Compounds and compositions for treating conditions associated with NLRP activity

A compound of Formula A

• or a pharmaceutically acceptable salt thereof, wherein:
• the substituents on the compound of Formula A are the following:
• Ar is a heteroaryl group
• X1 is O, S, N, CR41 or NR41;
• X10 is O, S, N, CR10 or NR10;
• X11 is O, S, N, CR1 or NR1;
• X2 is O, S, N, CR42 or NR42;
• X4 is CR4;
• each R20 is the same or different and is independently selected from hydrogen and C1-C6 alkyl;
• Y is CR2;
• Z is N or CR8;
• R8 is selected from H, CN, halo, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR11R12, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, and C1-C6 haloalkyl;
• R2 is C1-C6 haloalkyl, C3-C7 cycloalkyl or C1-C6 alkyl substituted with hydroxy;
• R3 is hydrogen, C1-C6 alkoxy, C1-C6 haloalkyl, CN, C1-C6 haloalkoxy, C3-C7 cycloalkyl or C1-C6 alkyl optionally substituted with hydroxy;
• R4 is C1-C6 haloalkyl, C3-C7 cycloalkyl or C1-C6 alkyl substituted with hydroxy;
• R5 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, CN, C1-C6 haloalkoxy, C3-C7 cycloalkyl or C1-C6 alkyl optionally substituted with hydroxy;
• provided that at least one of R2, R3, R4 and R5 is not hydrogen;
• 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 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 carbocyclic ring or a heterocyclic ring wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;
• n1 is from 2 to 5;
• m1 is from 1 to 10;
• wherein ring B is a carbocyclic ring or a heterocyclic ring wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;
• 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, F, 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 wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;
• each of R1, R10, R41 and R42 when bonded to carbon is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, CN, halo, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, C6-C10 aryl, CONR11R12, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR11R12, =NR13, COOC1-C6 alkyl, C6-C10 aryl, and CONR11R12;
• and each of R1, R41, R42 when bonded to nitrogen is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6alkyl, CO2C3-C8cycloalkyl, C6-C10 aryl, CONR11R12, C3-C7 cycloalkyl, S(O2)C1-C6 alkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkyl, C1-C6 alkoxy, NR11R12, =NR13, COOC1-C6 alkyl, C6-C10 aryl, and CONR11R12;
• or R1 and R10 taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring wherein 1 or 2 members are 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;
• or
• the substituents on the compound of Formula A are the following:
• Ar is a heteroaryl group
• X1 is O, S, N, CR41 or NR41;
• X10 is O, S, N, CR10 or NR10;
• X11 is O, S, N, CR10 or NR10;
• X2 is O, S, N, CR42 or NR42;
• X4 is CR4;
• each R20 is the same or different and is independently selected from hydrogen and C1-C6 alkyl;
• Y is CR2;
• Z is N or CR8;
• R8 is selected from H, CN, Cl, F, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, CONR11R12, C1-C6 alkyl, and C1-C6 haloalkyl;
• R2 is C1-C6 haloalkyl, C3-C7 cycloalkyl or C1-C6 alkyl optionally substituted with hydroxy;
• R3 is hydrogen, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C7 cycloalkyl or C1-C6 alkyl optionally substituted with hydroxy;
• R4 is C1-C6 haloalkyl, C3-C7 cycloalkyl or C1-C6 alkyl substituted with hydroxy;
• R5 is hydrogen, C1-C6 alkoxy, halo, C1-C6 haloalkyl, C3-C7 cycloalkyl or C1-C6 alkyl optionally substituted with hydroxy;
• provided that at least one of R2, R3, R4 and R5 is not hydrogen, and that R2 and R4 are not both hydroxymethyl;
• 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 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 carbocyclic ring or a heterocyclic ring wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;
• n1 is from 2 to 5;
• m1 is from 1 to 10;
• wherein ring B is a carbocyclic ring or a heterocyclic ring wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;
• 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, 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 wherein 1 or 2 members are heteroatoms independently selected from O, N, and S;
• each of R1, R10, R41 and R42 when bonded to carbon is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, CN, halo, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, C6-C10 aryl,
• CONR11R12, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl,
• C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR11R12, =NR13, COOC1-C6 alkyl, C6-C10 aryl, and CONR11R12;
• and each of R1, R10, R41 and R42 when bonded to nitrogen is independently selected from H, C1-C6 alkyl, C1-C6 haloalkyl, CO2C1-C6 alkyl, CO2C3-C8 cycloalkyl, C6-C10 aryl, CONR11R12, C3-C7cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C7 cycloalkyl and 3- to 7-membered heterocycloalkyl is optionally substituted with one or more substituents each independently selected from hydroxy, oxo, C1-C6 alkoxy, NR11R12, =NR13, COOC1-C6 alkyl, C6-C10 aryl, and CONR11R12;
• or R1 and R10 taken together with the atoms connecting them form a 3-to-8-membered carbocyclic or heterocyclic ring wherein 1 or 2 members are 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.