Nlrp3 inflammasome inhibitors and uses thereof

A compound having the structure of Formula (A) or Formula (B), or a pharmaceutically acceptable salt or a stereoisomer thereof:

• wherein;
• Y is C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl, wherein the C3-C8 cycloalkyl, 3- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to 9-membered heteroaryl is optionally substituted with one or more R6;
• X is NRX, —O—, —S—, —S(O)—, or —S(O)2—;
• RX is hydrogen, C1-C6alkyl, C1-C6haloalkyl, C1-C6heteroalkyl, C1-C6hydroxyalkyl, C1-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 R1A and R1B is independently hydrogen, halogen, —CN, —NO2, —OH, —ORa, —NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl;
• or R1A and R1B are taken together to form an oxo;
• or R1A and R1B are taken together to form a C3-C8cycloalkyl or 4 to 8 membered heterocycloalkyl;
• each of which is optionally substituted with one or more R11;
• each R11 is independently halogen, —OH, —CN, —NO2, —ORa, —NRcRd, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl;
• R3 is phenyl, 5 to 12 membered heteroaryl, C3-C12cycloalkyl, 4 to 12 membered heterocycloalkyl, or C1-C6alkyl;
• each of which is optionally substituted with one or more R8;
• each R8 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, —NRDC(═O)Ra, —NRDC(═O)ORb, —NRbS(═O)2Ra, —N═S(═O)RcRd, —P(═O)RcRd, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6heteroalkyl, C1-C6aminoalkyl, C3-C6cycloalkyl, C6-C10 aryl, or 4 to 6 membered heterocycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, cycloalkyl, aryl, or heterocycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re;
• RZN is hydrogen, C1-C6alkyl, or C1-C6haloalkyl;
• or RX and RZN together with the atoms to which they are attached form a 5 to 8 membered heterocycloalkyl which is optionally substituted with one or more R13;
• or R3 and RZN together with the atoms to which they are attached form a 5 to 13 membered heterocycloalkyl which is optionally substituted with one or more R13;
• each R13 is independently halogen, —OH, —CN, —NO2, —ORa, —NRcRd, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, or C1-C6aminoalkyl;
• each R6 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, C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C2-C6alkenyl, C2-C6alkynyl, or C3-C8cycloalkyl, wherein each of the alkyl, haloalkyl, hydroxyalkyl, heteroalkyl, aminoalkyl, alkenyl alkynyl, or cycloalkyl is optionally substituted with 1 to 4 substituents independently selected from Re;
• or two R6 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 R12;
• each R12 is independently halogen, —OH, —CN, —NO2, —ORa, —NRcRd, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, or 4 to 6 membered heterocycloalkyl;
• each Ra is independently 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 to 4 substituents independently selected from Re;
• each Rb is independently 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 to 4 substituents independently selected from Rc;
• Rc and Rd are each independently 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 to 4 substituents independently selected from Rc;
• 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;
• and
• 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, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6hydroxyalkyl, C1-C6aminoalkyl, C1-C6heteroalkyl, or C3-C6cycloalkyl.