Compounds and compositions for treating conditions associated with NLRP activity

A method for modulating NRLP3 activity, the method comprising contacting NRLP3 with a compound of Formula II,

• or a pharmaceutically acceptable salt thereof, wherein Formula II is selected from the group consisting of
• wherein
• X2 is N;
• X3 is NH or O;
• or when X3 is NH, X3 and R2 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R16;
• or when X3 is NH, X3 and R4 taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R16;
• Y is N or CR8;
• R8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR11R12, C1-C6 alkyl, C1-C6 haloalkoxy, and C1-C6 haloalkyl;
• R8′ is selected from CN, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR11R12, and C1-C6 haloalkyl;
• R2 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
• R2′ is hydrogen, halo, or C1-C6 alkyl optionally substituted with hydroxy;
• R2″ is hydrogen or C1-C6 alkyl;
• R3 is hydrogen, CN, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
• R3′ is hydrogen, halo, or C1-C6 alkyl optionally substituted with hydroxy;
• R3″ is hydrogen, CN, or C1-C6 alkyl;
• R4 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
• R4′ is hydrogen, halo, or C1-C6 alkyl optionally substituted with hydroxy;
• R4″ is hydrogen or C1-C6 alkyl;
• R5 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, or C1-C6 alkyl optionally substituted with hydroxy;
• R5′ is hydrogen, halo, or C1-C6 alkyl optionally substituted with hydroxy;
• R5″ is hydrogen, CN, or C1-C6 alkyl;
• or R2 and R3 taken together with the carbons connecting them form a four-membered to seven-membered ring A,
• or R2′ and R3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A,
• or R4 and R5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,
• or R4′ and R5′ taken together with the carbons connecting them form a four-membered to seven-membered ring B,
• or R2 and R3 taken together with the carbons connecting them form a four-membered to seven-membered ring A and R4 and R5 taken together with the carbons connecting them form a four-membered to seven-membered ring B,
• or R2′ and R3′ taken together with the carbons connecting them form a four-membered to seven-membered ring A and R4′ and R5′ taken together with the carbons connecting them form a four-membered to seven-membered ring B,
• wherein ring A is
• and ring B is
• wherein
• ring A is a saturated carbocyclic ring;
• n1 is from 2 to 5;
• m1 is from 1 to 10;
• wherein ring B is a saturated carbocyclic ring;
• n2 is from 2 to 5;
• m2 is from 1 to 10;
• wherein each R6 in each ring is the same or different and is selected from H, C1-C6 alkyl, C1-C6 alkoxy, NR11R12, oxo, and ═NR13;
• or two R6 taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S;
• R1 is selected from H, unsubstituted C1-C6 alkyl, C(R19)2OH, C(O)C2-C6 alkyl, and C3-C6 cycloalkyl;
• wherein each C(O)C2-C6 alkyl and C3-C6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, NR11R12, ═NR13 COOC1-C6 alkyl, and CONR11R12;
• R1′ is selected from unsubstituted C1-C6 alkyl, C(R19)2OH, C(O)C2-C6 alkyl, and C3-C6 cycloalkyl;
• wherein each C(O)C2-C6 alkyl and C3-C6 cycloalkyl above is optionally substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, NR11R12, ═NR13 COOC1-C6 alkyl, and CONR11R12;
• R10 is selected from H, Cl, C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl;
• wherein C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 heterocycloalkyl substituents are optionally substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, NR11R12, ═NR13 COOC1-C6 alkyl, and CONR11R12;
• R10″ is selected from Cl, C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl;
• wherein C1-C6 alkyl, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl are optionally substituted with one or more substituents each independently selected from hydroxy, C1-C6 alkoxy, NR11R12, ═NR13, COOC1-C6 alkyl, and CONR11R12;
• R10′″ is selected from Cl, C1-C6 alkyl substituted with hydroxy, C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl;
• wherein the C3-C6 cycloalkyl, and C3-C6 heterocycloalkyl above are each optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR11R12, ═NR13, COOC1-C6 alkyl, and CONR11R12;
• or R1 and R10 taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S, wherein the ring is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR11R12, ═NR13, COOC1-C6 alkyl, and CONR11R12;
• R13 is C1-C6 alkyl;
• each of R11 and R12 at each occurrence is independently selected from hydrogen, C1-C6 alkyl, CO2R15 and CONR17R18;
• R15 is C1-C6 alkyl;
• each of R17 and R18 at each occurrence is independently selected from hydrogen and C1-C6 alkyl;
• each R16 is the same or different and is selected from H, C1-C6 alkyl, C1-C6 alkoxy, NR11R12, oxo, and ═NR13;
• each R19 is the same and is C1-C6 alkyl;
• R20 is selected from H, halo, or C1-C6 alkyl optionally substituted with hydroxy;
• R21 is selected from H, halo, or C1-C6 alkyl substituted with hydroxy.