2024 / 094491 each Rb is independently hydrogen, Ci-C6alkyl, Ci-Cfihaloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; Rc and Rd are each independently hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, CT-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each ofthe alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from Re; or Rc and Rd 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 Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci -Cxalkyl, Ci -G, alkoxy. Ci -G, haloalky I, Ci -Cxhy dr oxy alkyl, Ci -Cxaminoalkyl, Ci -G.hctcroalkyl, or C3-C6cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, or 3; and w is 0, 1, 2, or 3.

[0082] In one aspect, the disclosure provides for a compound represented by Formula (V), or a pharmaceutically acceptable salt or a stereoisomer thereof: wherein; ring A is aryl,heteroaryl, cycloalkyl, or heterocycloalkyl; E is CRVE or N; RVE is hydrogen, halogen, -OH, -NRcRd, -CN, -ORa, -C(=O)Ra, G-Cealkyl, G-G>alkoxy. G -Ghaloalkyl. G-G,hydroxyalkyl, Ci-Cf,aminoalkyl, or G-G,heleroalkyl; R1 is hydrogen, halogen, -OH, -CN, -NO2, -NRcRd, Ci-C6alkyl, Ci-G,alkoxy, Ci-GEaloalkyl, Ci- Cehydroxyalkyl, Ci-Gsaminoalkyl, or Ci-Cgheteroalkyl; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cihydroxyalkyl, Ci-C6aminoalkyl, -35- WO 2024 / 240153 PCT / CN2024 / 094491 Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, Cs-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionallysubstituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CHa, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Cealkyl, Ci-Cgalkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, C1- Ceheteroalkyl, Cs-Cecycloalkyl, or 4 to 6 membered heterocycloalkyl; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cealkoxy, Ci- G.haloalkyl, Ct-Cehydroxy alkyl, Ci -G.aminoalkyl, 4-6 membered heterocycloalkyl, or C3- Gcydoalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; or two R2 are taken together to form an oxo; or two R2 are taken together to form a G-G,cycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from Rc; R3 is G-Gi>aryl, 5 to 12 memberedheteroaryl, C3-Ci2cycloalkyl, 4 to 12 membered heterocycloalkyl, G-G>alkyl, G-GJialoalkyl, Ci-Cdiydroxyalkyl, Ci-Cealkoxy, or Ci-Ccaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RaRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo, G-G,alkyl, Ci-C6haloalkyl, G-G,hydroxyalkyk Ci-Ghctcroalkyl, G-G.aminoalkyl, C3-C6cycloalkyl, 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 Re; each Ra is independently G-G, alkyl, Ci-G,haloalkyl, Ci-Cshydroxyalkyl, Ci-Ceaminoalkyl, Ci- Cftheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl, 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 Re; each Rb is independently hydrogen, Ci-Cealkyl, G-G,haloalkyl, Ci-Cshydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyf 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 Re; Rc and Rd are each independently hydrogen, Ci-Cealkyl, C1-C6haloalkyl, G-G>hydroxyalkyl, Ci- G,ami noalkyl, G-G,heleroalkyl. C2-G>alkenyl. C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, -36- WO 2024 / 240153 PCT / CN2024 / 094491 alkynyl,cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with 1 to 4 substituents independently selected from Re; or Rc and Rd 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 Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, G-Ghydroxyalkyl, Ci-Ceaminoalkyl, G-Ghctcroalkyl, or G,-G> cycloalky I; n is 1, 2, or 3; p is 0, 1,2, 3, 4, 5, or 6; and w is 0, 1, 2, 3, or 4.

[0083] In some embodiments of Formula (IV), Y is N. In some embodiments of Formula (IV), Y is CRCE. In some embodiments of Formula (IV), Y is CH.

[0084] In some embodiments of Formula (IV), Z is NR1 or O. In some embodiments of Formula (IV), Z is NR1. In some embodiments of Formula (IV), Z is O. Insome embodiments of Formula (IV), Z is S. In some embodiments of Formula (IV), Z is CR1R1. In some embodiments of Formula (IV), Z is absent.

[0085] In some embodiments of Formula (II), (Ila), (lib), (lie), or (lid), each RG and RF is independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, G-Galkoxy, Ci- Ghaloalkyl, G-Ghydroxyalkyl, Ci-G.aminoalkyl, or G-Gcycloalkyl. In some embodiments, each RG andRF is independently hydrogen, Ci-C6alkyl, or C3-C6cycloalkyl. In some embodiments, each RG and RF is independently Ci -G.alkyl. In some embodiments, each RG and RF is independently methyl or ethyl. In some embodiments, each RG and RF is independently Cs-Cecycloalkyl. In some embodiments, each RG and RF is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each RG and RF is hydrogen.

[0086] In some embodiments of Formula (II), (Ha), (lib), (lie), or (lid), RG is hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, G-G,alkyl, Ci-Cealkoxy, Ci-G,haloalkyl,G-Ghydroxyalkyl, Ci- Gaminoalkyl, or C3-C6cycloalkyl. In some embodiments, RG is hydrogen, Ci-G,alkyl, or C3- Gcycloalkyl. In some embodiments, RG is Ci-G>alkyl. In some embodiments, RG is methyl or ethyl. In some embodiments, RG is Cj-Gcycloalkyl. In some embodiments, RG is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, RG is hydrogen.

[0087] In some embodiments of Formula (II), (Ha), (Hb), (lie), or (lid), RF is hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-G,alkyl, G-Galkoxy, G-G,haloalkyl, G-Ghydroxyalkyl, Ci- Qaminoalkyl, or C3-C6cycloalkyl. In some embodiments, RF is hydrogen, Ci-G,alkyl, or C3- G,cycloalky I. In some embodiments, RF is G-Galkyl. In some embodiments, RF is methyl or ethyl. In some embodiments, RF is C3-G,cycloalkyl. In some embodiments, RF is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, RF is hydrogen. -37- WO 2024 / 240153 PCT / CN2024 / 094491

[0088] In some embodiments of Formula (II) or (lid), each RG’ and RF’ is independentlyhydrogen, Ci-Cealkyl, Ci-Cshaloalkyl, Ca-Cicycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments, each RG’ and RF’ is independently hydrogen or Ci-Cealkyl. In some embodiments, each RG’ and RF’ is independently Ci-Cealkyl. In some embodiments, each RG’ and RF’ is independently hydrogen.

[0089] In some embodiments of Formula (II) or (lid), RG’ is hydrogen, Ci-Cealkyl, Ci-Cihaloalkyl, Cs-Cecycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments, RG’ is hydrogen or Ci- Galkyl. In some embodiments, RG’ is Ci-Cealkyl. In some embodiments, RG’ is hydrogen.

[0090] In some embodiments of Formula (II) or (lid), RF’ is hydrogen, Ci -Cialkyl, Ci -Cehaloalkyl, C3- Gcycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments, RF’ is hydrogen or C1- Galkyl. In some embodiments, RF’ is Ci-Cealkyl. In some embodiments, RF’ is hydrogen.

[0091] In some embodiments of Formula (I) or (IV), RCE is hydrogen, Ci-Cealkyl, Ci-Cealkoxy, Ci- Ghaloalkyl. Ci-Cehydroxyalkyl,Ci-Ceaminoalkyl, or Ci-Ceheteroalkyl. In some embodiments, RCE is hydrogen.

[0092] In some embodiments of Formula (V), RVE is hydrogen, halogen, -OH, -NRcRd, -CN, -ORa, - C(=O)Ra, Ci-Csalkyl, G-G.alkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or C1- Cbheteroalkyl. In some embodiments, RVE is hydrogen. In some embodiments, RVE is halogen. In some embodiments, RVE is -OH. In some embodiments, RVE is -CN. In some embodiments, RVE is -ORa. In some embodiments, RVE is -O-C1 -Cealkyl, wherein the alkyl is optionally substituted with one or more halogen. In some embodiments, RVE is Ci-Cealkoxy. In some embodiments, RVE is Ci-Cehaloalkoxy. In some embodiments, RVE is -C(=O)Ra, e.g., acetyl. In some embodiments, RVE is Ci-Ccalkyl. In some embodiments, RVE is Ci-Cfthaloalkyl. In some embodiments, RVE is Ci-Cfthydroxyalkyl. In some embodiments, RVE is Ci -C6aminoalkyl. In some embodiments, RVE is or Ci-C6heteroalkyl. In some embodiments, RVE is alkylamino or dialkylamino. In someembodiments, RVE is -NRcRd. In some embodiments, RVE is -NRcRd, wherein Rc and Rd are each independently hydrogen, Ci-C&alkyl, Ci- C6haloalkyl, Ci-Cehydroxyalkyl, C।-Gaminoalkyl, or G-G,hctcroalkyl; or Rc and Rd 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 Re. In some embodiments, Rc and Rd are each independently hydrogen or C1-C6alkyl. In some embodiments, Rc and Rd 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.

[0093] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (nd), (III), (IV), or (V), ring A is Ce-Cioaryl. In some embodiments, ring A is Ce-Csaryl. In some embodiments, ring A is phenyl. In some embodiments, ring A is phenyl fused with aheterocycloalkyl. In some embodiments, ring A is phenyl fused with a cycloalkyl. -38- WO 2024 / 240153 PCT / CN2024 / 094491

[0094] In some embodiments of Formula (I), (II), (Ila), (Hb), (lie), (lid), (III), (IV), or (V), ring A is

[0095] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (Hd), (ΠΙ), (IV), or (V), 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.

[0096] In some embodiments of Formula (I), (II), (Ila), (Ilb), (He), (Hd), (III), (IV), or (V), ring A is bicyclic heteroaryl. In some embodiments, ring A is fused heteroaryl. In some embodiments, ring A is 5- 0- / 7¾__ | 3- / 7¾__ | 6 or 6-5 fused heteroaryl. In some embodiments o, ring A is \= / or \= / . in some 0- / 7¾__ | 3- / 7¾__ | embodiments, ring A is \= / . in some embodiments, ring A is \= /

[0097] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), wherein, R4’ is R4, or two R4’ are taken togetherwith 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 R6; and X is CH, CR4 or N.

[0098] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V),

[0099] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (Hd), (III), (IV), or (V), ring A is Ca-Cizcycloalkyl. In some embodiments, ring A is C3-Cf,cycloalkyl. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), ring A is 4-12 membered heterocycloalkyl. In some embodiments, ring A is 4-6 membered heterocycloalkyl.

[00100] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (ΠΙ), (IV), or (V), X is CR4. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), X is CH. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), X is N. -39- WO 2024 / 240153 PCT / CN2024 / 094491

[00101] In some embodiments of Formula (I), (II), (Ila), (Hb), (lie), (lid), (III), (IV), or (V), two R4’ are taken together to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R6. In some embodiments, two R4’ are taken together to form a cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R6.

[00102] In some embodiments of Formula (I), (II), (Ila), (lib), (He), (lid), (III), (IV), or (V),

[00103] In some embodiments of Formula (I), (II), (Ila), (lib), (He), (lid), (III), (IV), or (V),

[00104] some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V),

[00105] In some embodiments of Formula (I), (II), (Ila), (lib), (He), (Dd), (ΠΙ), (IV), or (V), each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)?Ra, -S(=O)2NRcRd, - NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, - OC(=O)NRcRd,-OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, - P(=O)(Rb)2, Ci-Ci, alky I, Ci -G.haloalkyl, G-Ghydroxyalkyl, Ci-C6aminoalkyl, Ci-Csheteroalkyl, C2- C6alkenyl, G-Galkynyl, C3-C8cycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl -40- WO 2024 / 240153 PCT / CN2024 / 094491 is optionally substituted with 1 to 4 substituents independently selected from R6. In some embodiments, each R4 is independently halogen, -CN, -NO2, -OH, -C(=O)Ra, -ORa, -SH, -SRa, -SF5, -NRcRd, Ci-Cealkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or C3-C8cycloalkyl. In some embodiments, each R4 is independently halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cghydroxyalkyl, or Ci -G, alkoxy I, which is optionally substituted with one or more halogen. In some embodiments, each R4 is independently methyl -OH, -CF3, -CF2H, -OCF3, or -OCF2H. In some embodiments, each R4 isindependently methyl CN, -OH, -CF3, -CF2H, -OCF3, or -OCF2H. In some embodiments, each R4 is independently -OH or -CF3. In some embodiments, each R4 is independently -OH. In some embodiments, each R4 is independently -CF3. In some embodiments, at least one R4 is -OH. In some embodiments, at least one R4 is -CF3. In some embodiments, at least one R4 is -CH3. In some embodiments, at least one R4 is -CN.

[00106] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (ΠΙ), (IV), or (V), each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci- Cealkyl, G-G.alkoxy, Ci-Cshaloalkyl, G-G,hydroxyalkyl, Ci-Ceaminoalkyl, G-Gheteroalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments, each R6 is independently halogen, Ci-C6alkyl, Ci-Cealkoxy, Ci-Cbhaloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci- C6heteroalkyl,C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments, each R6 is independently halogen or Ci-Csalkyl. In some embodiments, R6 is Ci-Cealkyl. In some embodiments, R6 is halogen.

[00107] In some embodiments of Formula (I), (III), (V), or (IV), each R1 is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRaRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, - OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, - P(=O)(Rb)2, Ci-C6alkyl, Ci-Cehaloalkyl, G-Ghydroxyalkyk Ci-Cbaminoalkyl, Ci-Cbheteroalkyl, C2- C6alkenyl, C2-C6alkynyl, G-Gcycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re. In some embodiments, each R1 is independently hydrogen, halogen, -CN,-NO2, -OH, -ORa, -NRcRd, Ci-C6alkyl, G-Qhaloalkyl. Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, or C3-C&cycloalkyl. In some embodiments, each R1 is independently hydrogen, halogen, Ci-C6alkyl, or C3-Cecycloalkyl. In some embodiments, each R1 is independently halogen, Ci-C6alkyl, or G-Ghaloalkyl. In some embodiments, each R1 is each independently halogen or G-Ghaloalkyl. In some embodiments, each R1 is each independently fluoro, chloro, bromo, CF3, or CHF2. In some embodiments, each R1 is independently Ci-Cf,alkyl. In some embodiments, each R1 is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or tert­ butyl. In some embodiments, each R1 is methyl. In some embodiments, each R1 is independently C3- Gcycloalkyl. In some embodiments, each R1 is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, R1 is hydrogen. -41- WO 2024 / 240153 PCT / CN2024 / 094491

[00108] In some embodiments of Formula (I), (III), (V), or (IV), R1 is hydrogen, halogen, -OH, -CN, - NO2,-NRcRd, Ci-Cealkyl, Ci-Csalkoxy, Ci-Cehaloalkyl, Ci-Cfihydroxyalkyl, Ci-Gsaminoalkyl, or Ci- Ceheteroalkyl, In some embodiments, R1 is hydrogen, halogen, or Ci-Cealkyl,

[00109] In some embodiments of Formula (I) or (IV), two R1 on the same atom or different atoms are taken together to form a CVCgcycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more Re. In some embodiments, two R1 on the same atom or different atoms are taken together to form a Cs-Cscycloalkyl. In some embodiments), two R1 on the same atom or different atoms are taken together to form a cyclopropyl, cyclobutyl, cyclopentyl, or cycloheptyl. In some embodiments, two R1 on the same atom or different atoms are taken together to form a 4 to 8 membered heterocycloalkyl. In some embodiments, two R1 on the same atom or different atoms are taken together to form a 4 membered, 5 membered, or 6 membered heterocycloalkyl.

[00110] In some embodiments of Formula (I) or (IV), two R1on the same atom are taken together to form an oxo.

[00111] In some embodiments of Formula (I), (II), (III), or (IV), R1’ is Ci-C6alkyl, Ci-C6alkoxy, Ci- Cjhaloalkyl, C1-C6 hydroxy alkyl, Ci-Ceaminoalkyl, C3-G,cycloalkyl, or 4 to 6 membered heterocycloalkyl. In some embodiments of Formula (I), (II), (ΠΙ), or (IV), R1’ is hydrogen or Ci-C6alkyl. In some embodiments, R1’ is Ci-C6alkyl. In some embodiments, R1’ is methyl, ethyl, isopropyl, or tert­ butyl. In some embodiments, R1’ is hydrogen.

[00112] In some embodiments of Formula (I) or (IV), R1 ’ and one of R1 are taken together to form a 4 to 6 membered heterocycloalkyl, which is optionally substituted with one or more Rc. In some embodiments, R1 ’ and one of R1 are taken together to form a 4 membered, 5 membered, or 6 membered heterocycloalkyl.

[00113] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (nd), (ΠΙ), (IV), or (V), each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Ci-Csalkoxy,Ci-Cehaloalkyl, Ci- Cbhydroxyalkyl, Ci-Cftaminoalkyl, 4-6 membered heterocycloalkyl, or Cs-Cocycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re. In some embodiments, each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci - Cfialkyl, Cj-C,alkoxy, Ci-Cfihaloalkyl, C1-C6hydroxyalky 1, Ci-C6aminoalkyl, or G-C,cycloalkyl.

[00114] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (nd), (ΠΙ), (IV), or (V), two R2 are taken together to form a C3-C6cycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from Re. In some embodiments, two R2 are taken together to form a G-Gcycloalkyl. In some embodiments, two R2are taken together to form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, two R2 are taken together to form a 4-6 membered heterocycloalkyl. In some embodiments, two R2 aretaken together to form a 4 membered, 5 membered, or 6 membered heterocycloalkyl.

[00115] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (nd), (ΠΙ), (IV), or (V), two R2 are taken together to form an oxo. -42- WO 2024 / 240153 PCT / CN2024 / 094491

[00116] In some embodiments of Formula (I), (II), (Ila), (lib), (He), (lid), (III), (IV), or (V), R3 is a Ca-Cncycloalkyl or 4 to 12 membered heterocycloalkyl; each of which is optionally substituted with one or more R5. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), R3 is a Ca-Cecycloalkyl, which is optionally substituted with 1, 2, or 3 R5. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), R3 is a 4 to 6 membered heterocycloalkyl, which is \ NH optionally substituted with 1, 2, or 3 R5. In some embodiments, R3 is + or + , each of which is optionally substituted with 1, 2, or 3 R5. In some embodiments of Formula (I), (II), (Ila), (lib), (lie),(lid), (ΙΠ), (IV), or (V), R5 is each independently selected from -OH, -ORa, -SH, -SRa, SF5, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceheteroalkyl, Ci-Ceaminoalkyl, and Ca-Cecycloalkyl.

[00117] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), R3 is a Ca-Cncycloalkyl which is optionally substituted with one or more R5. In some embodiments, R3 is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), R3 is monocyclic. In some embodiments of Formula (I), (II), (Ila), (lib), (He), (lid), (III), (IV), or (V), R3 is bicyclic. In some embodiments, R3 is

[00118] In some embodiments of Formula (I), (II), (Ila), (lib), (He), (Hd), (HI), (IV), or (V), R3 is a 4 to 12 membered heterocycloalkyl which is optionally substituted with one or more R5. In some embodiments, R3 is a 4 to 8 membered optionally substitutedheterocycloalkyl. In some embodiments, R3 is a 5 to 6 membered optionally substituted heterocycloalkyl. In some embodiments of Formula, R3 is a 6 membered optionally substituted heterocycloalkyl. In some embodiments, R3 is optionally substituted monocyclic heterocycloalkyl. In some embodiments, R3 is optionally substituted bicyclic heterocycloalkyl.

[00119] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), R3 is cyclohexyl or piperidine, each of which is optionally substituted. In some embodiments, R3 is optionally -43- WO 2024 / 240153 PCT / CN2024 / 094491 . In some embodiments, R3 is cyclohexyl. In some embodiments, R3 is optionally substituted KI LJ 2 . In some embodiments, R3 is cyclopentyl. In some embodiments, R3 is optionally substituted cyclopentyl. In some embodiments, R3 is OH

[00120] In some embodiments of Formula (I), (II), (Ila), (lib), (He), (lid), (III), (IV), or (V), R3 is Ci-Cealkyl, G-Ghaloalkyl, Ci-Cehydroxy alkyl, C-G.alkoxy, orG-Gaminoalkyl, each of which is optionally substituted with one or more R5. In some embodiments of Formula (I), (II), (Ila), (lib), (He), (lid), (III), (IV), or (V), R3 is optionally substituted Ci-Cealkyl. In some embodiments, R3 is G-Ghydroxyalkyl. In some embodiments, R3 is or . In some embodiments, R3 is In some embodiments, R3 is . In some embodiments, R3 is In some embodiments, R3 is embodiments, R3 is

[00121] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (Dd), (III), (IV), or (V), R3 is Ce- Cioaryl or 5 to 12 membered heteroaryl, each of which is optionally substituted with one or more R5. In some embodiments, R3 is G-Goaryl, which is optionally substituted with one or more R5. n some embodiments, R3 is optionally substituted phenyl. In some embodiments, R3 is 5 to 12 membered heteroaryl, which is optionally substituted with one or more R5. In some embodiments, R3 is 5 to 6 membered heteroaryl. In some embodiments, R3 is phenyl or 5 to 6 membered heteroaryl. Insome -44- WO 2024 / 240153 PCT / CN2024 / 094491 embodiments, R3 is phenyl or 5 to 6 membered heteroaryl, each of which is optionally substituted with one or more R5.

[00122] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), R3 is

[00123] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (nd), (ΠΙ), (IV), or (V), each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceheteroalkyl, Ci-Ceaminoalkyl, Ca-Cecycloalkyl, 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 Re. In some embodiments,each R5 is independently halogen, -OH, Ci-Cealkyl, Ca-Cicycloalkyl, 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 Re.

[00124] In some embodiments of Formula (I), (II), (Ila), (lib), (He), (Hd), (ΠΙ), (IV), or (V), each R5 is independently halogen. In some embodiments of Formula (I), (II), (Da), (Hb), (He), (lid), (III), (IV), or (V), each R5 is independently fluoro, bromo or chloro. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), each R5 is independently -OH. In some embodiments of Formula (I), (II), (Ha), (Hb), (lie), (Hd), (III), (IV), or (V), each R5 is independently Ci-Cealkyl. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (Hd), (ΙΠ), (IV), or (V), each R5 is independently methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, or tert-butyl.-45- WO 2024 / 240153 PCT / CN2024 / 094491

[00125] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), each R5 is independently Ca-Cficycloalkyl or 4 to 6 membered heterocycloalkyl. In some embodiments, each R5 is independently Cs-Cecycloalkyl. In some embodiments, each R5 is independently cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, each R5 is independently a 4 to 6 membered heterocycloalkyl. In some embodiments, each R5 is independently a 4 membered heterocycloalkyl. In some embodiments, each R5 is independently a 5 membered heterocycloalkyl. In some embodiments, each R5 is independently a 6 membered heterocycloalkyl. In some embodiments, each R5 is independently selected from -OH, -ORa, -SH, -SRa, SF5, -NRcRd, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-Ceheteroalkyl, Ci-Ceaminoalkyl, and Cx-Cecycloalkyl.

[00126] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), n is 3. In someembodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), n is 1 or 2. In some embodiments of Formula (I), (Π), (Ila), (Hb), (He), (lid), (ΠΙ), (IV), or (V), n is 2. In some embodiments of Formula (I), (II), (Ila), (lib), (He), (lid), (III), (IV), or (V), n is 1. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (Hd), (III), or (IV), n is 0.

[00127] In some embodiments of Formula (I), (II), (Ila), (Hb), (lie), (lid), (III), (IV), or (V), p is 6. In some embodiments of Formula (I), (II), (Ila), (lib), (He), (lid), (III), (IV), or (V), p is 5. In some embodiments of Formula (I), (Π), (Ila), (Hb), (lie), (lid), (ΠΙ), (IV), or (V), p is 4. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (ΙΠ), (IV), or (V), p is 3 In some embodiments of Formula (I), (II), (Ila), (Hb), (lie), (lid), (III), (IV), or (V), p is at least 3. In some embodiments of Formula (I), (II), (Ila), (Hb), (He), (lid), (ΙΠ), (IV), or (V), p is 1, 2, or 3. In someembodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (ΙΠ), (IV), or (V), p is 2 or 3. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (ΙΠ), (IV), or (V), p is 1 or 2. In some embodiments of Formula (I), (II), (Ila), (lib), (He), (lid), (III), (IV), or (V), p is 2. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), p is 1. In some embodiments of Formula (I), (II), (Ila), (lib), (De), (lid), (ΙΠ), (IV), or (V), p is 0.

[00128] In some embodiments of Formula (I), (III), or (IV), 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.

[00129] In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (nd), (ΠΙ), (IV), or (V), w is 4. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), w is 3. In some embodiments of Formula (I), (Π), (Ila), (lib),(lie), (lid), (ΠΙ), (IV), or (V), w is 2. In some embodiments of Formula (I), (II), (Ila), (nb), (He), (lid), (ΙΠ), (IV), or (V), w is 1. In some embodiments of Formula (I), (II), (Ila), (lib), (lie), (lid), (III), (IV), or (V), w is 0.

[00130] In some embodiments of a compound disclosed herein, each Ra is independently Ci-C6,alkyl, G-G.haloalkyl. G-G.hydroxyalkyl. G-G>aininoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re. In some embodiments of a compound -46- WO 2024 / 240153 PCT / CN2024 / 094491 disclosed herein, each Ra is independently Ci-Cealkyl, Ci-Cqhaloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with 1 to 4substituents independently selected from Rc. In some embodiments of a compound disclosed herein, each Ra is independently Ci-Cealkyl or Ci-Cehaloalkyl. In some embodiments of a compound disclosed herein, each Ra is independently Ci-Cealkyl.

[00131] In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, Ci- G, alkyl. G-G.haloalkyl. Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Cgheteroalkyl, Ci-Cgalkenyl, C2- G, 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 Re. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, Ci -G,alkyl, Ci -Ghaloalkyl, cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with 1 to 4 substituentsindependently selected from Re. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen, G-G,alkyl or G-Ghaloalkyl. In some embodiments of a compound disclosed herein, each Rb is independently hydrogen or Ci-G.alkyl. In some embodiments of a compound disclosed herein, each Rb is hydrogen. In some embodiments of a compound disclosed herein, each Rb is independently G-G,alkyl.

[00132] In some embodiments of a compound disclosed herein, Rc and Rd are each independently hydrogen, Ci-Csalkyl, Ci-G,haloalkyl, G-G.hydroxyalkyl, Ci-C6aminoalkyl, G-GJictcroalkyl, C2- Cealkenyl, C2-C6alkynyl, 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 Re. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen,G-G,alkyl, G-GJialoalkyl. cycloalkyl, or heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently optionally substituted with 1 to 4 substituents independently selected from Re. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen, G -G,alkyl or Ci -Cehaloalkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are independently hydrogen or Ci-C6alkyl. In some embodiments of a compound disclosed herein, each Rc and Rd are hydrogen. In some embodiments of a compound disclosed herein, each Rc and Rd are independently Ci- Cbalkyl.

[00133] In some embodiments of a compound disclosed herein, Rc and Rd 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 Re.

[00134] In some embodiments of a compound disclosed herein, each Re is independently halogen, oxo, -CN,-OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2,-S(=O)2NHCH3, -S(=O)2N(CH3)2, -nh2, -NHCH3j - N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci- Cihydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, or C3-C6cycloalkyl. In some embodiments of a compound disclosed herein, eachRe is independently halogen, -CN, -OH, Ci-C6,alkyl, G-G,alkoxy. Ci- -47- WO 2024 / 240153 PCT / CN2024 / 094491 Cfihaloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci-Ceheteroalkyl, or Ca-Cficycloalkyl. In some embodiments of a compound disclosed herein, each Re is independently halogen, -CN, -OH, Ci-Cfialkyl, or Cs-Cecycloalkyl. In some embodiments of a compound disclosed herein, each Rc is independently halogen, Ci-Cealkyl, or C3-C6cycloalkyl. In some embodiments of a compound disclosed herein, each Re is independently Ci-C6alkyl. In some embodiments of a compound disclosed herein, each Re is independently Cb-Cecycloalkyl. In some embodiments of a compound disclosed herein, each Re is independentlyhalogen.

[00135] In some embodiments of a compound disclosed herein, one or more of R1, R1’, R2, R3, R4, R5, R0, RCE, RG, RG’, RF, RF’, Ra, Rb, Rc, and Rd, and Re groups comprise deuterium at a percentage higher than the natural abundance of deuterium.

[00136] In some embodiments of a compound disclosed herein, one or more Ή are replaced with one or more deuteriums in one or more of the following groups R1, R1 R2, R3, R4, R5, R6, RCE, RG, RG’, RF, RF’, Ra, Rb, Rc, and Rd, and Re.

[00137] In some embodiments of a compound disclosed herein, the abundance of deuterium in each of R1, R1’, R2, R3, R4, R5, R6, RCE, RG, RG’, RF, RF’, Ra, Rb, Rc, and Rd, and Rc 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.

[00138] Any combination ofthe groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereofare chosen by one skilled in the field to provide stable moieties and compounds.

[00139] In some embodiments the compound disclosed herein, or a pharmaceutically acceptable salt or a stereoisomer thereof, is one of the compounds in Table 1 or Table 2. TABLE 1. -48- WO 2024 / 240153 PCT / CN2024 / 094491 -49- WO 2024 / 240153 PCT / CN2024 / 094491 13 OH yj] ,n=N χ'οΗ f3c 4- N-rt N 14 ^OHOH MF3c^^-7^V °h 4 ,N_ / N 15 °h ( Ί n=n rV' F3C%^ 2—4 / ^N\ 0H N 16 OH N=N y OH N 17 / X Ν'" OH \_J Η-N F3C%( ri—ri “ rLj Ή 18 OH OH \ / N=N Γ\ΩΗ F3C^Jb^ / -N 0H 4- N Racemic Stereoisomer 1 19 OH OH \ / N=N Γ^ηΗ F3C^Jb^ / -N 0H 4 N Racemic Stereoisomer 2 101 / CI / N~~ / °^V / n^<nVn' ul OH N -50- WO 2024 / 240153 PCT / CN2024 / 094491 TABLE 2. -51- WO 2024 / 240153 PCT / CN2024 / 094491 -52- WO 2024 / 240153 PCT / CN2024 / 094491 C. Further Forms of Compounds Disclosed Herein Isomers / Stereoisomers

[00140] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described hereinpossess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (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. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, 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, -53- WO 2024 / 240153 PCT / CN2024 / 094491separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography. Labeled compounds

[00141] In some embodiments, the compounds described herein exist in their isotopically-labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, 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. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chloride, such as 2H (D), 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36C1, 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. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability.

[00142] Insome embodiments, 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. In some embodiments, one or more of the substituents disclosed herein comprise deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more 1H are replaced with one or more deuteriums in one or more of the substituents disclosed herein.

[00143] In some embodiments, 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. Pharmaceutically acceptable salts

[00144] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases byadministering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions. -54- WO 2024 / 240153 PCT / CN2024 / 094491

[00145] In some embodiments, 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. In some embodiments, 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.

[00146] 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 saltsincluding, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,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, γ-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate,propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate and xylenesulfonate.

[00147] Further, 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-ethanedisulfonic acid,2- hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo- [2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-methylenebis-(3-hydroxy-2-ene-l - carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, 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.

[00148] In some embodiments, 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 organicprimary, -55- WO 2024 / 240153 PCT / CN2024 / 094491 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. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(Ci-4 alkyl)4, and the like.

[00149] Representative 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. Solvates

[00150] In some embodiments, the compounds described herein exist as solvates. In some embodiments, the disclosure provides for methods of treating diseases byadministering the compounds in the form of such solvates. In some embodiments, 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

[00151] In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulas described herein. 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, includingtemperature, solvent, and pH. Method of Treatment

[00152] 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. Disclosed herein is 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

[00153] Disclosed herein are methods of treating a disease modulated at least in part by NLRP3 inflammasome in a subject in need thereof, comprising administering to the subject a therapeutically affective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed herein.

[00154] 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 apharmaceutically acceptable salt thereof, disclosed herein.

[00155] In some embodiments, the disease or condition is an auto-immune disease. -56- WO 2024 / 240153 PCT / CN2024 / 094491

[00156] In some embodiments, the disease or condition is an auto-inflammatory disease.

[00157] In some embodiments, the disease or disorder is selected from mflammasome-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. 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 relatedcomplications (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. cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g. hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer related diseases / disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis). Dosing

[00158] In certain embodiments, the compositions containing the compound(s) described herein are administered for therapeutic treatments. In certain therapeutic applications, the compositions areadministered 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.

[00159] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion 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.

[00160] Once improvement of the patient’s conditionshas occurred, 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.

[00161] 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 -57- WO 2024 / 240153 PCT / CN2024 / 094491 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.

[00162] In some embodiments, doses employed for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In some embodiments, the daily dosages appropriate for the compound described herein, or a pharmaceutically acceptable salt thereof, arefrom about 0.01 to about 50 mg / kg per body weight. In various embodiments, 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.

[00163] 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. Pharmaceutical Compositions / Formulations

[00164] 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 describedherein are administered to animals.

[00165] In another aspect, provided herein are pharmaceutical 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. and Lachman, L, Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, (N.Y., 1980; and Pharmaceutical Dosage Forms and DrugDelivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference for such disclosure. EXAMPLES

[00166] The following examples are offered to illustrate, but not to limit the claimed invention. The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[00167] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art -58- WO 2024 / 240153 PCT / CN2024 / 094491 would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents canbe obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[00168] The compounds and salts of Formulas (I), (II), (Ila), (lib), (lie), (lid), (ΙΠ), (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. Abbreviations: ACN or MeCN Acetonitrile Z-BuONa Sodium ZerZ-butoxide CMBPCyanomethylene tributylphosphorane DCC Dicyclohexylcarbodiimide DCE 1,2-Dichloroethane DCM Dichloromethane DIAD Diisopropyl azodicarboxylate Dioxane 1,4-dioxane DMF YMDimethylformamide DMF-DMA Ν,Ν-Dimethylformamide dimethyl acetal (CAS NO.: 4637-24-5) DMSO Dimethylsulfoxide EA or EtOAc Ethyl Acetate ESI Electrospray ionization EtOH Ethanol FA Formic acid HOAc or AcOH Acetic acid HPLC High Performance Liquid Chromatography IBX 2-Iodoxybenzoic acid LC-MS Liquid chromatography—mass spectrometry Pd-PEPPSI-IHeptcl Dichloro[l,3-bis(2,6-di-4-heptylphenyl)imidazol-2- ylidene](3- chloropyridyl)palladium(II) (Chern. Eur. J. 2016,22,14534, catalyst 15) POC13 Phosphorus oxychloride PPh3 Triphenylphosphine Prep-HPLC Preparative-High Performance Liquid Chromatography Prep-SFC Preparative-supercritical fluid chromatography Prep-TLC Prep-TLC Preparative-thin layer chromatography rt room temperature -59- WO 2024 / 240153 PCT / CN2024 / 094491 RuPhos Pd G3Methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-l ,1 biphenyl)(2'-amino-l,r-biphenyl-2-yl)palladium(II) (CAS No. 1445085-77-7) TBAF Tetrabutylammonium fluoride TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran

[00169]

[00170] Example 1. Synthesis of Compound 1

[00171] Scheme 1. 1-9 (CH2O)n

[00172] Step 1: 3-(dimethylamino)-l-(2-methoxy-4-(trifluoromethyl)phenyl)prop-2-en-l-one

[00173] A solution of l-(2-methoxy-4-(trifluoromethyl)phenyl)ethan-l-one (4.00 g, 18.33 mmol) in DMF-DMA (9.71 mL, 73.33 mmol) was stirred at 100 *32 for 12 hours. The volatiles were removed under reduced pressure to give the title compound (5.00 g, crude) as a brown oil. LC-MS (ESI+): m / z: 274.2 (M+H)+. -60- WO 2024 / 240153 PCT / CN2024 / 094491

[00174] Step 2: Ethyl-4-(dimethylamino)-3-(2-methoxy-4-(trifluoromethyl)benzoyl)-2-oxobut-3- enoate

[00175] To a solution of ethyl 2-chloro-2-oxoacetate (2.04 mL, 18.30 mmol) in DCM (85.0 mL) was added a mixture of(3-(dimethylamino)-l-(2-methoxy-4-(trifluoromethyl)phenyl)prop-2-en-l-one (5.00 g, crude) and Pyridine (1.48 mL, 18.30 mmol) in DCM (50 mL) dropwise at 0 % under N2. The resulting mixture was stirred at 25 RD for 3 hours. Then, the mixture was quenched with HQ aqueous solution (20 mL, 1 M). The organic phase was washed with water (50 mL x 2), dried over anhydrous Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give the title compound (7.44 g, crude) as a brown solid. LC-MS (ESI+): m / z: 373.9 (M+H)+.

[00176] Step 3: ethyl 4-(2-methoxy-4-(trifluoromethyl)benzoyl)-lH-pyrazole-5-carboxylate

[00177] To a mixture of ethyl-4-(dimethylamino)-3-(2-methoxy-4-(trifluoromethyl)benzoyl)-2-oxobut- 3-enoate (7.44 g, crude) in EtOH (70.0 mL) was added methyl hydrazinecarboxylate (2.10 g, 23.31 mmol) and the reaction mixture was stirred at 25 RD for 0.5 hour. The volatiles were removed in vacuo to afford a residue. The residue was purified by flashcolumn chromatography on silica gel eluted with 0~40% ethyl acetate in petroleum ether to afford the title compound (5.2 g, 98.5% purity, 81.6% yield over 3 steps) as a yellow solid. LC-MS (ESI+): m / z: 342.9 (M+H)+. Ή NMR (400 MHz, DMSO-i / 6) δ = 13.86 (br.s, IH), 8.32(s, IH), 7.62 - 7.54(m, IH), 7.44-7.37 (m,2H),4.08 - 3.92 (m,2H), 3.77 (s, 3H), 1.10 - 0.96 (m, 3H).

[00178] Step 4: ethyl l-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-(2-methoxy-4- (trifluoromethyl)benzoyl)-lH-pyrazole-5-carboxylate

[00179] To a solution of ethyl 4-(2-methoxy-4-(trifluoromethyl)benzoyl)-177-pyrazole-5-carboxylate (1000.0 mg, 2.92 mmol), 3-((tert-butyldimethylsilyl)oxy)propan-1 -ol (611.9 mg, 3.21 mmol) and Ph2P (842.9 mg, 3.21 mmol) in THF (20.0 mL) was added DIAD (649.8 mg, 3.21 mmol) dropwise at 0 RD under N2 and the mixture was stirred at 25 RD for 15 min. The volatiles were removed in vacuo to afford a residue. The residue was purified by flash column chromatography on silica gel eluted with 0~20%ethyl acetate in petroleum ether to give the title compound (1100.0 mg, 73.2% yield) as colorless oil. LC-MS (ESI+): m / z: 515.1 (M+H)+. ΉNMR(400 MHz, DMSO-J6)6 = 7.87 (s. IH), 7.63 - 7.57 (m, IH), 7.45- 7.35 (m, IH), 4.40 - 4.24 (m,2H), 3.97 (q, / =7.2 Hz, 2H), 3.77 (s, 3H), 3.59 (t, J= 6.0 Hz, 2H), 2.04 - 1.92 (m, 2H), 1.00 (t, J= 7.2 Hz, 3H), 0.85 (s, 9H), 0.01 (s, 6H).

[00180] Step 5: l-(3-hydroxypropyl)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-lH-pyrazolo[3,4- djpyridazin-7-ol

[00181] To a solution of ethyl l-(3-((tert-butyldimethylsilyl)oxy)propyl)-4-(2-methoxy-4- (trifluoromethyl)benzoyl)-177-pyrazole-5-carboxylate (2200.0 mg, 4.27 mmol) in EtOH (20.0 mL) were added hydrazine hydrochloride (602.1 mg, 8.79 mmol) and the reaction mixture was stirred at 80 RD for 12 hours. TEA (1.83 mL, 13.19 mmol) was added and the mixture was stirred at 80 RD for 16 hours. After cooling to room temperature, the volatiles were removed in vacuo to afford a residue. H2O (30 mL) was added and the mixturewas extracted with ethyl acetate (50 mL x 2). The combined organic extracts -61- WO 2024 / 240153 PCT / CN2024 / 094491 were dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to the title compound (1.70 g, crude) as white solid. LC-MS (ESI+): m / z: 369.0 (M+H)+.

[00182] Step 6: 7-chloro-l-(3-chloropropyl)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-lH- pyrazolo[3,4-d]py ridazine

[00183] To a 100 mL round-bottomed flask with l-(3-hydroxypropyl)-4-[2-methoxy-4- (trifluoromethyl)phenyl]pyrazolo[4,3-i / ][l,2]diazin-7-ol (1900.0 mg, 5.16 mmol) and POCI3 (20.0 mL) was added pyridine (0.83 mL, 10.32 mmol) at 0 72. The mixture was stirred at 100 72 for 1 hour. The mixture was quenched with cold water (100 mL) at 0 72. Then, Nai ICO 3 solid was added to the mixture to adjust pH=7 .After phase separation, the aqueous phase was extracted with ethyl acetate (100 mLx 3). The combined organic extracts were dried over Na2SO4, filtered through a celite padand the filtrate was concentrated under reduced pressure to afford a crude. The crude was purified by flash column chromatography on silica gel eluted with 0~90% ethyl acetate in petroleum ether to give the title compound (1.33 g, 63.6% yield) as yellow solid. LC-MS (ESI+): m / z: 404.9 (M+H)+.

[00184] 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-l-carboxylate

[00185] To a solution of 7-chloro-l-(3-chloropropyl)-4-(2-methoxy-4-(trifluoromethyl)phenyl)-1H- pyrazolo[3,4-#]pyridazine (500.0 mg, 1.23 mmol), (R)-iert-butyl 3-aminopiperidine-l-carboxylate (370.7 mg, 1.85 mmol) and KI (307.3 mg, 1.85 mmol) in DMF (20.0 mL) was added TEA (0.51 mL, 3.70 mmol) at 25 72 and the mixture was stirred at 110 72 for 12 hours under N2. After cooling to room temperature, the volatiles were removed in vacuo to afford a residue. The residue was purified by flash column chromatography on silica gel eluted with 0~80%ethyl acetate in petroleum ether to give the title compound (360.0 mg, 78.5% purity, 43.1% yield) as colorless gum. LC-MS (ESI+): m / z: 533.1 (M+H)+.

[00186] Step 8: (R)-2-(6-(piperidin-3-yl)-6,7,8,9-tetrahydro-l,4,5,6,9a-pentaazabenzo[cd]azulen-3- yl)-5-(trifluoromethyl)phenol

[00187] To a solution of (7?)-ZerZ-butyl 3-(3-(2-methoxy-4-(trifluoromethyl)phenyl)-8,9-dihydro- l,4,5,6,9a-pentaazabenzo[cti]azulen-6(777)-yl)piperidine-l-carboxylate (360.0 mg, 0.68 mmol) in DCM (4.0 mL) was added BBn (0.20 mL, 2.03 mmol) at 0 72 and the reaction mixture was stirred at 25 72 for 5.5 hours. Then, the mixture was quenched with MeOH (1.0 mL) and concentrated under reduced pressure to afford the title compound (340.0 mg, crude) as a yellow solid. LC-MS (ESI+): m / z: 419.0 (M+H)+.

[00188] Step 9: (R)-2-(6-(l-methylpiperidin-3-yl)-6,7,8,9-tetrahydro-l,4,5,6,9a- pentaazabenzo[cd]azulen-3-yl)-5-(trifluoromethyl)phenol

[00189] To a mixture of (7?)-2-(6-(piperidin-3-yl)-6,7,8,9-tetrahydro-l,4,5,6,9a-pentaazabenzo[cif|azulen-3-yl)-5-(trifluoromethyl)phenol (340.0 mg, crude) in MeOH (5.0 mL) was added TEA (75.8 mg, 0.75 mmol). Then, HOAc (49.1 mg, 0.82 mmol) and (CH2O)n (61.3 mg, 2.04 mmol) were added in sequence and the mixture was stirred at 25 72 for 1 hour. NaBH3CN (64.1 mg, 1.02 mmol) was added and the resulting mixture was stirred at 25 72 for 12 hours. The mixture was quenched with H2O (10 mL) and the organic volatiles were removed in vacuo. The aqueous phase was extracted -62- WO 2024 / 240153 PCT / CN2024 / 094491 with ethyl acetate (20 mL x 2). The combined organic extracts were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by Prep- HPLC (Column: WelchXtimate C18 150*25mm*5um, Mobile Phase: water (lOmM NH4HCO3)-ACN, Mobile Phase B: acetonitrile Flow rate: 25 mL / min, gradient condition from 55% B to 85%) and lyophilized to give the title compound. LC-MS (ESI+): m / z: 433.0 (M+H)+. Ή NMR (400 MHz,methanol-d4) δ = 8.57 (s, 1H), 8.14 (d, J= 8.4 Hz, 1H), 7.25 (d, J= 8.4 Hz, 1H), 7.21 (s, 1H), 5.40 - 5.25 (m, 1H), 4.68 - 4.53 (m, 2H), 3.85 - 3.73 (m, 1H), 3.72 - 3.60 (m, 1H), 3.14 - 3.03 (m, 1H), 2.97 - 2.81 (m, 1H), 2.42 - 2.28 (m, 5H), 2.27 - 2.19 (m, 1H), 2.07 - 1.98 (m, 1H), 1.96 - 1.67 (m, 4H).

[00190] Example 2. Synthesis of Compound 2.

[00191] Scheme 2.

[00192] Step 1: 4-(2-methoxy-4-(trifluoromethyl)phenyl)-lH-pyrazolo[3,4-d]pyridazin-7-ol

[00193] To ethyl 4-(2-methoxy-4-(trifluoromethyl)benzoyl)-1 H-pyrazole-5-carboxylate (2000.0 mg, 5.84 mmol) inEtOH (40.0 mL) was added hydrazine hydrochloride (800.5 mg, 11.69 mmol) at 20 RS and the mixture was stirred at 80 RS for 16 hours. The volatiles were removed in vacuo to give residue. The residue was purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to give the title compound (1670.0 mg, 95.2% purity, 87.7% yield) as yellow solid. LC­ MS (ESI+): m / z: 311.2 (M+H)+.

[00194] Step 2: 7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-lH-pyrazolo[3,4-d]pyridazine

[00195] A mixture of 4-(2-mcthoxy-4-(trifluoromethyl Jphenyl)-1 / 7-pyrazolo[3,4-i / ]pyiidazin-7-ol (1.67 g, 5.38 mmol) in POCh (28.0 mL, 0.30 mol) was stirred at 100 RS for 10 min. After cooling to room -63- WO 2024 / 240153 PCT / CN2024 / 094491 temperature, the mixture was quenched with Η2Ο (200 mL) at 0 TJ. Then, the mixture was adjusted to pH = 7 with solid NaHCOa and the aqueous phase was extracted with ethyl acetate (100 mL x 3). The combined organic extracts were dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to afford a residue. The residue was purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to give the title compound (1670.0 mg, 84.4% purity, 79.7% yield) as yellow solid. LC-MS (ESI+): m / z: 329.1 (M+H)+.

[00196] Step 3:l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-7-chloro-4-(2-methoxy-4- (trifluoromethyl)phenyl)-lH-pyrazolo[3,4-d]pyridazine

[00197] To a mixture of 7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-177-pyrazolo[3,4- J]pyridazine (1200.0 mg, 3.65 mmol) in toluene (40.0 mL) were added 2-((tert- butyldimethylsilyl)oxy)ethan-l-ol (643.6 mg, 3.65 mmol) and 2-(tributyl-Z5- phosphaneylidene)acetonitrile (1057.5 mg, 4.38 mmol) at 20 TJ and the mixture was stirred at 50 TJ for 3.5 hours. The mixture was purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to give title compound (1150.0 mg, 98.6% purity, 63.8% yield) as yellow oil. LC-MS (ESI+): m / z: 487.1 (M+H)+.

[00198] Step 4: 2-(7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-lH-pyrazolo[3,4-d]pyridadn-l- yl)ethan-l-ol

[00199] To a mixture of l-(2-((ter / -butyldimethylsilyl)oxy)ethyl)-7-chloro-4-(2-methoxy-4- (trifluoromethyl)phenyl)-lZ / -pyrazolo[3,4-J]pyridazine (1150.0 mg, 2.36 mmol) andHOAc (0.41 mL, 7.17 mmol) in THF (20.0 mL) was added TBAF (7.1 mL, 7.08 mmol, 1 M in THF) at 20 TJ and the mixture was stirred for 12 hours. The mixture was purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to give the title compound (860.0 mg, 99.3% purity, 97.1% yield) as white solid. LC-MS (ESI+): m / z: 373.0 (M+H)+.

[00200] Step 5: 2-(7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-lH-pyrazolo[3,4-d]pyridazin-l- yl) acetaldehyde

[00201] To a mixture of 2-(7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-1 / / -pyrazolo[3,4- J]pyridazin-l-yl)ethan-l-ol (785.0 mg, 2.11 mmol) in MeCN (16.0 mL) was added IBX (1179.5 mg, 4.21 mmol) at 20 TJ and the mixture was stirred at 70 Tl for 3 hours. After cooling to room temperature, the mixture was filtered through a celite pad and the filtrate was concentrated to give the title compound (960.0 mg, crude) as yellow solid. LC-MS (ESI+): m / z: 389.0 (M+H30)+.

[00202] Step 6:(R)-N-(2-(7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-lH-pyrazolo[3,4- d]pyridazin-l-yl)ethyl)-l-methylpiperidin-3-amine

[00203] To a mixture of 2-(7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-lH-pyrazolo[3,4- d\pyridazin-1-yl)acetaldehyde (450.0 mg, 1.21 mmol) and (R)-}-methylpiperidin-3-amine (166.4 mg, 1.46 mmol) in MeOH (9.0 mL) was added HOAc (69 pL, 1.21 mmol) and NaBH3CN (91.5 mg, 1.46 mmol) at 20 TJ and the mixture was stirred at 25 TJ for 12.5 hours. The mixture was adjusted to pH = 1 with HC1 aqueous solution (IM) and the aqueous phase was extracted with ethyl acetate (10 mL x 3). Then, the aqueous phase was adjusted to pH = 8 with saturated Na2CO3 aqueous solution and extracted -64- WO 2024 / 240153 PCT / CN2024 / 094491 with ethyl acetate (10 mL x 3). The combined organic extracts were dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give the title compound (220.0 mg, crude) as yellow oil. LC-MS (ESI+): m / z:469.1 (M+H)+.

[00204] Step 7: (R)-8-(2-methoxy-4-(trifluoromethyl)phenyl)-5-(l-methylpiperidin-3-yl)-4,5-dihydro- 3H-2,2a, 5,6,7-pentaazaacenaphthylene

[00205] To a mixture of (7?)-Ar-(2-(7-chloro-4-(2-methoxy-4-(trifluoromethyl)phenyl)-177-pyrazolo[3,4- J]pyridazin-l-yl)ethyl)-l-methylpiperidin-3-amine (85.0 mg, 0.18 mmol) in DMF (4.5 mL) was added TEA (0.10 mL, 0.72 mmol) at 20 ‘U and the mixture was stirred at 150 +2 for 5 hours under microwave. After cooling to room temperature, the volatiles were removed in vacuo to give residue. The residue was dissolved in FEO (5 ml). Then, the mixture was adjusted to pH = 8 with saturated Na3CO3 aqueous solution and extracted with ethyl acetate (10 mL x 3). The combined organic extracts were dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give the title compound (100.0 mg, crude) as brown oil. LC-MS (ESI+): m / z: 433.1 (M+H)+.

[00206] Step 8:(R)-2-(5-(l-methylpiperidin-3-yl)-4,5-dihydro-3H-2,2a,5,6,7-pentaazaacenaphthylen- 8-yl)-5-(trifluoromethyl)phenol

[00207] To a mixture of (R)-8-(2-methoxy-4-(trifluoromethyl)phenyl)-5-(l-methylpiperidin-3-yl)-4,5- dihydro-377-2,2a,5,6,7-pentaazaacenaphthylene (200.0 mg, 0.46 mmol) in DCM (10.0 mL) was added BBr3 (0.27 mL, 2.77 mmol) at 0 +2 and the mixture was stirred at 25 Xl for 12 hours. The mixture was quenched with MeOH (5.0 mL) at 25 *32 and the mixture was concentrated under reduced pressure to afford a residue. MeCN (1.0 mL) was added and the mixture was adjusted to pH = 8 with ΝΗ3·Η2θ aqueous solution (10% w / w). The resulting mixture was adjusted to pH = 5 with FA and filtered. The filtrate was purified by Prep-HPLC (Column: Welch Xtimate Cl 8 150*30mm*5um, Mobile Phase: water(FA)-ACN, Mobile Phase B: acetonitrile Flow rate: 30 mL / min, gradient condition from 4% B to 44%) and lyophilized to give the title compound. LC-MS (ESI+): m / z: 419.1 (M+H)+. Ή NMR (400 MHz,methanol-i / 4) δ = 8.63 (s, 1H), 8.26 (d, J= 8.4 Hz, 1H), 7.28 (d, J= 8.4 Hz, 1H), 7.23 (s, 1H), 4.89 -4.84(m, 1H), 4.63 - 4.54 (m, 2H), 4.10 - 3.95 (m, 2H), 3.27 - 3.20 (m, 1H), 3.10 - 3.01 (m, 1H), 2.72 - 2.61 (m, 1H), 2.52 (s, 3H), 2.38 - 2.27 (m, 1H), 2.09 - 1.94 (m, 2H), 1.94 - 1.81 (m, 2H).

[00208] Example 3. Synthesis of Compound 3.

[00209] Scheme 3.

[00210] Step 1: (R)-l-(3-(2-methoxy-4-(trifluoromethyl)phenyl)-8,9-dihydro-l,4,5,6,9a- pentaazabenzo[cd]azulen-6(7H)-yl)propan-2-ol

[00211] To a solution of intermediate 1-7 (250.0 mg, 0.62 mmol) in DMF (10.0 mL) were added (R)-l- aminopropan-2-ol (69.5 mg, 0.93 mmol), KI (153.6 mg, 0.93 mmol) and TEA (0.26 mL, 1.85 mmol) at 25 +2 and the mixture was stirred at 110 'U for 12 hours. After cooling to room temperature, the mixture -65- WO 2024 / 240153 PCT / CN2024 / 094491 was concentrated under reduced pressure to afford a residue. H2O (10 mL) was added and the mixture was adjusted to pH = 8 with Na2COa aqueous solution. The mixture wasextracted with ethyl acetate (20 mL x 3). The combined organic extracts were dried over Na2SC>4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give title compound (350.0 mg, crude) as brown oil. LC-MS (ESI+): m / z 408.1 (M+H)+.

[00212] Step 2: (R)- 2-(6-(2-hydroxypropyl)-6,7,8,9-tetrahydro-l,4,5,6,9a-pentaazabenzo[cd]azul-en- 3-yl)-5-(trifluoromethyl)phenol

[00213] To a mixture of (JQ-l-(3-(2-methoxy-4-(trifluoromethyl)phenyl)-8,9-dihydro-l,4,5,6,9a- pentaazabenzo[ci / ]azulen-6(777)-yl)propan-2-ol (350.0 mg, crude) in DCM (5.0 mL) was added BBn (0.17 mL, 1.72 mmol) at 0 ft? and the mixture was stirred at 25 ft? for 0.5 hour. The mixture was quenched with MeOH (10.0 mL) at 25 ft? and the volatiles were removed in vacuo to afford a residue. The residue was adjusted to pH = 8 with ΝΗ3Ή2Ο aqueous solution (10% w / w). The mixture was purified by Prep-HPLC (Column: Phenomenex C18 80*30mm*5um, Mobile Phase: water (ΝΗ3·Η2Ο +NH4HCO3)-ACN, Mobile Phase B:acetonitrile Flow rate: 25 mL / min, gradient condition from 50% B to 80%) and lyophilized to give title compound.

[00214] LC-MS (ESI+): m / z 394.3 (M+H)+.1H NMR (400MHz, methanol^) δ = 8.59 (s, 1H), 8.17 (d, J= 8.0 Hz, 1H), 7.33 - 7.25 (m, 1H), 7.24 (s, 1H), 4.68 - 4.61 (m, 2H), 4.38 - 4.26 (m, 1H), 4.18-4.10 (m, 1H), 4.02 - 3.92 (m, 2H), 3.70 - 3.60 (m, 1H), 2.56 - 2.35 (m, 2H), 1.28 (d, J= 6.4 Hz, 3H).

[00215] Example 4. Synthesis of Compound 4.

[00216] Scheme 4.

[00217] Step 1: (3R,5R)-N-(2-(7-chloro-4-(2-methoxy-4-(tnfluoromethyl)phenyl)-lH-pyrazolo[3,4- d]pyridazine-l-yl)ethyl)-5-fluoro-l-methylpiperidin-3-amine

[00218] To amixture of intermediate 2-5 (450.0 mg, 1.21 mmol), (3A,5A)-5-fluoro-l-methylpiperidin- 3-amine hydrochloride (245.6 mg, 1.46 mmol) in MeOH (5.0 mL) was added TEA (0.20 mL, 1.46mmol) at 25 and the mixture was stirred for 5 minutes. Then, HOAc (90.0 pL, 1.58 mmol) was added and the resulting mixture was stirred at 25 ft? for 1 hour. To the reaction mixture wasadded NaBH iCN (152.5 mg, 2.43 mmol) and the resulting mixture was stirred at 25 ft? for 12 hours. The mixture was quenched with H2O (10 mL) at 0 ft? and the organic volatiles were removed in vacuo to give a residue. The residue was adjusted to pH = 1 with HC1 aqueous solution (1 M) and extracted with ethyl acetate (20 -66- WO 2024 / 240153 PCT / CN2024 / 094491 mL x 3). The aqueous phase was adjusted to pH = 8 with NaOH aqueous solution and then extracted with ethyl acetate (20 mL x 3). The combined organic extracts were dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give the title compound (280.0 mg, 82.32% purity, 39.1% yield) as a colorless oil. LC-MS (ESI+): m / z: 487.3 (M+H)+.

[00219] Step 2: (3R,5R)-5-(5-fluoro-l-methylpiperidin-3-yl)-8-(2-methoxy-4- (trifluoromethyl)phenyl)-4,5-dihydro-3H-2,2a,5,6,7-pentaazaacenaphthylene

[00220] To a mixture of (3R,5R)-jV-(2-(7-chloro-4-(2-methoxy-4-(trifluorometiiyl)phenyl)-lH-pyrazolo[3,4-< / ]pyridazin-l-yl)ethyl)-5-fluoro-l-methylpiperidin-3-amine (220.0 mg, 0.45 mmol), t- BuONa (65.1 mg, 0.68 mmol) in THF (5.0 mL) was added Pd-PEPPSI-IHeptcl (44.0mg, 0.045 mmol) at 25 *32 and the resulting mixture was stirred at 80 *32 for 12 hours under N2. After cooling to room temperature, the mixture was adjusted to pH = 1 with HC1 aqueous solution (IM) and extracted with ethyl acetate (20 mL x 3). The aqueous phase was adjusted to pH = 8 with NaOH aqueous solution and then extracted with ethyl acetate (20 mL x 3). The combined organic extracts were dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give the title compound (200.0 mg, 67.3% purity, 66.4% yield) as a yellow solid. LC-MS (ESI+): m / z: 451.3 (M+H)+.

[00221] Step 3: (3R,5R)-2-(5-(5-fluoro-l-methylpiperidin-3-yl)-4,5-dihydro-3H-2,2a,5,6,7- pentaazaacenaphthylen-8-yl)-5-(trifluoromethyl)phenol

[00222] To a solution of(37?,5R)-5-(5-fluoro-l-methylpiperidin-3-yl)-8-(2-methoxy-4- (trifluoromethyl)phenyl)-4,5-dihydro-3 / / -2,2a,5,6,7-pentaazaacenaphthylene (90.0 mg, 0.20 mmol) in DCM (1.0 mL) was added BBr3 (57.8 pL, 0.60 mmol) at 0 and the resulting mixture was stirred at 25 *32 for 1 hour. The reaction mixture was quenched with MeOH (1.0 mL) and the volatiles were removed in vacuo to afford a crude. The crude was purified by Prep-HPLC (Column: Phenomenex Cl8 150><30mm, Mobile Phase: \vatcr (NH^HLO+NILHCOq-ACN, Mobile Phase B: acetonitrile Flow rate: 25 mL / min, gradient condition from 48% B to 78%) and lyophilized to give the title compound.

[00223] LC-MS (ESI+): m / z: 437.1 (M+H)+. ΉNMR(400 MHz, methanol-ώ) δ = 8.63 (s, 1H), 8.26 (d, .7= 8.0 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.23 (s, 1H), 5.15 - 4.97 (m, 2H), 4.62 - 4.57 (m, 2H), 4.15 - 3.93 (m, 2H), 3.17 - 3.05 (m, 2H), 2.59 - 2.50 (m, 1H), 2.45 - 2.32 (m, 4H), 2.30 - 2.15 (m, 2H).

[00224] Synthesis of intermediate 16-4, which was used in the synthesis ofcompound 16 16-1 16-2 16-3 16-4

[00225] To a solution of benzyl alcohol (8.80 g, 81.38 mmol) in HCl / dioxane (120 mL, 4M) was added compound 16-1 (15.00 g, 65.09 mmol) dropwise at 0 °C. Then, the mixture was stirred at 80 °C for 6 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0-10% ethyl acetate in petroleum ether to give intermediate 16-2 (7.30 g, 63.6% yield) as yellow oil. 1H NMR (400 MHz, -67- WO 2024 / 240153 PCT / CN2024 / 094491 CDCI3) δ = 7.40 - 7.30 (m, 5 Η), 4.77 - 4.58 (m, 3 Η), 2.81 - 2.68 (m, 2 Η), 2.35 - 2.26 (m, 1 Η), 1.98 - 1.90 (m, 1 Η).

[00226] To a solution of intermediate 16-2 (7.30 g, 41.43 mmol) in DCE (15 mL) were slowly added (7?)-l-phenylethan-l-amine (6.50 g, 53.64 mmol) and HOAc (2.4 mL, 41.43 mmol). The reaction was stirred at room temperature for 16 h. Then, to the mixture was added NaBEL (1.57 g, 41.43 mmol) at 0 %' andstirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NaHCCh solution (50 mL) and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0~4% ethyl acetate in petroleum ether to give a crude and the crude was re-purified by flash chromatography on C18 column to give the intermediate 16-3 (2.00 g, 17.2% yield) as yellow oil. LC-MS (ESI+): m / z 282.2 (M+H) +.

[00227] To a solution of intermediate 16-3 (700.0 mg, 2.49 mmol) in isopropyl alcohol (8 mL) was added Pd / C (238.0 mg, 10wt%). The mixture was stirred at 60 °C for 16 h under H2 (latm). The mixture was filtered through a Celite pad and the filtrate was concentrated under reduced pressure to give intermediate 16-4 (200.0 mg, crude) as colorless oil, which was useddirectly for synthesis of Compound 16. LC-MS (ESI+): m / z 88.3 (M+H) +.

[00228] Synthesis of intermediate 18-6, which was used in the synthesis of compound 18 18'4 18-5

[00229] To a mixture of intermediate 18-1 (10.1 g, 76.40 mmol) and KOH (5.1 g, 91.68 mmol) in H2O (100 mL) was added a solution of KMnO4 (36.2 g, 229.20 mmol) in H2O (200 mL) dropwise at 0 °C. The mixture was stirred at rt for 16 h. The resulting precipitate was filtered and washed with water (50 mL). The filtrate was concentrated under reduced pressure to give intermediate 18-2 (10.1 g, 71.7% yield) as white solid, which was used directly for the next step. Ή NMR (400 MHz, D2O) δ= 4.52 - 4.41 (m, 1 H), 4.31 - 4.19 (m, 1 H), 3.91 - 3.84 (m, 1 H), 1.38 (s, 3 H), 1.33 (s, 3 H).

[00230] To a mixture of intermediate 18-2 (10.1 g, 54.82 mmol) in DCM (100 mL) was added N,O- dimethylhydroxylamine hydrochloride (13.5 g, 138.26 mmol), DCC (28.5 g, 138.26 mmol) and TEA (28.0 g, 276.52 mmol) at 0 °C. The resulting mixture wasstirred at rt for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (from 0% to 30 %) in petroleum ether to give intermediate 18-3 (3.0 g, 28.9% yield) as colorless oil. ’H NMR (400 MHz, CDCL) δ= 4.96 - 4.84 -68- WO 2024 / 240153 PCT / CN2024 / 094491 (m, 1 H), 4.32 - 4.24 (m, 1 H), 4.11 - 4.02 (m, 1 H), 3.72 (s, 3 H), 3.22 (s, 3 Η), 1.50 (s, 3 Η), 1.44 (s, 3 H).

[00231] To a solution of 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 N2. The resulting mixture was stirred at 0 °C for 1 h. The mixture was quenched with saturated NH4CI aqueous solution (20 mL) and extracted with Et2O (50 mL x 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and the filtrate was concentrated underreduced pressure to give intermediate 18-4 (2.0 g, crude) as colorless oil, which was used for next step directly.

[00232] To a solution of intermediate 18-4 (2.0 g, crude) in DCM (30 mL) was added benzylamine (1.6 g, 15.12 mmol) and AcOH (908 mg, 15.12 mmol) at 0 °C. After stirred at 0 °C for 30 min, to the mixture was added Sodium Triacetoxyborohydride (4.1 g, 19.24 mmol) and the resulting mixture was stirred at rt for 16 h. The mixture was quenched with saturated NaHCOs aqueous (100 mL) and extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (from 0% to 20%) in petroleum ether to give racemic stereoismoer 1 of intermediate 18-5 (2.5 g, crude, used for Compound 19) as light yellow oil and racemic stereoismoer 2 of intermediate 18-5 (550 mg, 17.0% yield over 2steps, used for Compound 18) as light yellow oil which were used directly for the next step, respectively. 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)+. 5—? Pd / C, Pd(OH)? 5 BnHN 0 h2 h2N 0 18-5 18-6 Racemic Stereoisomer 2

[00233] To a solution of racemic stereoismoer 2 of intermediate 18-5 (520 mg, 2.21 mmol) in isopropyl alcohol (10 mL) and 36 wt% Hydrochloric Acid (0.2 mL) were added Pd(OH)2 (100 mg) and 10wt% Pd / C (100 mg). The mixture was stirred at rt for 5 h under atmosphere of H2 balloon. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give intermediate 18-6 (300 mg, 93.5 % yield) as white solid, which was used directly for Compound 18. LC-MS (ESI+): m / z 146.2 (M+H) +.

[00234] Synthesis of Compound 12

[00235] The synthetic route for intermediate 12-1 was similar to that for intermediate 1-8 by replacing (7?)- / er / -butyl3-aminopiperidine-l-carboxylate with (4-methoxyphenyl)methanamine. -69- WO 2024 / 240153 PCT / CN2024 / 094491

[00236] To a solution of intermediate 12-1 (120.0 mg, 0.26 mmol) in DCM (3.0 mL) was added TFA (3.0 mL, 39.18 mmol) at 30 *32 and the resulting mixture was stirred at 80 *32 for 4 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to afford intermediate 12-2 (140.0 mg, crude) as brown solid. LC-MS (ESI+): m / z: 350.1 (M+H)+.

[00237] To a mixture of intermediate 12-2 (140.0 mg, crude) and DCM (5.0 mL) was added BBn (0.12 mL, 1.20 mmol) at -40 °C and the reaction mixture was stirred at 20 °C for 1 h. The mixture was quenched by adding MeOH (10.0 mL) and the mixture was concentrated to afford a residue. To the residue was added MeOH. The mixture was adjusted to pH = 9 with ΝΗ3·Η2Ο (0.3 mL) and purified by Prep-HPLC (Column: Welch Xtimate Cl 8 150*25mm*5pm, Mobile Phase: water (NH4HCO3)-ACN, Flow rate:25 mL / min, gradient condition from 45% B to 75%)and Prep-HPLC (Column: Cl 8 150><30mm, Mobile Phase: water (FA)-ACN, Flow rate: 30 mL / min, gradient condition from 20% B to 50%) in sequence to give compound 12. LC-MS (ESI+): m / z: 336.1 (M+H)+. Ή NMR (400 MHz, DMSO-ί / δ) δ = 14.84 (br.s, 1H), 8.80 (s, 1H), 8.36 - 8.23 (m, 2H), 7.31 - 7.23 (m, 2H), 4.72 - 4.59 (m, 2H), 3.65 - 3.56 (m, 2H), 2.35 - 2.25 (m, 2H).

[00238] 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 BBr3. Compound No. Analytical data 7 LC-MS (ES1+): m / z 394.2 (M+H)+. Ή NMR (400 MHz, CD3OD) δ - 8.5 8 (s, 1H), 8.15 (d, J - 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H),7.22 (s, 1H), 5.49 - 5.35 (m, 1H), 4.71 - 4.54 (m, 2H), 3.88 - 3.66 (m, 4H), 2.53 - 2.31 (m, 2H), 1.33 (d, J= 6.8 Hz, 3H). 8 LC-MS (ESI+): m / z 408.2 (M+H)+. Ή NMR (400 MHz,CD3OD) δ = 8.5 8 (s, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.2 8 (d, J = 8.0Hz,lH),7.24(s, 1H),4.75 - 4.57 (m, 2H), 4.05 - 3.96 (m, 1H), 3.93 - 3.85 (m,2H),3.79-3.71 (m, 1H),3.62-3.46 (m,2H),2.53 -2.38 (m, 2H), 2.34 - 2.22 (m, 1H), 1.07 (d, J= 6.8 Hz, 3H). 9 LC-MS (ESI+): m / z 394.1 (M+H)+. Ή NMR (400 MHz, CD3OD) δ = 8.61 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.29 (d, J -8.0Hz, lH),7.24(s, 1H),4.75 -4.61 (m, 2H), 4.36 -4.28 (m, 1H), 4.24 - 4.13 (m, 1H),4.O4-3.92 (m,2H),3.74 -3.62 (m, 1H),2.54-2.38 (m, 2H), 1.28 (d, J= 6.4 Hz,3H). 10 LC-MS (ESI+): m / z 379.9 (M+H)+. Ή NMR (400 MHz, CD3OD) δ = 8.60 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.24 (s. 1H),4.69 -4.62 (m,2H),4.11 -4.04 (m, 2H), 3.99 - 3.90 (m,4H), 2.50-2.41 (m, 2H). 11 LC-MS (ESI+): m / z 420.1 (M+H)+. Ή NMR (400 MHz,DMSO-( / >)0= 14.64 (br.s, 1H), 8.76 (s, 1H), 8.26 (d, J= 8.0 Hz, 1H),7.31 -7.21 (m,2H),5.93 -5.80 (m, 1H),4.70 - 4.63 (m, 1H), 4.62 - 4.50 -70- WO 2024 / 240153 PCT / CN2024 / 094491 (m,2H),4.34-4.26 (m,1H),3.69-3.55 (m,2H),2.37 - 2.26 (m,2H),2.15 - 1.94 (m, 2H), 1.91 -1.77 (m, 2H), 1.73 - 1.53 (m, 2H). 13 LC-MS (EST +): m / z 420.1 (M+H)+. Ή NMR (400 MHz, DMSO- / ,) δ = 14.63 (br.s, 1H), 8.78 (s, 1 H), 8.28 (d, J= 8.0 Hz, 1 H), 7.32 - 7.27 (m, 2 H), 5.42 - 5.30 (m, 1 H), 4.93 - 4.80 (m, 1 H), 4.74 - 4.68 (m. 1 H),4.59 -4.52 (m, 1 H),4.27 -4.21 (m, 1 H),3.80 - 3.74 (m, 1 H), 3.62 -3.56 (m, 1 H), 2.38 -2.32 (m,2H),2.02 - 1.89 (m,2 H), 1.78 - 1.70 (m,2H), 1.64 - 1.55 (m, 2 H). 14 LC-MS(ESI+): m / z 410.1 (M+H)+. Ή NMR: (400 MHz, DMSO- / 6) δ = 14.53 (br.s, 1 H), 8.76 (s, 1 H), 8.26 (d, J= 8.0Hz, 1 H), 7.35 - 7.26 (m, 2 H), 4.92 (d, / =5.2 Hz, 1 H),4.73 -4.50(m,3H), 4.15-4.11 (m,l H),4.01 -3.99 (m, 1 H), 3.98 - 3.88 (m, 2 H), 3.77 - 3.68 (m, 1 H), 3.48 - 3.37 (m, 2 H), 2.39 - 2.33 (m, 2 H). 15 LC-MS(ESI+): m / z 434.1 (M+H)+. Ή NMR: (400 MHz, DMSO-A) δ = 14.06 (br.s, 1 H), 8.73 (s, 1 H), 8.24 (d, J = 7.6Hz, 1 H), 7.35 - 7.28 (m,2H),5.31 -5.23 (m,2H),4.69 -4.58 (m,2 H), 3.83 - 3.77 (m, 1 H),3.65-3.59 (m, 1 H),2.42-2.38 (m, 1 H),2.78 - 2.21 (m, 1 H),2.13 -2.10 (m, 1 H), 1.96 -1.91 (m, 1 H), 1.81 -1.78 (m, 3 H), 1.71 -1.66 (m, 1 H), 1.16 (s, 3 H). 16 LC-MS(ES1+): m / z 406.0 (M+H)+. Ή NMR (400 MHz, DMSO- / ) 8= 8.75 (s,l H),8.25-8.16(m, 1 H),7.35 -7.25 (m, 2 H), 5.05 -4.90 (m, 2 H),4.70 -4.55 (m, 3 H), 3.96 -3.80 (m,2 H), 2.75 - 2.65 (m.lH),2.45-2.41 (m,lH),2.34-2.26 (m,2 H),2.12-2.08 (m, 1 H), 1.71 -1.59(m, 1H). 18 LC-MS(ESI+): m / z 424.0 (M+H)+. Ή NMR(400 MHz,CD3OD)6 = 8.50 (s, 1 H), 7.96 (d, / = 8.0Hz, 1 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.30 (s. 1 H), 5.29 -5.14 (m, 1 H),4.73 -4.68 (m,2 H), 4.02 - 3.88 (m, 3 H), 3.73 - 3.62 (m, 2 H), 2.54 - 2.43 (m, 2 H), 1.45 (d, / =6.8 Hz, 3 H). 19 LC-MS(ESI+): m / z 424.0 (M+H)+. Ή NMR(400 MHz,CD3OD)δ = 8.56 (s, 1 H), 8.14 -8.08 (m, 1 H), 7.38 -7.26 (m, 2 H), 5.22-5.11 (m, 1 H),4.76-4.61 (m, 2 H), 3.96 - 3.84 (m, 3 H), 3.64 - 3.57 (m,2 H),2.51 -2.41 (m,2H), 1.45 (d, / =6.4 Hz, 3 H). The compounds below were prepared using a synthesis method similar tothat 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 for last step under the condition of BBr3. Compound No. Analytical data 5 LC-MS (ESI+): m / z 431.1 (M+H)+. Ή NMR (400 MHz, CD3OD) δ = 8.63 (s, 1H), 7.9 8 (d, / = 8.0 Hz, 1H), 7.45 (d, / = 8.4Hz, 1H),7.41 (s, 1H),4.84-4.74 (m, 3H), 4.46 - 4.33 (m, 1H), 4.22 - 4.11 (m, 1H),4.1O-3.99 (m, 1H),3.89 - 3.75 (m, 1H),3.71 -3.56(m, 1H), 3.53 - 3.38 (m, 3H),2.80-2.67 (m,lH),2.39-2.25 (m, 1H), 2.24 - 2.16 (m, 2H), 2.15 - 2.02 (m, 1H). 6 LC-MS (ESI+): m / z 380.1 (M+H)+. -71- WO 2024 / 240153 PCT / CN2024 / 094491 Ή NMR (400 MHz,CD3OD)8= 8.65 (s, 1H), 8.28 (d,7= 8.0 Hz, 1H), 7.29 (d, J= 8.4Hz, 1H),7.24(s,lH),4.68-4.54 (m,2H), 4.33 -4.23 (m, 1H), 4.22 - 4.06 (m, 2H), 3.94 - 3.86 (m, 1H), 3.67 - 3.57 (m, 1H), 1.30 (d, J= 6.4 Hz, 3H).

[00239] Synthesis of Compound 17 thiophosgene ν2η4·η2ο h2n SON 17-1 17-2

[00240] To a mixture of CaCO3(7.49 g, 74.91 mmol) in DCM (30 mL) and water (15 mL) were added compound 17-1 (5.00 g, 24.97 mmol) and thiophosgene (4.31 g, 37.48 mmol) slowly at 0 °C under Ar. The reaction was stirred at room temperature for 1 h. To the reaction mixture was added water (30 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (80 mL), dried over NaaSCh, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0~10% ethyl acetate in petroleum ether to give intermediate 17-2 (5.50 g, 90.9% yield) as colorless oil. LC-MS(ESI+): m / z 143.1 (M+H-100)+.

[00241] To a solution of intermediate 17-2 (5.50 g, 22.71 mmol) in MeOH (20 mL) was added 85% hydrazine hydrate (3.91 mL, 68.34 mmol) under Ar. The mixture was stirred at room temperature for 1 h. To the reaction mixture was added water (50 mL) and the mixture was extracted with DCM (50 mL x 2). Thecombined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give intermediate 17-3 (5.90 g, 94.7% yield) as white solid. LC-MS(ESI+): m / z 219.1 (M+H-56)+.

[00242] To a mixture of intermediate 17-3 (5.10 g, 18.59 mmol) in ACN (50 mL) was added CH J (2.33 mL, 37.18 mmol) at 0 °C under N2. The mixture was stirred at room temperature for 2 h. To the reaction mixture was added NaHCO3 (50 mL) solution and extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give intermediate 17-4 (5.30 g, 98.9% yield) as yellow oil, which was used for next step directly. LC-MS(ESI+): m / z 289.1 (M+H)+. OBn KCN EtOH HN ’HCI OBn NH3 z0Bn Br^ / H2N 17-5 17-6 17-7 17-8

[00243] To a solution of intermediate 17-5 (20.00 g, 87.30 mmol) in ethylene glycol (200 mL) wasadded KCN (6.82 g, 104.76 mmol). The reaction was stirred at 100 °C for 3 h. To the cooled reaction mixture was added water (200 mL) and the mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by -72- WO 2024 / 240153 PCT / CN2024 / 094491 column chromatography on silica gel eluted with 0-16% ethyl acetate in petroleum ether to give intermediate 17-6 (13.60 g, 88.9% yield) as yellow oil. LC-MS(ESI+): m / z 176.1 (M+H)+.

[00244] To the solution of intermediate 17-6 (4.00 g, 22.83 mmol) in EtOH (15 mL) was bubbled HC1 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. LC-MS(ESI+): m / z 222.2 (M+H-HC1)+.

[00245] A solution of intermediate 17-7 (5.05 g, 19.59 mmol) inNHs / MeOH (15 mL, 2M) was stirred at room temperature for 1.5 h. The mixture was concentrated to give intermediate 17-8 (4.00 g, crude). LC-MS(ESI+): m / z 193.1 (M+H)+. χ HN OBn OH OH N— θ- / ¾ / DMF-DMA 12 / / Se / 1 H2N 17-8 f3c— / yy ---- - F3cy yy --- * F3cy yy -------- - \= / xo \= / y \= / o 17-9 17.10 17-11

[00246] To a solution of intermediate 17-9 (2.30 g, 11.27 mmol) in DMF (30 mL) was added DMF- DMA (1.61 g, 13.52 mmol). The resulting mixture was stirred at 75 RS for 4 h. To the cooled reaction mixture was added water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0-20% ethyl acetate in petroleum ether to give intermediate 17-10 (2.39 g, 81.8% yield). LC-MS (ESI+): m / z 260.0 (M+H)+.

[00247] To a solution of intermediate 17-10 (2.10 g,8.10 mmol) in CHCL (35 mL) were added iodine (4.11 g, 16.20 mmol) and pyridine (705.0 mg, 8.91 mmol) at room temperature. The mixture was stirred -73- WO 2024 / 240153 PCT / CN2024 / 094491 at room temperature for 16 h. To the reaction mixture was quenched with saturated Na2S2O3 solution (40 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0~8% ethyl acetate in petroleum ether to give intermediate 17-11 (2.50 g, 90.7% yield). Ή NMR (400 MHz, CDCI3) δ = 8.32 - 8.28 (m, 2 H), 7.71 (s, 1H), 7.63 - 7.61 (m, 1 H).

[00248] To a solution of intermediate 17-11 (2.00 g, 5.88 mmol) in ACN (15 mL) were added intermediate 17-8 (5.66 g, 29.41 mmol) andK2CO3 (2.44 g, 17.65 mmol). The mixture was stirred at 80 °C for 1 h. To the cooled reaction mixture was addedwater (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0~50% ethyl acetate in petroleum ether to give intermediate 17-12 (1.40 g, 58.8% yield) as yellow oil. LC-MS(ESI+): m / z 405.2 (M+H)+.

[00249] To a solution of 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)+.

[00250] The solution of intermediate 17-13 (810.0 mg, 1.29 mmol) in DCM / TFA (1 mL / 5 mL) was stirred at 80 °C for 16 h. The mixture was concentrated to give intermediate 17-14 (600.0 mg, 87.6% yield) as yellow oil, which was used for next step directly. LC-MS(ESI+): m / z 533.1 (M+H)+.

[00251] To a solution of intermediate 17-14 (680.0 mg, 1.28 mmol) in MeOH / H2O (5 mL / 5 mL) was added K2CO3 (883.0 mg, 6.39 mmol). The reaction was stirred at room temperature for 2 h. To the reaction mixture was added water (10 mL) and the mixture was extracted with DCM / MeOH (10:1) (30 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give intermediate 17-15 (500.0 mg, 89.8% yield) as yellow solid, which was used for next step directly. LC-MS(ESI+): m / z 437.2 (M+H)+.

[00252] To a solution of intermediate 17-15 (558 mg, 1.28 mmol) in DCM / MeOH (5 mL / 0.5 mL) was addedformaldehyde (0.29 mL, 3.84 mmol) and one drop AcOH. After stirred at 0 °C for 30 min, NaBH(OAc)3 (813.8 mg, 3.84 mmol) was added. The reaction was stirred at room temperature for another 30 min. To the reaction mixture was added water (10 mL) and the mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered through a celite pad and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with 0-30% MeOH in DCM to give intermediate 17-16 (300.0 mg, 52.3% yield). LC-MS(ESI+): m / z 451.2 (M+H)+. -74- WO 2024 / 240153 PCT / CN2024 / 094491

[00253] To a solution of intermediate 17-16 (100.0 mg, 0.22 mmol) in THF (0.5 mL) was added CMBP (80.0 mg, 0.33 mmol). The mixture was stirred at 80 °C for 40 h. The mixture was concentrated to give the residue, which was purified by Prep-HPLC [Column: SunFire Prep C18 OBD 10pm 19*250 mm Column; Mobile Phase:(0.1% FA in water - ACN); B%: 5%-32%, 11 min] to give compound 17. LC- MS(ESI+): m / z433.2(M+H)+. ‘HNMR: (400MHz, CD3OD) δ = 8.05 (d, J= 8.4 Hz, 1 H), 7.89 (s, 1 H), 7.29 (d, J= 8.0 Hz, 1 H), 7.25 (s, 1 H), 4.66 - 4.61 (m, 1 H), 3.76 - 3.70 (m. 2 H), 3.66 - 3.61 (m, 1 H), 3.52 - 3.45 (m, 2 H), 3.43 - 3.35 (m, 1 H), 3.00 (t, J= 11.6 Hz, 1 H), 2.81(s, 3 H), 2.79 - 2.73 (m, 1 H), 2.21 - 2.16 (m, 3 H), 2.10 - 2.08 (m, 1 H), 1.98 - 1.87 (m, 2 H).

[00254] Synthesis of Compound 101 OH 101-2101-1 101-5 101-6 101-7 Compound 101

[00255] To a solution of compound 101-1 (500 mg, 2.30 mmol) in dioxane (10 mL) were added Pd(OAc)2 (52 mg, 0.23 mmol), 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.5 g, 11.50 mmol), dicyclohexyl(2-phenylphenyl)phosphane (81 mg, 0.23 mmol) and TEA (1.6 mL, 11.50 mmol). The mixture was stirred at 100 °C for 16 h under N2. To the cooled reaction mixture was added water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (50 mL),dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel eluted with ethyl acetate (from 0% to 5%) in petroleum ether to give intermediate 101-2 (200 mg, 32.9% yield) as yellow oil. LC-MS(ESI+): m / z 265.1 (M+H)+.

[00256] To a solution of intermediate 101-3 (700.0 mg, 2.53 mmol) in dioxane (10.0 mL) was added intermediate 17-1 (657.8 mg, 3.28 mmol) at 25 RD and the resulting mixture was stirred at 100 RD for 12 h. After cooling to room temperature, 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)+.

[00257] To a solution of intermediate 101-4 (260.0 mg, 0.65 mmol) in N, TV-dimethylmethanamide (10.0 mL) were added1,2-dibromoethane (0.17 mL, 1.96mmol) and Cs2CO3 (1066.1 mg, 3.27 mmol) at -75- WO 2024 / 240153 PCT / CN2024 / 094491 25 °C and the resulting mixture was stirred at 80 °C for 1.5 h. After cooling to room temperature, to the mixture was added H?O (10 mL) and the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic extracts were dried over Na?SO4, filtered and the filtrate was concentrated under reduced pressure to afford a crude. The crude was purified by flash column chromatography on silica gel eluted with 0-100% ethyl acetate in petroleum ether to give a crude product, which was purified by prep- SFC (Column: DAICEL CHIRALCEL OJ (250mm*30mm, lOpm), Condition: CO2-EtOH (0.1%ΝΗ3Η?Ο), Begin B: 35%, FlowRate: 80 ml / min) to afford intermediate 101-5 (30.0 mg, 10.9% yield) as white solid. LC-MS (ESI+): m / z: 423.1 (M+H)+. Ή NMR (400 MHz, DMSO-tie) δ = 7.87 (s, 1H), 4.27-4.19 (m, 2H),4.17 - 4.08 (m,2H), 4.05 -3.95 (m, 1H), 3.87 - 3.77 (m, 1H), 3.71 -3.61 (m, 1H), 3.15-3.03(m, 1H), 2.84 - 2.71 (m, 1H), 2.02 - 1.84 (m, 2H), 1.75 (m, 1H), 1.53 - 1.44 (m, 1H), 1.41 (s, 9H).

[00258] A mixture of intermediate 101-5 (130 mg, 0.31 mmol), intermediate 101-2 (122 mg, 0.47 mmol), RuPhos Pd G3 (26 mg, 0.03 mmol) and K?CO3 (127 mg, 0.93 mmol) in H2O / dioxane (0.3 mL / 3 mL) was stirred at 100 °C for 16 h under N2. To the cooled reaction mixture was added water (20 mL) and the mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by Prep-TLC (EA:DCM=1:1) to give intermediate 101-6 (82 mg, 55.0% yield) as yellow oil. LC-MS(ESI+): m / z 481.2 (M+H)+

[00259] The solution of intermediate 101-6 (62 mg, 0.13 mmol) and TFA (0.5 mL) in DCM (2 mL) was stirred at rt for 50 min. The mixture was concentrated to give intermediate 101-7 (49 mg, crude) as yellow oil, which was used for next step without furtherpurification. LC-MS(ESI+): m / z 381.2 (M+H)+

[00260] To a solution of intermediate 101-7 (49 mg, crude) in MeOH (1 mL) were added formaldehyde (103 mg, 1.30 mmol, 37.0~40.0% in water) and AcOH (8 mg, 0.13 mmol). After stirred at rt for 30 min, to the mixture was added sodium cyanoborohydride (16 mg, 0.26 mmol). The mixture was stirred at rt for 1.5 h. The mixture was concentrated under reduced pressure to give a residue, which was diluted with water (10 mL). The pH of mixture was adjusted to 7-8 by saturated sodium bicarbonate solution. The mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na?SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by Prep-HPLC (Column: Cl 8 OBD 10pm 19*250 mm; Mobile Phase: [0.1% FA in water - ACN]; B%: 5% - 10%, 8.42 min) to give Compound 101. LC-MS(ESI+): m / z 395.2 (M+H)+. Ή NMR (400 MHz, DMSO-ti6) δ= 9.27 (br.s, 1 H), 7.64 (s, 1 H),6.37 - 6.31 (m, 2 H), 4.32 - 4.21 (m, 2 H), 4.13 -4.03 (m,2 H), 3.86 - 3.79 (m, 1 H), 3.72 (s, 3 H), 2.98 - 2.91 (m, 1 H), 2.74 - 2.64 (m, 1 H), 2.23 (s, 3 H), 2.22 - 2.16 (m, 1 H), 2.01 (s, 3 H), 1.94 - 1.88 (m, 2 H), 1.74 - 1.54 (m, 3 H).

[00261] The compounds below were prepared using a synthesis method similar to that described in Compound 101 by substituting the appropriate starting materials, reagents and reaction conditions. Compound No. Analytical data 102 LC-MS (ESI+): m / z 390.2 (M+H)+. -76- WO 2024 / 240153 PCT / CN2024 / 094491 H NMR (400 MHz, DMSO-ti6) δ= 10.04 (br.s, 1 H), 7.69 (s, 1 H), 7.22 (s, 1 H), 7.11 (s, 1 H), 4.29 - 4.23 (m, 2 H), 4.20 - 4.08 (m, 2 H), 3.86 - 3.76 (m, 1 H), 2.98 - 2.91 (m, 1 H), 2.75 - 2.67 (m, 1 H), 2.23 (s, 3 H), 2.21 - 2.16 (m, 1 H), 2.06 (s, 3 H), 1.95 - 1.86 (m, 2 H), 1.77 - 1.55 (m, 3 H). 103 LC-MS (ESI+): m / z: 433.2 (M+H)+. Ή NMR (400 MHz, DMSO-ti6) δ = 9.85 (br.s, 1H), 8.16 (0.67H from HCOOH), 7.71 (s, 1H), 7.10 (s, 1H), 7.06 (s, 1H), 4.28 - 4.23(m, 2H),4.14 - 4.08 (m, 2H), 3.89 - 3.84 (m, 1H), 3.09-3.01 (m, 1H), 2.86 - 2.78 (m, 1H), 2.48-2.41 (m, 1H), 2.34 (s, 3H), 2.19 - 2.05 (m, 4H), 1.96 - 1.85 (m, 1H), 1.84 - 1.68 (m, 2H), 1.68 -1.55 (m, 1H).

[00262] Example B-l: NLRP3 inflammasome assay

[00263] Reagent and Material Reagent Name Article Number IX Assay Buffer 250 mol / L HEPES (pH7.4), Sigma-H3375 lOmmol / LKCl, Sigma-P9333 5mmol / L MgCb, Sigma-449172 Wash buffer Same as assay buffer, store at 4°C NLRP3 cell lysate Prepared by WuXi [3H]-MCC950 Pharmaron-TRQ42137 MCC950 TOCRIS-5479 Assay / source plate 96-well plate (Corning-3631) GF / B Plate PerkinElmer-600517 DMSO Sigma-472301 Microscint-20 PerkinElmer-6013621

[00264] Assay Procedure

[00265] 1) Compound dilutions for IC50S test: Starting at 100 μΜ, 3 fold dilutions were conducted. Next 11 doses were dispensed at 1% DMSO concentration. 9 |uL of compound (lOmM stock from compound management team) as added to 384LDV plate. Echo was used for the dilution and transfer the compoundsto assay the plate at 100 μΜ (top concentration at 1% DMSO, 1.25 μΕ).

[00266] 2) Radioligand dilution: working concentration was 25nM [3H]-MCC950. 1 μΕ [3H]-MCC950 (23 μΜ stock) was added to 919 μΕ assay buffer.

[00267] 3) Prepare and transfer 100 μΐ of insect cell lysate to a 96-well assay plate. Final concentration: 15 μg / well for IC50 test.

[00268] 4) Transfer 25 (iL of diluted ligand to the assay plate.

[00269] 5) Cover assay plates with foil tape and incubate 1.5 hour, at room temperature with gentle shaking.

[00270] 6) Using the Packard Harvester, filter the wells of the assay plate through the wells of the GF / B filter plates. Wash 8 times with cold washing buffer (4 ft?, 0.4 mL per well per wash). -77- WO 2024 / 240153 PCT / CN2024 / 094491

[00271] 7) Place the filter plates in an oven for 0.5 hours at 50 %.

[00272] 8) Seal the bottom of the dry filter plates with backing tape. Dispense 50 pL Microscint-20 to each well of the filter plate and cover GF / B plate with TopSeal-A.

[00273] 9) Microbeta was used to count the signal.

[00274] 10) Microbeta Setting: Count Time was 30 seconds per well.

[00275] Example B-2: NLRP3 inflammasome Activation Assay on human monocytes

[00276] Day 1: Isolate human monocytes from PBMC Isolate monocytes from PBMC using human pan monocytes isolation kit and a LS Column. Resuspend monocytes in RPMI 1640 medium and count cells, then seed monocytes in 96-well plates and incubate at 37%, 5% CO2 overnight. Day 2: Stimulate cells with LPS & ATP 1. Remove culture medium and pre-treat monocytes by adding different concentrations of compounds or DMSO as a control to corresponding wells and incubate at 37%, 5% CO2. Compounds and DMSO are diluted using serum free RPMI 1640 medium. 2. Add serum-free RPMI 1640 medium containing LPS to all wells, then incubate cells for some time at 37%, 5% CO2. 3. At the end of incubation, the cells were stimulated with ATP for some time except the cells in negative control wells. Transfer the supernatants to newplates and store at -80%. Day 3: Run ELISA Run Elisa according to the procedures from BD Biosciences.

[00277] Example B-3: IL-Ιβ release THP-1 assay

[00278] THP-1 cells Culture RPMI 1640 medium, 10% FBS, 1%PS, 55uM β-Mer at 37% & 5% CO2 incubator.

[00279] IL-Ιβ release detection

[00280] 1) Seed THP-1 in complete RPMI 1640 medium containing PMA into 96 well plate coated with poly-L-lysin incubate for 24 hours.

[00281] 2) Remove medium, wash the differentiated THP-1 cells with PBS, add FBS free RPMI 1640 medium.

[00282] 3) Add LPS and incubate for 3 hours at 37% & 5% CO2 incubator.

[00283] 4) Add compounds and incubate for 30 minutes at 37% & 5% CO2 incubator.

[00284] 5) Add Nigericin and incubate for 1 hour at 37% & 5% CO2 incubator.

[00285] 6) Collect supernatant to test IL-1 β by Elisa.

[00286] Data analysis

[00287] a) Assay robustness check with DMSO and Low control data:

[00288] H=Ave (DMSO)

[00289] L= Ave (Low control)

[00290] SD (H) =STDEV (DMSO)

[00291] SD (L) =STDEV (Lowcontrol) -78- WO 2024 / 240153 PCT / CN2024 / 094491

[00292] CV% (H) =100* (SD H / Ave H)

[00293] CV% (L) = 100*SD L / Ave L

[00294] Z'= 1 -3*(SD_H+ SD L) / (Ave_H - Ave_L)

[00295] change%=Sample / Ave_L* 100

[00296] b) Fit the cpd IC50 from non-linear regression equation:

[00297] Y=Bottom + (Top-Bottom) / (l + 10A((LogIC50-X)*HillSlope))

[00298] X: cpd concentration

[00299] Y: change%

[00300] Top and Bottom: Plateaus in same units as Y

[00301] logIC50: same log units as X

[00302] HillSlope: Slope factor or Hill slope

[00303] Example B-4: NLRP3 Enzymatic Activity ADP-Glo Assay

[00304] NLRP3 activity test experiment, measuring the hydrolysis of NLRP3 on the substrate ATP using the ADP-Glo assay. First, after adding an inhibitor containing 0.5% DMSO with Echo, add 5 pL of NLRP3 (ICE, YM2306T-H06MHS) enzyme solution to each well, centrifuge at 1000 rpm for 1 min at room temperature and react for 10 min. Then add 5 pL of ATP (Promega, V915A) substrate solution to each well for 90 min at room temperature;NLRP3 and ATP were prepared in 50 mM HEPES, 10 mM MgC12, 0.01% Brij-35, 1 mMEGTA, and 2 mM DTTbuffers at final concentrations of 15 nM and 1 pM, respectively. Subsequently, lOpL 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. Finally, 20uL ADP-Glo detection solution (Promega, V9102) is added to each well, centrifuged at 1000 rpm for 1 min and reacted for 45 min at room temperature. 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. TABLE 3. NLRP3 Inflammasome IC50 (nM), example B-l: 0<A<10; 10<B<100; 100<C<1000; 1000<D. THP-1 IL-Ιβ ICso (nM), example B-3: 0<A<10; 10<B<100; 100<C<1000; 1000<D. Enzymatic Activity ADP-Glo IC50 (nM), example B-4: 0<A<10; 10<B<100;100<C<1000; 1000<D. Compound No. NLRP3, ICSO (nM), Example B-l THP-1 IL-Ιβ, IC50 (nM), Example B-3 NLRP3 ADP- Glo_IC50 (nM), Example B-4 1 B B 2 B B 3 C C 4 C 5 D 6 C 7 C 8 C -79- WO 2024 / 240153 PCT / CN2024 / 094491 9 C 10 B 11 C 12 D 13 C C 14 C 15 D 16 C 17 B B 18 D 19 D 101 B B 102 B B 103 A B

[00305] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. -80- WO 2024 / 240153 PCT / CN2024 / 094491 CLAIMS WHAT IS CLAIMED IS: 1. A compound having the structure of Formula (I), or a pharmaceutically acceptable salt thereof: Formula (I), wherein, ring A is aryl, heteroaryl, cycloalkyl, orheterocycloalkyl; B is C or N: D is C or N; E is C, CRCE or N; RCE is hydrogen, -OH, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cshaloalkyl, Cj-C,hydroxyalkyl, Ci- Ceaminoalkyl, or Ci-Cqheteroalkyl; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, - S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, Ci-Csheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, - C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- Cgaminoalkyl, Cj-C„hctcroalkyL C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; ring C is phenyl, 5 to 7-membered heteroaryl, Cs-Cgcycloalkyl, or 5 to 8 membered heterocycloalkyl; each R1 is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, - S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, - S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-Gsaminoalkyl, Ci-CXheteroalkyl, C2-Cealkenyl, C2-C6alkynyl, C3-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; or two R1 on the same atom ordifferent atoms are taken together to form a C3-Cscycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more Rc; -81- WO 2024 / 240153 PCT / CN2024 / 094491 or two R1 on the same atom are taken together to form an oxo; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cealkoxy, Ci- Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, 4-6 membered heterocycloalkyl, or C3- Cecycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; or two R2 are taken together to form an oxo; or two R2 are taken together to form a Cs-Cecycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from Re; R3 is Ci-Cealkyl, Ci-Cdialoalkyl, Ci-GhydiOxyalkyl. Ci-Cealkoxy, Ci-Ceaminoalkyl, Ce-Cioaryl, 5 to 12 membered heteroaryl, C3-Ci 2cycloalkyl, or 4 to 12 membered heterocycloalkyl; each ofwhich is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NReRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-CTheteroalkyl, Ci-C6aminoalkyl, C3-C6cycloalkyl, 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 Re; each Ra is independently Ci-Cxalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Cgaminoalkyl, Ci- Cxheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl orheteroaryl is optionally substituted with 1 to 4 substituents independently selected from Re; each Rb is independently hydrogen, Ci-Cealkyl, Ci-Cihaloalkyl, Ci-Ghydroxyalkyk Ci- Cxaminoalkyl, G-GJicteroalkyk C2-G,alkcnyl, G-G>alkynyl, cycloal kyk 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 Re; Rc and Rd are each independently hydrogen, Ci-Csalkyl, Ci-Ghaloalkyl. Ci-Cf,hydroxyalkyl, Ci- Cxaminoalkyl, G-G,licteroalkyk C2-G,alkcriyl, G-G>alkynyl, cycloal kyk 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 Re; or Rc and Rd are taken together with the atom to which theyare attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - -82- WO 2024 / 240153 PCT / CN2024 / 094491 C(=O)OCH3, Ci-Cealkyl, Ci-Coalkoxy, Ci-Cohaloalkyl, Ci-Cohydroxyalkyl, Ci-Coaminoalkyl, Ci-Coheteroalkyl, or C3-Cocycloalkyl; n is 0, 1, 2, or 3; p is 0, 1,2, 3, 4, 5, or 6; q is 0, 1,2, or 3; and w is 0, 1,2, 3, or 4. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof: wherein, ring A is Ce-Cioaryl, 4-12 membered heteroaryl, CVCncycloalkyl, or 4-12 membered heterocycloalkyl; B is C or N: D is C or N; E is C, CRCE or N; RCE is hydrogen, -OH, Ci-Coalkyl, Ci-Coalkoxy, Ci-Cohaloalkyl, Ci-Cohydroxyalkyl, Ci- Coaminoalkyl, or Ci-Coheteroalkyl; ring C is phenyl, 5 to 7-membered heteroaryl, Cs-Cscycloalkyl, or 5 to 8membered heterocycloalkyl; each R1 is independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Coalkyl, Ci- Cealkoxy, Ci-Cohaloalkyl, Ci-Cohydroxyalkyl, Ci-Coaminoalkyl, or Cs-Cocycloalkyl; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Coalkyl, Ci-Coalkoxy, Ci- Cohaloalkyl, Ci-Cohydroxyalkyl, Ci-Coaminoalkyl, or Cs-Cocycloalkyl; R3 is phenyl, 5 to 12 membered heteroaryl, C3-Ci2cycloalkyl, 4 to 12 membered heterocycloalkyl, or Ci-Coalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(-O)NR4U, -SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, Ci-Coalkyl, Ci-Cohaloalkyl, Ci-Cohydroxyalkyl, Ci-Coheteroalkyl, Ci-Coaminoalkyl, Cs-Cocycloalkyl, 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 Re; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, - S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-Coalkyl, Ci-Cohaloalkyl, Ci-Cohydroxyalkyl, Ci-Coaminoalkyl, Ci-Coheteroalkyl, C2-Coalkenyl, C2-Coalkynyl, Ci-Cscycloalkyh or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; -83- WO 2024 / 240153 PCT / CN2024 / 094491 each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2,-NHCH3, -N(CH3)2, -C(=O)CH3, - C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, C1- Ceaminoalkyl, Ci-Ceheteroalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; each Ra is independently Ci-Ci alkyl, Ci-Cbhaloalkyl, Ci-Cihydroxyalkyl, C1-C0 aminoalkyl, Ci- Cbheteroalkyl, C2-Cbalkenyl, C2-C6alkynyl, 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 Re; each Rb is independently hydrogen, Ct-Cealkyl, Ci -Cehaloalkyl, Ci-G,hydiOxyalkyl, C1- Cbaminoalkyl, Ci-Csheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 4substituents independently selected from Re; Rc and Rd are each independently hydrogen, Ci-G,alkyl, G-Ghaloalkyl, G-G.hydroxyalkyl, C1- Cbaminoalkyl, Ci-G,licteroalkyI, Cx-G.alkenyI, Cx-GalkynyI, 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 Re; or Rc and Rd 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 Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Cealkyl, G-Galkoxy. G-GJialoalkyl. G-G.hydroxyalkyl, Ci-G,ami noalkyl, G-G,hctcroalkyl, or Cs-Cecycloalkyl; n is 1 or 2; p is 0, 1,2, 3,4, or 5; q is 0, 1,2, or 3; and w is 0, 1, 2, or 3. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl or 5 to 6 membered heteroaryl. 4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, pyrrole, imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or triazinyl. 5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring C is: -84- WO 2024 / 240153 PCT / CN2024 / 094491 6. 7. 8. hydrogen, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, C3- Cecycloalkyl, or 4 to 6 membered heterocycloalkyl. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring C is Cs-Cficycloalkyl or 5 to 6 membered heterocycloalkyl. The compound of any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein ring C is cyclopentyl,cyclohexyl, pyrrolidinyl, piperidinyl, or morpholinyl. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring C is: wherein, Y is CRCE or N; RCE is hydrogen, -OH, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, or Ci-Cgheteroalkyl; Z is absent, NR1’, S, O, or CR'R1; each R1 is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, - C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, - NRbS(=O)2Ra, -S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-C6aminoalkyl, Ci-Csheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, -85- WO 2024 / 240153 PCT / CN2024 / 094491 hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4substituents independently selected from Re; or two R1 on the same atom or different atoms are taken together to form a Cx-Cxcycloalkyl or 4 to 8 membered heterocycloalkyl, each of which is optionally substituted with one or more Re; or two R1 on the same atom are taken together to form an oxo; R1’ is hydrogen, Ci-Cealkyl, Ci-Cialkoxy, Ci-CTshaloalkyl, Ci-Ghydroxyalkyl, Ci-C6aminoalkyl, Ca-Cecycloalkyl, or 4 to 6 membered heterocycloalkyl; or R1 ’ and one of R1 are taken together to form a 4 to 6 membered heterocycloalkyl, which is optionally substituted with one or more Re; and 9. p is 0, 1, 2, 3, 4, or 5. The compound of any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein ring C is: wherein, -86- WO 2024 / 240153 PCT / CN2024 / 094491 R1’ is hydrogen, Ci-Cealkyl, Ci-Cialkoxy, G-Ghaloalkyl, Ci-Ghydroxyalkyl, G-Gaminoalkyl. Ca-Cicycloalkyl, or 4 to 6 membered heterocycloalkyl; or R1 ’ and one of R1 are taken together to form a 4 to 6 memberedheterocycloalkyl, which is optionally substituted with one or more Re. 10. The compound of claim 1, or a pharmaceutically acceptable salt therein, wherein the compound has the structure of Formula (II), or a pharmaceutically acceptable salt thereof: Formula (II), wherein, ring A is Ce-Cioaryl, 4-12 membered heteroaryl, C3-Ci2cycloalkyl, or 4-12 membered heterocycloalkyl; B, D, or E are each independently C or N; G is O, S, N, NRG’, or CRG; F is O, S, N, NRF’, or CRF; wherein G and F are not both O or S at the same time; each RG and RF is independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Ci- Cgalkoxy, Ci-Cehaloalkyl, Ci-Cihydroxyalkyl, Ci-Ciaminoalkyl, or G-C,cycloalkyl; each RG’ andRF’ is independently hydrogen, Ci-C6alkyl, Ci-Cfihaloalkyl, Ca-Gcycloalkyl, or 4 to 6 membered heterocycloalkyl; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Cj-G>alkoxy, Ci- Cghaloalkyl, Cj-Ghydroxyalkyl, Ci-Ceaminoalkyl, or G-C.cycloalkyl; R3 isphenyl, 5 to 12 membered heteroaryl, Ca-Cncycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-Cealkyl, G-Cehaloalkyl, Ci-Cfihydroxyalkyl, G-Cealkoxy, or G-Ceaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OCGO)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo (=0), Ci-C6alkyl, Ci-C6haloalkyl, G-GhydiOxyalkyl. G-Ghctcroalkyl, Ci-C6aminoalkyl, Cs-Gcycloalkyl, 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 Re; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=0)NRcRd, -NRbC(=O)Ra,-NRbC(=0)0Rb, -C(=O)Ra, - C(=O)ORb, -C(=0)NRcRd, -0C(=0)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, - S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-Ceaminoalkyl, G-GJicteiOalkyl, C2-G,alkenyl. G-Galkynyl. G-Cwycloalkyl, or 4-12 -87- WO 2024 / 240153 PCT / CN2024 / 094491 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, - C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, G-Galkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- Ceaminoalkyl, C-Gheteroalkyl, C3-Cecycloalkyl, or 4 to 6 membered heterocycloalkyl; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, G-Ghydroxyalkyl, Ci-Cgaminoalkyl, Ci- Ceheteroalkyl,C2-C6alkenyl, C2-C6alkynyl, 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 Re; each Rh is independently hydrogen, Ci-Cealkyl, Ci-Cghaloalkyl, Ci-Cehydroxyalkyl, Ci- Gaminoalkyl, G-Gheteroalkyl, C2-Galkenyl, C2-Coalkynyl, 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 Re; Rc and Rd are each independently hydrogen, Ci-G,alkyl, G-Ghaloalkyl, Ci-Ghydroxyalkyl, Ci- Gaminoalkyl, Ci-Gheteroalkyl, C2-Galkenyl, G-Galkynyl, 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 Re; or Rc and Rd 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 Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Cealkyl, G-Galkoxy, Ci-Ghaloalkyl, G-Ghydroxyalkyl, Ci-Gaminoalkyl, Ci-Gheteroalkyl, or C3-Gcycloalkyl; n is 0, 1, 2, or 3; p is 0, 1,2, 3, 4, or 5; and w is 0, 1, 2, or 3. 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein B and D are each C; and E is N. 12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) has the structure of Formula (Ila), or a pharmaceuticallyacceptable salt thereof: -88- WO 2024 / 240153 PCT / CN2024 / 094491 Formula (Ila), wherein, G is CRG or N; and F is CRF or N. 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein G is CRG; and F is N. 14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein G is N; and F is CRF. 15. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein B is N; and D and E are each C. 16. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) has the structure of Formula (Kb), or a pharmaceutically acceptable salt thereof: wherein, G is CRG or N; and F is CRF or N. 17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein G is CRG. 18. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein G is N. 19. The compound of any one of claims 16-18, or a pharmaceutically acceptable salt thereof, wherein F is N. 20. Thecompound of claim 10, or a pharmaceutically acceptable salt thereof, wherein D is N; and B and E are each C. 21. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) has the structure of Formula (lie), or a pharmaceutically acceptable salt thereof: Formula (lie), wherein, G is CRG or N; and F is CRF or N. 22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein G is N. 23. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein G is CRG. -89- WO 2024 / 240153 PCT / CN2024 / 094491 24. The compound of any one of claims 21-23, or a pharmaceutically acceptable salt thereof, wherein F is N. 25. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein B, D, and E are each C. 26. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) has the structure of Formula (lid), or a pharmaceutically acceptable saltthereof: Formula (lid) wherein, G is NRG’, CRG, O, or S; and F is NRF’, CRF, N, O, or S, wherein G and F are not both O or S at the same time. 27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein G is O or S; and F is CRF. 28. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein G is CRG; and F is O or S. 29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (HI), or a pharmaceutically acceptable salt thereof: Formula (III), wherein, ring A is Ce-Cioaryl, 4-12 membered heteroaryl, Cs-Cncycloalkyl, or 4-12 membered heterocycloalkyl; H, J, and K are each independently N or CR1; each R1 is independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NReRd, Ci-Cealkyl, Ci- G, alkoxy. Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Cs-Cucycloalkyl; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-C&alkyl, Ci-C^alkoxy, Ci- Cqhaloalkyl, Ci-Cehydroxyalkyl, Ci-G,aminoalkyl, or G-G,cycloalkyl; R3 is phenyl, 5 to 12 membered heteroaryl, Cs-Cncycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-G,alkyl, Ci-G,haloalkyl. G-G,hydroxyalkyl, G-G,alkoxy, or Ci-C6aminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -90- WO 2024 / 240153 PCT / CN2024 / 094491 -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo (=0), Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cghydroxyalkyl, Ci-Csheteroalkyl, Ci-C6aminoalkyl, C3-C6cycloalkyl, 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 Re; each R4 is independently halogen, -CN, -NO2, -OH,-ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OCGO)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, - S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, G-Gaminoalkyl. Ci-G,hctcroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-Cscycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, - C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci- Cftaminoalkyl, G-GJicteroalkyl. C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; each Ra is independently Ci-C6alkyl,Ci-C6haloalkyl, G-GhydiOxyalkyl, Ct-Cfiaminoalkyl, Ci- Cbheteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 Re; each Rb is independently hydrogen, G-G,alkyl, Ci-Cehaloalkyl, G-Ghydroxyalkyl, Ci- Ceaminoalkyl, Ci-Cfiheteroalkyl, C2-Cf,alkenyl, C2-C6alkynyl, 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 Re; Rc and Rd are each independently hydrogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cf,hydroxyalkyl, Ci- G.aminoalkyl, Ci-Cfiheteroalkyl, C2-Cf,alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl, 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 Re; or Rc and Rd 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 Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - -91- WO 2024 / 240153 PCT / CN2024 / 094491 C(=O)OCH3, Ci-Cealkyl, Ci-C6alkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ciaminoalkyl, Ci-Cgheteroalkyl, or C3-C6cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1,2, 3, 4, or 5; and w is 0, 1,2, or 3. 30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein H is N. 31. The compound of claim 29, or a pharmaceuticallyacceptable salt thereof, wherein J is N. 32. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein K is N. 33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IV), or a pharmaceutically acceptable salt thereof: Formula (IV), wherein, ring A is Ce-Cioaryl, 4-12 membered heteroaryl, Cs-Cncycloalkyl, or 4-12 membered heterocycloalkyl; Y is CRCE or N; RCE is hydrogen, -OH, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci- Ceaminoalkyl, or Ci-Ceheteroalkyl; Z is absent, NR1, S, O, or CR^1; each R1 is independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Ci- Cealkoxy, Ci-Cghaloalkyl, Ci-Cehydroxyalkyl, Ci-Ciaminoalkyl, or Ca-Gscycloalkyl; each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cealkoxy, Ci- Cehaloalkyl, C1-C6hydroxyalky 1, Ci-CTaminoalkyl, or G-C / cycloalkyl: R3 is phenyl, 5 to 12 membered heteroaryl, Cj-Cncycloalkyl,4 to 12 membered heterocycloalkyl, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cihydroxyalkyl, Ci-Cealkoxy, or Ci-C6aminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)R\ -S(O)2NReRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo (=0), Ci-C6alkyl, Ci-C6haloalkyl, Ci-Cehydroxyalkyl, Ci-Ceheteroalkyl, Ci-C6aminoalkyl, Cs-Cecycloalkyl, 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 Re; -92- WO 2024 / 240153 PCT / CN2024 / 094491 each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb,-C(=O)Ra, - C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, - S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, G-G>ami noalkyl, Ci-CTheteroalkyl, C2-Cealkenyl, C2-C6alkynyl, G-Gwycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, - C(=O)OH, -C(=O)OCH3, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, C1- Ceaminoalkyl, Ci-Ceheteroalkyl, C3-C6 cycloalkyl, or 4 to 6 membered heterocycloalkyl; each Ra is independently Ci-Cealkyl, Ci-Cehaloalkyl, G-G>hydiOxyalkyl, Ci-Cgaminoalkyl, Ci- Cqheteroalkyl, C2-G alkenyl, C2-C6alkynyl, 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 Re; each Rb is independently hydrogen, Ci-Chalky 1, Ci-Cehaloalkyl, Ci-G,hydiOxyalkyl, C1- G.aminoalkyl, Ci-Cgheteroalkyl, G-G>alkcnyl, C2-C6alkynyl, 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 Re; Rc and Rd are each independently hydrogen, Ci-G,alkyl, G-G,haloalkyl, G-G,hydroxyalkyL Ci- Ceaminoalkyl, Ci-Cfiheteroalkyl, C2-Cf,alkenyl, C2-C6alkynyl, 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 Re; or Rc and Rd 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 Re; each Re is independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, G-G,alkyl, G-Galkoxy. Ci-Cf,haloalkyl, G-G,hydroxyalkyl, Ci-G,ami noalkyl, G-Gheteroalkyl, or C3-C6cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1,2, 3, 4, or 5; q is 0, 1,2, or 3; and w is 0, 1,2, or 3. -93- WO 2024 / 240153 PCT / CN2024 / 094491 34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein Y is N. 35. The compound of claims 33 or 34, or a pharmaceutically acceptable salt thereof, wherein Z is NR1 or O. 36. The compound of claim 33 or 34, or a pharmaceuticallyacceptable salt thereof, wherein Z is CR1^. 37. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein Z is absent. 38. The compound of any one of claims 1 -37, or a pharmaceutically acceptable salt thereof, wherein each R1 is independently hydrogen, halogen, Ci-C<,alkyl, or C3-C6cycloalkyl. 39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein each R1 is hydrogen. 40. The compound of any one of claims 1 -39, or a pharmaceutically acceptable salt thereof, wherein q is 0. 41. A compound having the structure of Formula (V), or a pharmaceutically acceptable salt thereof: wherein; ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; E is CRVE or N; RVE is hydrogen, halogen, -OH, -NRcRd, -CN, -ORa, -C(=O)Ra, Ci-Cealkyl, Ci-Ckalkoxy. Ci -Cehaloalkyl. Ci-Cehydroxyalkyl, Ci-Cf,aminoalkyl, or Ci-Cfiheteroalkyl; R1 is hydrogen, halogen, -OH, -CN, -NO2, -NRcRd, Ci-Cealkyl, Ci-Cealkoxy, Ci-Cehaloalkyl, Ci- Cehydroxyalkyl,Ci-Ceaminoalkyl, or Ci-Cgheteroalkyl; each R4 is independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, - N=S(=O)(Rb)2, -P(=O)(Rb)2, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cfihydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-C6alkenyl, C2-Cealkynyf C;-Cscycloalkyk or4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from R6; each R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, - S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, - C(=O)OCH3, Ci-Cealkyl, Ci-C6alkoxy, Ci-Cehaloalkyl, Ci-Ghydroxyalkyl, Ci-Csaminoalkyl, Ci- Ceheteroalkyl,C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl; -94- WO 2024 / 240153 PCT / CN2024 / 094491 each R2 is independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, Ci-Cealkyl, Ci-Coalkoxy, Ci- Cohaloalkyl, Ci-Cehydroxyalkyl, Ci-Coaminoalkyl, 4-6 membered heterocycloalkyl, or C3- Gcydoalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re; or two R2 are taken together to form an oxo; or two R2 are taken together to form a Gi-Gcycloalkyl or 4-6 membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 substituents independently selected from Rc; R3 is C6-Cioaryl, 5 to 12 membered heteroaryl, C3-Ci2cycloalkyl, 4 to 12 membered heterocycloalkyl, Ci-Cealkyl, Ci-Cehaloalkyl, G-Ghydroxyalkyl, Ci-Cgalkoxy, or Ci-Ceaminoalkyl; each of which is optionally substituted with one or more R5; each R5 is independently halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, - SH, -SRa, SF5, -S(=O)Ra,-S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRhSGO)2Ra. -N-SGO)RcRd. -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo, Ci-Coalkyl, G-Ghaloalkyl, Ci -Ghydroxyalkyl, Ci -Ghetcroalkyl, Ci-Coaminoalkyl, C3-C6cycloalkyl, 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 Re; each Ra is independently G-Coalkyl, G-Ghaloalkyl, Ci-Cehydroxyalkyl, Ci-Coaminoalkyl, C1- Coheteroalkyl, C2-Coalkenyl, C2-Coalkynyl, 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 Re; each Rb is independently hydrogen, G-Coalkyl, Ci-Cohaloalkyl, Ct-Cohydroxyalkyl,Ci-Coaminoalkyl, Ci-Ceheteroalkyl, C2-Coalkenyl, C2-G,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 Re; Rc and Rd are each independently hydrogen, Ci-Coalkyl, Ci-Cohaloalkyl, Ci-Cohydroxyalkyl, Ci- Coaminoalkyl, Ci-Coheteroalkyl, G-G,alkcnyl. C2-Coalkynyl, 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 Re; or Re and Rd 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 Re; each Re isindependently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, - S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3,-N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, -95- WO 2024 / 240153 PCT / CN2024 / 094491 Ci-Cealkyl, Ci-Cealkoxy, Ci-Cshaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, or Ca-Cicycloalkyl; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, or 6; and w is 0, 1, 2, 3, or 4. 42. The compound of any one of claims 1-41, or pharmaceutically acceptable salt thereof, wherein w is 0. 43. The compound of any one of claims 1 -42, or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl, 5 to 12 membered heteroaryl, or 4 to 12 membered heterocycloalkyl; each of which is optionally substituted with one or more R5. 44. The compound of any one of claims 1 -43, or a pharmaceutically acceptable salt thereof, wherein R3 is 4 to 12 membered heterocycloalkyl; which is optionally substituted with one or more R5. 45. The compound of claim 44, or a pharmaceutically acceptable saltthereof, wherein R3 is a 4 to 6 membered optionally substituted heterocycloalkyl. 46. The compound of claim 44, or a pharmaceutically acceptable salt thereof, R3 is an optionally substituted piperidine. 47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein R3 is F OH 48. The compound of any one of claims 1 -43, or a pharmaceutically acceptable salt thereof, wherein R3 is C3-Ci2cycloalkyl, which is optionally substituted with one or more R5. 49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R3 is -96- WO 2024 / 240153 PCT / CN2024 / 094491 50. The compound of any one of claims 1 -49, or a pharmaceutically acceptable salt thereof, wherein ring A is Ci-Cioaryl. 51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl. 52. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein ring A is 53. The compound of any one of claims 1 -11 or 39-49, or a pharmaceuticallyacceptable salt thereof, wherein ring A is 5 or 6-membered heteroaryl. 54. The compound of claim 53, or a pharmaceutically acceptable salt thereof, wherein ring A is pyridine. 55. The compound of any one of claims 1 -11 or 39-49, or a pharmaceutically acceptable salt thereof, wherein ring A is bicyclic heteroaryl. 56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein ring A is 57. The compound of any one of claims 1 -11 or 39-49, or a pharmaceutically acceptable salt thereof, wherein, R4’ is R4, or two R4’ 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 R6; and X is CH, CR4 or N. 58. The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein 59. The compound of claim 57 or 58, or a pharmaceutically acceptable salt thereof, wherein X is CR4 or CH. 60. The compound of claim 57 or 58, or a pharmaceuticallyacceptable salt thereof, wherein X is N. 61. The compound of claim 57 or 58, or a pharmaceutically acceptable salt thereof, wherein two R4’ are taken together to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R6. 62. The compound of claim 57 or 58, or a pharmaceutically acceptable salt thereof, wherein two R4’ are taken together to form a cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R6. -97- WO 2024 / 240153 PCT / CN2024 / 094491 63. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein 64. The compound of any one of claims 1 -63, or a pharmaceutically acceptable salt thereof, wherein each R4 is independently halogen, -CN, -NO2, -OH, -C(=O)Ra, -ORa, -SH, -SRa, -SFs, -NRcRd, Ci-Cbalkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, or Ci-Gcycloalkyl. 65. The compound of claim 64, or a pharmaceutically acceptable salt thereof, wherein each R4 isindependently halogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-CVJiydroxyalkyl, or Ci-Cealkoxyl, which is optionally substituted with one or more halogen. 66. The compound of claim 64 or 65, or a pharmaceutically acceptable salt thereof, wherein each R4 is independently -CN, methyl, -OH, -CF3, -CF2H, -OCF3, or -OCF2H. 67. The compound of claim 64 or 65, or a pharmaceutically acceptable salt thereof, wherein each R4 is independently -OH or -CF3. 68. The compound of any one of claims 1 -67, or a pharmaceutically acceptable salt thereof, wherein p is 2 or 3. 69. The compound of any one of claims 1 -67, or a pharmaceutically acceptable salt thereof, wherein p is 2. 70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt thereof, wherein n is 1. 71. The compound of any one of claims 1 -69, or a pharmaceutically acceptable salt thereof, wherein n is 2. 72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt thereof, wherein the compounds is acompound of Table 1 or Table 2. 73. A pharmaceutical composition comprising a compound of any one of claims 1-72, or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable excipient. 74. A method of modulating NOD-like receptor protein 3 (NLRP3) inflammasome activity in a subject, comprising administering to the subject a compound of any one of claims 1-72, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition of claim 73. 75. A method of inhibiting NLRP3 inflammasome activity in a subject, comprising administering to the subject a compound of any one of claims 1-72, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition of claim 73. 76. A method of treating a disease or disorder in which the NLRP3 signaling contributes to the pathology, and / or symptoms, and / or progression, of the disease or disorder, comprising administering a therapeuticallyeffective amount of a compound of any one of claims 1-72, or a -98- WO 2024 / 240153 PCT / CN2024 / 094491 pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition of claim 73. 77. The method of claim 76, wherein the disease or disorder is an auto-immune or auto- inflammatory disease. 78. The method of claim 76, wherein 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. gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy e.g acute, chronic), kidney related diseases (e.g. hyperoxaluria, lupusnephritis, 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. cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and type II diabetes and related complications, peripheral artery disease (PAD), acute heart failure), inflammatory skin diseases (e.g. hidradenitis suppurativa, acne), wound healing and scar formation, asthma, sarcoidosis, age-related macular degeneration, and cancer related diseases / disorders (e.g. colon cancer, lung cancer, myeloproliferative neoplasms, leukemias, myelodysplastic syndromes (MDS), myelofibrosis). -99- INTERNATIONAL SEARCH REPORT International application No. PCT / CN2024 / 094491 A. CLASSIFICATION OF SUBJECT MATTER C07D487 / 16(2006.01)i;C07D498 / 16(2006.01)i; A61K31 / 395(2006.01)1; A61P29 / 00(2006.01)i; A61P35 / 00(2006.01)i; A61P9 / 00(2006.01)i; A61P3 / 10(2006.01)i According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC: C07D,A61K,A61P Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) CNKI,CNTXT,WOTXT,ENTXT,USTXT,REGISTRY,CAPLUS,MARPAT:substructure search according to claim 1,NLRP3, inflammatory,inflammation,immue, NASH,diabete,cardiovascular, peripheral artery diseas,PAD, MDS,cancer,tumor,tumour C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A CN 115461345 A ( JANSSENPHARM NV) 09 December 2022 (2022-12-09) the whole document 1-78 A WO 2023036330 Al (SIMCERE ZAIMING PHARMACEUTICAL CO LTD) 16 March 2023 (2023-03-16) the whole document 1-78 | | Further documents are listed in the continuation of Box C. | | See patent family annex. * Special categories of cited documents: “T” later document published after the international filing date or priority “A” document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand the to be of particular relevance principle or theory underlying the invention “D” document cited by the applicant in the international application “X” document of particular relevance; the claimed invention cannot be “E” earlier application or patent but published on or after the international considered novel or cannot be considered to involve an inventive step filing date when the document is taken alone “L” document which may throw doubts on priority claim(s) orwhich is “Y” document of particular relevance; the claimed invention cannot be cited to establish the publication date of another citation or other considered to involve an inventive step when the document is special reason (as specified) combined with one or more other such documents, such combination “O” document referring to an oral disclosure, use, exhibition or other being obvious to a person skilled in the art means document member of the same patent family “P” document published prior to the international filing date but later than the priority date claimed Date of the actual completion of the international search 17 August 2024 Date of mailing of the international search report 23 August 2024 Name and mailing address of the ISA / CN CHINA NATIONAL INTELLECTUAL PROPERTY ADMINISTRATION 6, Xitucheng Rd., Jimen Bridge, Haidian District, Beijing 100088, China Authorized officer WANG,ShaoHua Telephone No. (+86) 010-62086353 Form PCT / ISA / 210 (second sheet) (July 2022) Box No. IIObservations where certain claims were found unsearchable (Continuation of item 2 of first sheet) INTERNATIONAL SEARCH REPORT International application No. PCT / CN2024 / 094491 This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. Q Claims Nos.: 74-78 because they relate to subject matter not required to be searched by this Authority, namely: Claims 74-78 are directed to a method of treatment of the human / animal body (PCT Rule 39.1 (iv)). Nonetheless, the search has been carried out based on the corresponding use of the compounds / composition in the manufacture of medicaments. 2. | | Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3. | | Claims Nos.: because they are dependent claims and are not drafted in accordance with the second andthird sentences of Rule 6.4(a). Form PCT / ISA / 210 (continuation of first sheet) (July 2022) INTERNATIONAL SEARCH REPORT Information on patent family members International application No. PCT / CN2024 / 094491 Patent document cited in search report Publication date (day / month / year) Patent family member)s) Publication date (day / month / year) CN 115461345 A 09 December 2022 JP 2023523418 A 05 June 2023 KR 20230005252 A 09 January 2023 US 2023203064 Al 29 June 2023 AU 2021260115 Al 05 January 2023 WO 2021214284 Al 28 October 2021 2022013323 A 30 November 2022 EP 4139312 Al 01 March 2023 BR 112022020798 A2 29 November 2022 CA 3176029 Al 28 October 2021 WO 2023036330 Al 16 March 2023 None Form PCT / ISA / 210 (patent family annex) (July 2022) (19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480033897.X (22) Application Date 2024.05.21 (66) Domestic Priority Data PCT / CN2023 / 095515 2023.05.22 CN (85) PCT International Application Enters National Phase Date: 2025.11.20 (86) PCT International Application Application Data: PCT / CN2024 / 094491 2024.05.21 (87) PCT International Application Publication Data: WO2024 / 240153 EN 2024.11.28 (71) ApplicantInsin Intelligent Technology Intellectual Property Limited Address: 26 / F, Tower 3, Exchange Square, 8 Connaught Place, Central, Hong Kong, China (72) Inventors: Wu Jianping, Qin Luoheng, Ding Xiaoyu, Li Chaopeng (74) Patent Agency: Beijing Zhongzi Law Firm 11247 Patent Attorneys: Jia Shicong, Huang Gesheng (51) Int.Cl. C07D 487 / 16 (2006.01) C07D 498 / 16 (2006.01) A61K 31 / 395 (2006.01) A61P 29 / 00 (2006.01) A61P 35 / 00 (2006.01) A61P 9 / 00 (2006.01) A61P 3 / 10 (2006.01) (54) Invention Title: NLRP3 Inflammasome Inhibitor and Its Use (57) Abstract: This article describes a NOD-like receptor protein 3 (NLRP3) inflammasome inhibitor and a pharmaceutical composition comprising said inhibitor. The subject compounds and compositions may be used to treat diseases or disorders associated with the NLRP3 inflammasome pathway. Claims 18 pages, Description 77 pages, CN 121175313 A 2025.12.19 CN 1 21 17 53 13 A 1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof: Formula (I), wherein, ring A is aryl, heteroaryl, cycloalkyl or heterocycloalkyl; B is C or N; D is C or N; E is C, CRCE or N; RCE is hydrogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; R4 is each independently a halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl or 4-12 heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, ynyl, heterocyclic alkyl or cycloalkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from R6.R6 can be halogen, oxo, -CN, -OH, -NO2, -ORα, -NRcRd, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; the ring C can be phenyl, 5- to 7-membered heteroaryl, C5-C8 cycloalkyl, or 5- to 8-membered heterocyclic alkyl; R1 can be independently hydrogen, halogen, -CN, -NO2, -OH, -OR a, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(R b) 2. C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-12-membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, ynyl, heterocyclic alkyl, or cycloalkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; or two R1s on the same atom or different atoms together form a C3-C8 cycloalkyl or a 4-8-membered heterocyclic alkyl, each optionally substituted by one or more Res; or two R1s on the same atom together form an oxoalkyl; Claims 1 / 18 page 2 CN 121175313 A R2s are each independently a halogen, -OH, -CN, -NO2, -OR a, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, 4-6-membered heterocyclic alkyl or C3-C6 cycloalkyl, wherein the heterocyclic alkyl or cycloalkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; or two R2s together form an oxo group; or two R2s together form a C3-C6 cycloalkyl or 4-6-membered heterocyclic alkyl, each optionally substituted by 1-4 substituents, said substituents being independently selected from Re;R3 is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 aminoalkyl, C6-C10 aryl, 5-12 heteroaryl, C3-C12 cycloalkyl, or 4-12 heterocyclic alkyl; each of which is optionally substituted by one or more R5s; each of R5s is independently a halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl or heterocyclic alkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re; Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1- C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re;Alternatively, Rc and Rd, together with the atoms they are attached to, form a heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally substituted with 1 to 4 substituents, each substituent being independently selected from Re; each Re is independently a halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, or 3; and w is 0, 1, 2, 3, or 4. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof: wherein, ring A is C6-C10 aryl, 4-12 heteroaryl, C3-C12 cycloalkyl, or 4-12 heterocyclic alkyl; AB is C or N; D is C or N; E is C, CRCE, or N; RCE is hydrogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; ring C is phenyl, 5- to 7-membered heteroaryl, C5-C8 cycloalkyl, or 5- to 8-membered heterocyclic alkyl; R1 is each independently hydrogen, halogen, -OH, -CN, -NO2, -OR a, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C3-C6 cycloalkyl; R2 is independently a halogen, -OH, -CN, -NO2, -OR a, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C3-C6 cycloalkyl; R3 is phenyl, 5-12-membered heteroaryl, C3-C12 cycloalkyl, 4-12-membered heterocycloalkyl, or C1-C6 alkyl; each is optionally substituted by one or more R5s; R5 is independently a halogen, -OH, -CN, -NO2, -OR a, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, - SRa, SF5, ‑S(=O)R a, ‑S(=O)2R a, ‑S(=O)(=NRb)Ra, ‑S(=O)2NR cRd, ‑NRcRd, ‑NRbC(=O)NRcRd, ‑NRbC (=O)Ra, ‑NRbC(=O)ORb, ‑NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl or heterocyclic alkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; R4 is each independently a halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-12 membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, ynyl, heterocyclic alkyl, or cycloalkyl is optionally substituted with 1-4 substituents, said substituents being independently selected from R6; each R6 being independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O) OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocycloalkyl; Ra is each independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re;Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re; Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the alkyl, haloalkyl, hydroxyalkyl, and heteroalkyl groups are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups are each independently hydrogen ... Each of the following groups—alkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl—is optionally substituted with 1 to 4 substituents, said substituents being independently selected from Re; or Rc and Rd together with the atoms to which they are attached form a heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 1 to 4 substituents, said substituents being independently selected from Re; each of Re is independently halogenated, oxo-, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; n is 1 or 2; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, or 3; and w is 0, 1, 2, or 3. 3. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the cyclic C is phenyl or a 5-6 heteroaryl group. 4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein the ring C is phenyl, furanyl, thiophene, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or triazinyl. 5. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein the ring C is: or, wherein R1' is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or a 4-6-membered heterocyclic alkyl. 6. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the ring C is a C5-C6 cycloalkyl or a 5-6-membered heterocyclic alkyl.7. The compound of any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein the ring C is cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, or morpholinyl. Claims 4 / 18 page 5 CN 121175313 A 8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the ring C is: , or , wherein Y is CRCE or N; RCE is hydrogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Z is absent, is NR1', S, O, or CR1R1; R1 is independently hydrogen, halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, or 4-12 heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocyclic alkyl, or cycloalkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; or two R1s on the same atom or different atoms together form a C3-C8-C8 cycloalkyl or a 4-8 heterocyclic alkyl, each optionally substituted by one or more Res; or two R1s on the same atom together form an oxoalkyl; R1' is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; or R1' and one R1 together form a 4-6-membered heterocyclic alkyl, optionally substituted by one or more Res; and p is 0, 1, 2, 3, 4, or 5. 9. A compound of any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein the ring C is: (Claims 5 / 18, page 6, CN 121175313 A) or, wherein R1' is hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl, or a 4- to 6-membered heterocyclic alkyl; orR1' and one R1 together form a 4-6 membered heterocyclic alkyl group, which is optionally substituted by one or more Re. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (II) or a pharmaceutically acceptable salt thereof: Formula (II), wherein ring A is C6-C10 aryl, 4-12 heteroaryl, C3-C12 cycloalkyl or 4-12 heterocycloalkyl; B, D or E are each independently C or N; AG is O, S, N, NRG' or CRG; F is O, S, N, NRF' or CRF; wherein G and F are not simultaneously O or S; RG and RF are each independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C3-C6 cycloalkyl; RG' and RF' are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or 4- to 6-membered heterocyclic alkyl; R2 is each independently halogen, -OH, -CN, -NO2, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C3-C6 cycloalkyl; R3 is phenyl, 5-12-membered heteroaryl, C3-C12 cycloalkyl, 4-12-membered heterocyclic alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or C1-C6 aminoalkyl; each is optionally substituted by one or more R5s; R5 is each independently halogen, -OH, -CN, -NO2, -OR a, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, SF5, -S(=O)R a, -S(=O)2R a, -S(=O)(=NRb)Ra, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC (=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo(=O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl C3-C6 cycloalkyl or 4-6 heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocyclic alkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; R4 are each independently a halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O) NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2R a, -S(=O)(=NRb)Rb, -N=S(=O) (Rb)2, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-12 membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, ynyl, heterocyclic alkyl, or cycloalkyl is optionally substituted with 1-4 substituents, said substituents being independently selected from R6; each R6 being independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O) OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6-membered heterocycloalkyl; Ra is each independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re; Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; or Rc and Rd together with the atoms to which they are attached form a heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1-4 substituents. (Claims 7 / 18, page 8, CN 121175313 A) said substituents are independently selected from Re; each of Re is independently halogenated, oxo-, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl or C3-C6 cycloalkyl; n is 0, 1, 2 or 3; p is 0, 1, 2, 3, 4 or 5; and w is 0, 1, 2 or 3. 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein B and D are each C; and E is N. 12. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has the structure of formula (IIa) or a pharmaceutically acceptable salt thereof: Formula (IIa), wherein G is CRG or N; and F is CRF or N. 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein G is CRG; and F is N. 14. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein G is N; and F is CRF. 15. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein B is N; and D and E are each C. 16. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has the structure of formula (IIb) or a pharmaceutically acceptable salt thereof: Formula (IIb), wherein G is CRG or N; and F is CRF or N. 17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein G is CRG. 18. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein G is N. 19. The compound of any one of claims 16-18 or a pharmaceutically acceptable salt thereof, wherein F is N. 20. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein D is N; and B and E are each C. Claims, page 8 / 18, CN 121175313 A21. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has the structure of formula (IIc) or a pharmaceutically acceptable salt thereof: Formula (IIc), wherein G is CRG or N; and F is CRF or N. 22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein G is N. 23. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein G is CRG. 24. The compound of any one of claims 21-23 or a pharmaceutically acceptable salt thereof, wherein F is N. 25. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein B, D, and E are each C. 26. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has the structure of formula (IId) or a pharmaceutically acceptable salt thereof: Formula (IId), wherein G is NRG', CRG, O, or S; and F is NRF', CRF, N, O, or S, wherein G and F are not simultaneously O or S. 27. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein G is O or S; and F is CRF. 28. The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein G is CRG; and F is O or S. 29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (III) or a pharmaceutically acceptable salt thereof: Claims 9 / 18 pages 10 CN 121175313 A Formula (III), wherein, ring A is C6-C10 aryl, 4-12-membered heteroaryl, C3-C12 cycloalkyl or 4-12-membered heterocycloalkyl; H, J and K are each independently N or C1; R1 are each independently hydrogen, halogen, -OH, -CN, -NO2, -OR a, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C3-C6 cycloalkyl; R2 are each independently halogen, -OH, -CN, -NO2, -OR a, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C3-C6 cycloalkyl; R3 is phenyl, 5-12-membered heteroaryl, C3-C12 cycloalkyl, 4-12-membered heterocycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or C1-C6 aminoalkyl; each of which is optionally substituted by one or more R5s; each of the R5s is independently halogen, -OH, -CN, -NO2, -OR a, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, SF5, -S(=O)Ra a, -S(=O)2Ra. -S(=O)(=NRb)Ra, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC (=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a. -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo(=O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl or heterocyclic alkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; R4 can be halogen, -CN, -NO2, -OH, -ORα, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(R b) 2. C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, ynyl, heterocycloalkyl or cycloalkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from R6; R6 is independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, -S(= O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6 membered heterocyclic alkyl; Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl.The alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups are optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re; Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups, said substituents being independently selected from Re; Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re; or Rc and Rd together with the atoms to which they are attached form a heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re; Re is each independently halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O) 2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, or 5; and w is 0, 1, 2, or 3. 30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein H is N. 31. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein J is N. 32. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein K is N. 33. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IV) or a pharmaceutically acceptable salt thereof: Formula (IV), wherein ring A is a C6-C10 aryl, a 4-12-membered heteroaryl, a C3-C12 cycloalkyl, or a 4-12-membered heterocycloalkyl; Y is CRCE or N;RCE is hydrogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Z is absent, or is NR1, S, O, or CR1R1; R1 is each independently hydrogen, halogen, -OH, -CN, -NO2, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C3-C6 cycloalkyl; Claims 11 / 18 pages 12 CN 121175313 A R2 is each independently halogen, -OH, -CN, -NO2, -OR a, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C3-C6 cycloalkyl; R3 is phenyl, 5-12-membered heteroaryl, C3-C12 cycloalkyl, 4-12-membered heterocycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or C1-C6 aminoalkyl; each of which is optionally substituted by one or more R5s; R5 is independently halogen, -OH, -CN, -NO2, -OR a, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)(=NRb)Ra, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo(=O), C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl or heterocyclic alkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; R4 is independently halogen, -CN, -NO2, -OH, -OR a,‑SH,‑SRa,‑SF5,‑S(=O)R a,‑S(=O)2R a,‑S(= O)2NR cRd,‑NRcRd,‑NRbC(=O)NRcRd,‑NRbC(=O)Ra,‑NRbC(=O)ORb,‑C(=O)Ra,‑C(=O)ORb,‑C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8-C8 cycloalkyl or 4-12 membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, ynyl, heterocyclic alkyl or cycloalkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from R6; each R6 being independently halogen, oxo, -CN, -OH, -NO2, -OR a, -NRcRd, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4 to 6 membered heterocyclic alkyl; Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re; Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1- C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re;Alternatively, Rc and Rd, together with the atoms to which they are attached, form a heterocyclic alkyl group, wherein the heterocyclic alkyl group is optionally substituted with 1-4 substituents, each substituent being independently selected from Re; each Re is independently a halogen, oxo, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; Claims 12 / 18 pages 13 CN 121175313 A n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, or 3; and w is 0, 1, 2, or 3. 34. The compound of claim 33 or a pharmaceutically acceptable salt thereof, wherein Y is N. 35. The compound of claim 33 or 34 or a pharmaceutically acceptable salt thereof, wherein Z is NR1 or O. 36. The compound of claim 33 or 34 or a pharmaceutically acceptable salt thereof, wherein Z is CR1R1. 37. The compound of claim 33 or 34 or a pharmaceutically acceptable salt thereof, wherein Z is absent. 38. The compound of any one of claims 1-37 or a pharmaceutically acceptable salt thereof, wherein R1 is each independently hydrogen, halogen, C1-C6 alkyl, or C3-C6 cycloalkyl. 39. The compound of claim 38 or a pharmaceutically acceptable salt thereof, wherein R1 is each hydrogen. 40. The compound of any one of claims 1-39 or a pharmaceutically acceptable salt thereof, wherein q is 0. 41. A compound having the structure of formula (V) or a pharmaceutically acceptable salt thereof: Formula (V), wherein: ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; E is CRVE or N; RVE is hydrogen, halogen, -OH, -NRcRd, -CN, -ORa, -C(=O)Ra, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R1 is hydrogen, halogen, -OH, -CN, -NO2, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R4 is each independently halogen, -CN, -NO2, -OH, -ORa, -SH, -SRa, -SF5, -S(=O)R a,‑S(=O)2R a,‑S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, -OC(=O)NRcRd, -OC(=O)Ra, -OC(=O)ORb, -NRbS(=O)2Ra, -S(=O)(=NRb)Rb, -N=S(=O)(Rb)2, -P(=O)(Rb)2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C8 cycloalkyl, or 4-12 membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, ynyl, heterocyclic alkyl, or cycloalkyl is optionally substituted with 1-4 substituents, said substituents being independently selected from R6; each R6 being independently halogen, oxo, -CN, -OH, -NO2, -ORa, -NRcRd, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O) OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl or 4- to 6-membered heterocyclic alkyl; R2 is each independently a halogen, -OH, -CN, -NO2, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, CN 121175313 A, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, 4- to 6-membered heterocyclic alkyl or C3-C6 cycloalkyl, wherein the heterocyclic alkyl or cycloalkyl is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re; or two R2 together form an oxo group; Alternatively, two R2 groups may be used together to form a C3-C6 cycloalkyl or a 4-6 heterocycloalkyl group, each optionally substituted with 1-4 substituents, said substituents being independently selected from Re; R3 is a C6-C10 aryl, 5-12 heteroaryl, C3-C12 cycloalkyl, 4-12 heterocycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or C1-C6 aminoalkyl; each optionally substituted with one or more R5 groups; R5 is independently a halogen, -OH, -CN, -NO2, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, SF5, -S(=O)Ra, -S(=O)2R a, -S(=O)(=NRb)Ra, -S(=O)2NR cRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC (=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2R a, -N=S(=O)RcRd, -P(=O)RcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 heteroalkyl, C1-C6 aminoalkyl, C3-C6 cycloalkyl or 4-6 membered heterocyclic alkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl or heterocyclic alkyl is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted by 1 to 4 substituents, said substituents being independently selected from Re; Rb is each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted by 1-4 substituents, said substituents being independently selected from Re; Rc and Rd are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1- C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted with 1 to 4 substituents, said substituents being independently selected from Re; or Rc and Rd together with the atoms to which they are attached form a heterocycloalkyl group, wherein the heterocycloalkyl group is optionally substituted with 1 to 4 substituents, said substituents being independently selected from Re; each of Re is independently halogenated, oxo-, -CN, -OH, -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, or C3-C6 cycloalkyl; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, or 6; and w is 0, 1, 2, 3, or 4. 42. A compound of any one of claims 1-41 or a pharmaceutically acceptable salt thereof, wherein w is 0. 43. A compound of any one of claims 1-42 or a pharmaceutically acceptable salt thereof, wherein R3 is phenyl, 5-12-membered heteroaryl, or 4-12-membered heterocycloalkyl; each optionally substituted by one or more R5. 44. The compound of any one of claims 1-43 or a pharmaceutically acceptable salt thereof, wherein R3 is a 4-12-membered heterocyclic alkyl group; optionally substituted with one or more R5 groups. Claims 14 / 18 pages 15 CN 121175313 A 45. The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein R3 is a 4-6-membered optionally substituted heterocyclic alkyl group. 46. The compound of claim 44 or a pharmaceutically acceptable salt thereof, wherein R3 is optionally substituted piperidine. 47. The compound of claim 46 or a pharmaceutically acceptable salt thereof, wherein R3 is, or . 48. The compound of any one of claims 1-43 or a pharmaceutically acceptable salt thereof, wherein R3 is a C3-C12 cycloalkyl group, optionally substituted with one or more R5 groups. 49. The compound of claim 48 or a pharmaceutically acceptable salt thereof, wherein R3 is or . 50. The compound of any one of claims 1-49 or a pharmaceutically acceptable salt thereof, wherein ring A is a C6-C10 aryl. 51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl. 52. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl. 53. The compound of any one of claims 1-11 or 39-49 or a pharmaceutically acceptable salt thereof, wherein ring A is a 5- or 6-membered heteroaryl. 54. The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein ring A is pyridine. 55. The compound of any one of claims 1-11 or 39-49 or a pharmaceutically acceptable salt thereof, wherein ring A is a bicyclic heteroaryl. 56. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or phenyl. 57. A compound of any one of claims 1-11 or 39-49, or a pharmaceutically acceptable salt thereof, wherein is , or ; wherein,R4' is R4, or two R4' together with the atoms they are attached to form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each optionally substituted by one or more R6 groups; and X is CH, CR4, or N. 58. The compound of claim 57 or a pharmaceutically acceptable salt thereof, wherein X is CR4 or CH. 59. The compound of claim 57 or 58 or a pharmaceutically acceptable salt thereof, wherein X is CR4 or CH. 60. The compound of claim 57 or 58 or a pharmaceutically acceptable salt thereof, wherein X is N. 61. The compound of claim 57 or 58 or a pharmaceutically acceptable salt thereof, wherein two R4' together form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group, each optionally substituted by one or more R6 groups. Claims 16 / 18 pages 17 CN 121175313 A 62. The compound of claim 57 or 58 or a pharmaceutically acceptable salt thereof, wherein two R4' together form a cycloalkyl or heterocycloalkyl group, each optionally substituted by one or more R6 groups. 63. The compound of claim 55 or a pharmaceutically acceptable salt thereof, wherein R4 is, or . 64. The compound of any one of claims 1-63 or a pharmaceutically acceptable salt thereof, wherein each of R4 is independently a halogen, -CN, -NO2, -OH, -C(=O)Ra, -ORa, -SH, -SRa, -SF5, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C3-C8 cycloalkyl. 65. The compound of claim 64 or a pharmaceutically acceptable salt thereof, wherein each of R4 is independently a halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or C1-C6 alkoxy, optionally substituted with one or more halogens. 66. The compound of claim 64 or 65 or a pharmaceutically acceptable salt thereof, wherein each of R4 is independently -CN, methyl, -OH, -CF3, -CF2H, -OCF3, or -OCF2H. 67. The compound of claim 64 or 65 or a pharmaceutically acceptable salt thereof, wherein each of R4 is independently -OH or -CF3. 68. The compound of any one of claims 1-67 or a pharmaceutically acceptable salt thereof, wherein p is 2 or 3. 69. The compound of any one of claims 1-67 or a pharmaceutically acceptable salt thereof, wherein p is 2. 70. The compound of any one of claims 1-69 or a pharmaceutically acceptable salt thereof, wherein n is 1. 71. The compound of any one of claims 1-69 or a pharmaceutically acceptable salt thereof, wherein n is 2. 72. The compound of any one of claims 1-71 or a pharmaceutically acceptable salt thereof, wherein the compound is a compound listed in Table 1 or Table 2. 73. A pharmaceutical composition comprising a compound of any one of claims 1-72 or a pharmaceutically acceptable salt or thereof.74. A method for modulating the activity of an individual's NOD-like receptor protein 3 (NLRP3) inflammasome, the method comprising administering to the individual a compound of any one of claims 1-72 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 73. 75. A method for inhibiting the activity of an individual's NLRP3 inflammasome, the method comprising administering to the individual a compound of any one of claims 1-72 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 73. 76. A method for treating a disease or disorder, wherein NLRP3 signaling promotes the pathology and / or symptoms and / or progression of the disease or disorder, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-72 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 73. 77. The method of claim 76, wherein the disease or disorder is an autoimmune or autoinflammatory disease. Claims 17 / 18, page 18, CN 121175313 A 78. The method of claim 76, wherein the disease or disorder is selected from inflammasome-related diseases / disorders, immune diseases, inflammatory diseases, autoimmune diseases, or autoinflammatory diseases, such as autoinflammatory febrile syndromes (e.g., cold pyridine-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 diseases (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy, e.g., acute, chronic), kidney-related diseases (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), neuroinflammatory-related diseases (e.g., multiple sclerosis, brain infection, acute injury, neurodegene...

Claims

1. A compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof: Formula (I), wherein, 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, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; R 4 each independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -OC(=O)R a , -OC(=O)OR b , -NR b S(=O)2R a , -S(=O)(=NR b )R b , -N=S(=O)(R b )2, -P(=O)(R b )2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, or 4-12 membered heterocycloalkyl, wherein each alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1-4 substituents independently selected from R 6 ; R 6 each independently halogen, oxo, -CN, -OH, -NO2, -OR a , -NR c R d , -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; ring C is phenyl, 5- to 7-membered heteroaryl, C5-C8 cycloalkyl, or 5- to 8- membered heterocycloalkyl; R 1 each independently is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -OC(=O)R a , -OC(=O)OR b , -NR b S(=O)2R a , -S(=O)(=NR b )R b , -N=S(=O)(R b )2, -P(=O)(R b )2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; or two R on the same atom or on different atoms 1 together form a C3-C8cycloalkyl or 4-8 membered heterocycloalkyl, each of which is optionally substituted with one or more R e substituents; or two R on the same atom 1 together form oxo; R 2 each independently halogen, -OH, -CN, -N02, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, 4-6 membered heterocycloalkyl, or C3-C6 cycloalkyl, wherein heterocycloalkyl or cycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; or two R 2 together form oxo; or two R 2 together with the carbon atom to which they are attached form a C3-C6cycloalkyl or 4-6 membered e ; R 3 It is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 aminoalkyl, C6-C 10 Aryl, 5-12 heteroaryl, C3-C 12 Cycloalkyl or 4-12 membered heterocycloalkyl; each optionally surrounded by one or more R 5 replace; R 5 each independently halogen, -OH, -CN, -NO2, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , SF5, -S(=O)R a , -S(=O)2R a , -S(=O)(=NR b )R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)R c R d , -P(=O)R c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, or 4-6 membered heterocycloalkyl, wherein each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R a each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 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 from 1-4 substituents independently selected from R e ; R b each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1-4 substituents independently selected from R e ; R c and R d each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 1-4 substituents independently selected from R e ; or R c and R d with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R e each independently halogen, oxo, -CN, -OH, -S(=0)CH3, -S(=0)2CH3, -S(=0)2NH2, -S(=0)2NHCH3, -S(=0)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=0)CH3, -C(=0)OH, -C(=0)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, or 6; q is 0, 1, 2, or 3; and w is 0, 1, 2, 3, or 4.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof: wherein, Cycloalkyl or 4- to 12-membered heterocycloalkyl; 10 C6-C10aryl, 4- to 12-membered heteroaryl, C3-C10cycloalkyl, or 4- to 12-membered heterocycloalkyl; 12 C6-C10aryl, 4- to 12-membered heteroaryl, C3-C B is C or N; D is C or N; E is C, CR CE or N; R CE is hydrogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; ring C is phenyl, 5- to 7-membered heteroaryl, C5-C8 cycloalkyl, or 5- to 8- membered heterocycloalkyl; R 1 each independently hydrogen, halogen, -OH, -CN, -N02, -OR a , -NR c R d , Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, or C3-C6cycloalkyl; R 2 each independently halogen, -OH, -CN, -N02, -OR a , -NR c R d , Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, or C3-C6cycloalkyl; R 3 is phenyl, 5-12 membered heteroaryl, C3-C 12 cycloalkyl, 4-12 membered heterocycloalkyl, or C1-C6alkyl; each of which is optionally substituted with one or more R 5 substituents; R 5 each independently halogen, -OH, -CN, -NO2, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , SF5, -S(=O)R a , -S(=O)2R a , -S(=O)(=NR b )R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)R c R d , -P(=O)R c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, or 4-6 membered heterocycloalkyl, wherein each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R 4 each independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -OC(=O)R a , -OC(=O)OR b , -NR b S(=O)2R a , -S(=O)(=NR b )R b , -N=S(=O)(R b )2, -P(=O)(R b )2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, or 4-12 membered heterocycloalkyl, wherein each alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1-4 substituents independently selected from R 6 ; R 6 each independently halogen, oxo, -CN, -OH, -NO2, -OR a , -NR c R d , -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; R a each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 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 from 1-4 substituents independently selected from R e ; R b each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1-4 substituents independently selected from R e ; R c and R d each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 1-4 substituents independently selected from R e ; or R c and R d with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R e each independently halogen, oxo, -CN, -OH, -S(=0)CH3, -S(=0)2CH3, -S(=0)2NH2, -S(=0)2NHCH3, -S(=0)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=0)CH3, -C(=0)OH, -C(=0)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; n is 1 or 2; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, or 3; and w is 0, 1, 2, or 3.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl or 5-6 membered heteroaryl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring C is phenyl, furanyl, thienyl, oxazolyl, isoxazolyl, pyrrolyl, imidazolyl, triazolyl, pyridyl, pyridazinyl, pyrimidinyl, or triazinyl.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein ring C is: or wherein R 1 is hydrogen, Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, C3-C6cycloalkyl, or 4-6 membered heterocycloalkyl.

6. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring C is C5-C6 cycloalkyl or 5-6 membered heterocycloalkyl.

7. The compound of any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein ring C is cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, or morpholinyl.

8. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein ring C is: , , , wherein, Y is CR CE or N; R CE is hydrogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Z is absent, NR 1 ', S, O or CR 1 R 1 ; R 1 each independently is hydrogen, halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -OC(=O)R a , -OC(=O)OR b , -NR b S(=O)2R a , -S(=O)(=NR b )R b , -N=S(=O)(R b )2, -P(=O)(R b )2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, or 4-12 membered heterocycloalkyl, wherein each alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; or two R on the same atom or on different atoms 1 together form a C3-C8-cycloalkyl or 4-8 membered heterocycloalkyl, each optionally substituted with one or more R e substituents; or two R on the same atom 1 together form oxo; R 1 ’ is hydrogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; or R 1 ' and one R 1 together form a 4-6 membered heterocycloalkyl group, which is optionally substituted with one or more R e ; and p is 0, 1, 2, 3, 4, or 5.

9. The compound of any one of claims 1, 2, or 6, or a pharmaceutically acceptable salt thereof, wherein ring C is: or wherein, R 1 R is hydrogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; or R 1 ’ and one R 1 together form a 4-6 membered heterocycloalkyl group, which is optionally substituted by one or more R e groups.

10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (II) or a pharmaceutically acceptable salt thereof: Formula (II), wherein, Ring A is C6-C 10 Aryl, 4-12 heteroaryl, C3-C 12 Cycloalkyl or 4-12 membered heterocyclic alkyl; 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 simultaneously O or S; R G and R F each independently is hydrogen, halogen, -OH, -CN, -N02, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C3-C6 cycloalkyl; R G’ and R F’ each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; R 2 each independently halogen, -OH, -CN, -N02, -OR a , -NR c R d , Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, or C3-C6cycloalkyl; R 3 phenyl, 5-12 membered heteroaryl, C3-C10cycloalkyl, 4-12 membered 12 heterocycloalkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, or C1-C6aminoalkyl; each of which is optionally substituted with one or more R 5 substituents; R 5 each independently halogen, -OH, -CN, -NO2, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , SF5, -S(=O)R a , -S(=O)2R a , -S(=O)(=NR b )R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)R c R d , -P(=O)R c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , oxo (=O), C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, or 4-6 membered heterocycloalkyl, wherein each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R 4 each independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -OC(=O)R a , -OC(=O)OR b , -NR b S(=O)2R a , -S(=O)(=NR b )R b , -N=S(=O)(R b )2, -P(=O)(R b )2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, or 4-12 membered heterocycloalkyl, wherein each alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1-4 substituents independently selected from R 6 ; R 6 each independently halogen, oxo, -CN, -OH, -NO2, -OR a , -NR c R d , -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; R a each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 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 from 1-4 substituents independently selected from R e ; R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl groups is optionally substituted with from 1-4 substituents independently selected from R e ; R c and R d each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 1-4 substituents independently selected from R e ; or R c and R d with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R e each independently halogen, oxo, -CN, -OH, -S(=0)CH3, -S(=0)2CH3, -S(=0)2NH2, -S(=0)2NHCH3, -S(=0)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=0)CH3, -C(=0)OH, -C(=0)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, or 5; and w is 0, 1, 2, or 3.

11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein B and D are each C; and E is N.

12. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) has the structure of Formula (IIa) or a pharmaceutically acceptable salt thereof: Formula (IIa), wherein, G is CR G or N; and F is CR F or N.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein G is CR G ; and F is N.

14. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein G is N; and F is CR F .

15. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein B is N; and D and E are each C.

16. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) has the structure of Formula (IIb) or a pharmaceutically acceptable salt thereof: Formula (IIb), wherein, G is CR G or N; and F is CR F or N.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein G is CR G .

18. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein G is N.

19. The compound of any one of claims 16-18, or a pharmaceutically acceptable salt thereof, wherein F is N.

20. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein D is N; and each of B and E is C.

21. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) has the structure of Formula (lie) or a pharmaceutically acceptable salt thereof: Formula (lie), wherein, G is CR G or N; and F is CR F or N.

22. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein G is N.

23. The compound of claim 21, or a pharmaceutically acceptable salt thereof, wherein G is CR G .

24. The compound of any one of claims 21-23, or a pharmaceutically acceptable salt thereof, wherein F is N.

25. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein each of B, D, and E is C.

26. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (II) has the structure of Formula (lid) or a pharmaceutically acceptable salt thereof: Formula (lid), wherein, G is NR G’ , CR G , O or S; and F is NR F’ , CR F , N, O or S, wherein G and F are not simultaneously O or S.

27. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein G is O or S; and F is CR F .

28. The compound of claim 26, or a pharmaceutically acceptable salt thereof, wherein G is CR G ; and F is O or S.

29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (III) or a pharmaceutically acceptable salt thereof: Formula (III), wherein, Cycloalkyl or 4- to 12-membered heterocycloalkyl; 10 C6-C10aryl, 4- to 12-membered heteroaryl, C3-C10cycloalkyl, or 4- to 12-membered heterocycloalkyl; 12 C6-C10aryl, 4- to 12-membered heteroaryl, C3-C H, J, and K are each independently N or CR 1 ; R 1 each independently hydrogen, halogen, -OH, -CN, -N02, -OR a , -NR c R d , Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, or C3-C6cycloalkyl; R 2 each independently halogen, -OH, -CN, -N02, -OR a , -NR c R d , Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, or C3-C6cycloalkyl; R 3 is phenyl, 5-12 membered heteroaryl, C3-C 12 cycloalkyl, 4-12 membered heterocycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or C1-C6 aminoalkyl; each of which is optionally substituted with one or more R 5 substituents; R 5 each independently halogen, -OH, -CN, -NO2, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , SF5, -S(=O)R a , -S(=O)2R a , -S(=O)(=NR b )R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)R c R d , -P(=O)R c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , oxo (=O), C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, or 4-6 membered heterocycloalkyl, wherein each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R 4 each independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -OC(=O)R a , -OC(=O)OR b , -NR b S(=O)2R a , -S(=O)(=NR b )R b , -N=S(=O)(R b )2, -P(=O)(R b )2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, or 4-12 membered heterocycloalkyl, wherein each alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1-4 substituents independently selected from R 6 ; R 6 each independently halogen, oxo, -CN, -OH, -NO2, -OR a , -NR c R d , -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; R a each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 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 from 1-4 substituents independently selected from R e ; R b each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1-4 substituents independently selected from R e ; R c and R d each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 1-4 substituents independently selected from R e ; or R c and R d with the atom to which they are attached to form a heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R e each independently halogen, oxo, -CN, -OH, -S(=0)CH3, -S(=0)2CH3, -S(=0)2NH2, -S(=0)2NHCH3, -S(=0)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=0)CH3, -C(=0)OH, -C(=0)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, or 5; and w is 0, 1, 2, or 3.

30. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein H is N.

31. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein J is N.

32. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein K is N.

33. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IV) or a pharmaceutically acceptable salt thereof: Formula (IV), wherein, Cycloalkyl or 4- to 12-membered heterocycloalkyl; 10 C6-C10aryl, 4- to 12-membered heteroaryl, C3-C10cycloalkyl, or 4- to 12-membered heterocycloalkyl; 12 C6-C10aryl, 4- to 12-membered heteroaryl, C3-C Y is CR CE or N; R CE is hydrogen, -OH, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Z is absent, NR 1 , S, O or CR 1 R 1 ; R 1 each independently hydrogen, halogen, -OH, -CN, -N02, -OR a , -NR c R d , Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, or C3-C6cycloalkyl; R 2 each independently halogen, -OH, -CN, -N02, -OR a , -NR c R d , Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, or C3-C6cycloalkyl; R 3 phenyl, 5-12 membered heteroaryl, C3-C10cycloalkyl, 4-12 membered 12 heterocycloalkyl, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6alkoxy, or C1-C6aminoalkyl; each of which is optionally substituted with one or more R 5 substituents; R 5 each independently halogen, -OH, -CN, -NO2, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , SF5, -S(=O)R a , -S(=O)2R a , -S(=O)(=NR b )R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)R c R d , -P(=O)R c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , oxo (=O), C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, or 4-6 membered heterocycloalkyl, wherein each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R 4 each independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -OC(=O)R a , -OC(=O)OR b , -NR b S(=O)2R a , -S(=O)(=NR b )R b , -N=S(=O)(R b )2, -P(=O)(R b )2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, or 4-12 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl groups is optionally substituted with 1-4 substituents independently selected from R 6 ; R 6 each independently halogen, oxo, -CN, -OH, -NO2, -OR a , -NR c R d , -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; R a each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 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 from 1-4 substituents independently selected from R e ; R b each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1-4 substituents independently selected from R e ; R c and R d each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 1-4 substituents independently selected from R e ; or R c and R d together with the atoms on which they are attached form a heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R e each independently halogen, oxo, -CN, -OH, -S(=0)CH3, -S(=0)2CH3, -S(=0)2NH2, -S(=0)2NHCH3, -S(=0)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=0)CH3, -C(=0)OH, -C(=0)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; n is 0, 1, 2, or 3; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, or 3; and w is 0, 1, 2, or 3.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein Y is N.

35. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein Z is NR 1 or O.

36. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein Z is CR 1 R 1 .

37. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein Z is absent.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein R 1 each independently is hydrogen, halogen, Ci-C6alkyl, or C3-C6cycloalkyl.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein R 1 each is hydrogen.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein q is 0.

41. A compound having the structure of Formula (V) or a pharmaceutically acceptable salt thereof: Formula (V), wherein: Ring A is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl; E is CR VE or N; R VE is hydrogen, halogen, -OH, -NR c R d , -CN, -OR a , -C(=O)R a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl; R 1 is hydrogen, halogen, -OH, -CN, -NO2, -NR c R d , Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, or Ci-C6heteroalkyl; R 4 each independently halogen, -CN, -NO2, -OH, -OR a , -SH, -SR a , -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , -OC(=O)NR c R d , -OC(=O)R a , -OC(=O)OR b , -NR b S(=O)2R a , -S(=O)(=NR b )R b , -N=S(=O)(R b )2, -P(=O)(R b )2, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C8cycloalkyl, or 4-12 membered heterocycloalkyl, wherein each alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl, alkynyl, heterocycloalkyl, or cycloalkyl is optionally substituted with 1-4 substituents independently selected from R 6 ; R 6 each independently halogen, oxo, -CN, -OH, -NO2, -OR a , -NR c R d , -S(=O)CH3, -S(=O)2CH3, -S(=O)2NH2, -S(=O)2NHCH3, -S(=O)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=O)CH3, -C(=O)OH, -C(=O)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 4- to 6-membered heterocycloalkyl; R 2 each independently halogen, -OH, -CN, -N02, -OR a , -NR c R d , Ci-C6alkyl, Ci-C6alkoxy, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, Ci-C6aminoalkyl, 4-6 membered heterocycloalkyl, or C3-C6 cycloalkyl, wherein heterocycloalkyl or cycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; or two R 2 together form oxo; or two R 2 together with the carbon atom to which they are attached form a C3-C6cycloalkyl or 4-6 membered heterocycloalkyl, each optionally substituted with 1-4 substituents independently selected from R e ; R 3 C6-C12 aryl, 5-12 membered heteroaryl, C3-C8 cycloalkyl, 4-12 membered 10 heterocycloalkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or C1-C6 aminoalkyl; each of which is optionally substituted with one or more R 12 5 substituents;​ R 5 each independently halogen, -OH, -CN, -NO2, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , SF5, -S(=O)R a , -S(=O)2R a , -S(=O)(=NR b )R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -N=S(=O)R c R d , -P(=O)R c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , oxo, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, or 4-6 membered heterocycloalkyl, wherein each of alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, or heterocycloalkyl is optionally substituted with 1-4 substituents independently selected from R e ; R a each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 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 from 1-4 substituents independently selected from R e ; R b each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally substituted with 1-4 substituents independently selected from R e ; R c and R d each independently is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, 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 1-4 substituents independently selected from R e ; or R c and R d with the atom to which they are attached to form a heterocycloalkyl, wherein heterocycloalkyl is optionally substituted with 1-4 substituents selected independently from R e ; R e each independently halogen, oxo, -CN, -OH, -S(=0)CH3, -S(=0)2CH3, -S(=0)2NH2, -S(=0)2NHCH3, -S(=0)2N(CH3)2, -NH2, -NHCH3, -N(CH3)2, -C(=0)CH3, -C(=0)OH, -C(=0)OCH3, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl; n is 1, 2, or 3; p is 0, 1, 2, 3, 4, 5, or 6; and w is 0, 1, 2, 3, or 4.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein w is 0.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, wherein R 3 is phenyl, 5-12 membered heteroaryl, or 4-12 membered heterocycloalkyl; each of which is optionally substituted with one or more R 5 .

44. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R 3 is 4-12 membered heterocycloalkyl; which is optionally substituted with one or more R 5 substituents.

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R 3 is 4-6 membered optionally substituted heterocycloalkyl.

46. The compound of claim 44, or a pharmaceutically acceptable salt thereof, R 3 is an optionally substituted piperidine.

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein R 3 is , or .

48. The compound of any one of claims 1-43, or a pharmaceutically acceptable salt thereof, wherein R 3 is C3-C 12 cycloalkyl, optionally substituted with one or more R 5 substituents.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein R 3 is or .

50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt thereof, wherein ring A is C6-Cio aryl. 10 aryl.

51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

52. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein ring A is .

53. The compound of any one of claims 1-11 or 39-49, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 5- or 6-membered heteroaryl.

54. The compound of claim 53, or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridine.

55. The compound of any one of claims 1-11 or 39-49, or a pharmaceutically acceptable salt thereof, wherein Ring A is a bicyclic heteroaryl.

56. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein ring A is or .

57. The compound of any one of claims 1-11 or 39-49, or a pharmaceutically acceptable salt thereof, wherein is , or ; wherein, R 4 ’ is R 4 , or two R 4 ’ together with the atom to which they are attached 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.

58. The compound of claim 57, or a pharmaceutically acceptable salt thereof, wherein is .

59. The compound of claim 57 or 58, or a pharmaceutically acceptable salt thereof, wherein X is CR 4 or CH.

60. The compound of claim 57 or 58, or a pharmaceutically acceptable salt thereof, wherein X is N.

61. The compound of claim 57 or 58, or a pharmaceutically acceptable salt thereof, wherein two R 4 together form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each of which is optionally substituted with one or more R 6 .

62. The compound of claim 57 or 58, or a pharmaceutically acceptable salt thereof, wherein two R 4 groups together form a cycloalkyl or heterocycloalkyl, each of which is optionally substituted with one or more R 6 groups.

63. The compound of claim 55, or a pharmaceutically acceptable salt thereof, wherein is , or .

64. The compound of any one of claims 1-63, or a pharmaceutically acceptable salt thereof, wherein R 4 each independently is halogen, -CN, -NO2, -OH, -C(=O)R a , -OR a , -SH, -SR a , -SF5, -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C3-C8 cycloalkyl.

65. The compound of claim 64, or a pharmaceutically acceptable salt thereof, wherein R 4 each independently halogen, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6hydroxyalkyl, or Ci-C6alkoxy optionally substituted with one or more halogen.

66. The compound of claim 64 or 65, or a pharmaceutically acceptable salt thereof, wherein R 4 each independently -CN, methyl, -OH, -CF3, -CF2H, -OCF3, or -OCF2H.

67. The compound of claim 64 or 65, or a pharmaceutically acceptable salt thereof, wherein R 4 each independently -OH or -CF3.

68. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, wherein p is 2 or 3.

69. The compound of any one of claims 1-67, or a pharmaceutically acceptable salt thereof, wherein p is 2.

70. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt thereof, wherein n is 1.

71. The compound of any one of claims 1-69, or a pharmaceutically acceptable salt thereof, wherein n is 2.

72. The compound of any one of claims 1-71, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Table 1 or Table 2.

73. A pharmaceutical composition comprising a compound of any one of claims 1-72, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

74. A method of modulating NOD-like receptor protein 3 (NLRP3) inflammasome activity in an individual, comprising administering to the individual a compound of any one of claims 1-72, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 73.

75. A method of inhibiting NLRP3 inflammasome activity in an individual, comprising administering to the individual a compound of any one of claims 1-72, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 73.

76. A method of treating a disease or disorder, wherein NLRP3 signaling contributes to the pathology and / or symptoms and / or progression of the disease or disorder, comprising administering a therapeutically effective amount of a compound of any one of claims 1-72, or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 73.

77. The method of claim 76, wherein the disease or disorder is an autoimmune or autoinflammatory disease.

78. The method of claim 76, wherein the disease or disorder is selected from an inflammasome-related disease / disorder, an immune disease, an inflammatory disease, an autoimmune disease or an autoinflammatory disease, for example autoinflammatory fever syndromes (e.g., cryopyrin-associated periodic syndromes), a liver-related disease / disorder (e.g., chronic liver disease, viral hepatitis, nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, and alcoholic liver disease), an inflammatory arthritis-related disease (e.g., gout, pseudogout (chondrocalcinosis), osteoarthritis, rheumatoid arthritis, arthropathy such as acute, chronic), a kidney-related disease (e.g., hyperoxaluria, lupus nephritis, type I / II diabetes and related complications (e.g., nephropathy, retinopathy), hypertensive nephropathy, hemodialysis-related inflammation), a neuroinflammation-related disease (e.g., multiple sclerosis, brain infections, acute injury, neurodegenerative diseases, Alzheimer’s disease), a cardiovascular / metabolic disease / disorder (e.g., cardiovascular risk reduction (CvRR), hypertension, atherosclerosis, type I and II diabetes and related complications, peripheral arterial disease (PAD), acute heart failure), an inflammatory skin disease (e.g., hidradenitis suppurativa, acne), wound healing and scarring, asthma, sarcoidosis, age-related macular degeneration, and a cancer-related disease / disorder (e.g., colon cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis).