Sulfonimidamide compounds as inhibitors of interleukin-1 activity

A method of treatment of a disorder that is responsive to inhibition of inflammasome, comprising administering an effective amount of a compound of Formula (I-5)

• or pharmaceutically acceptable salts, solvates, isomers, prodrugs, or tautomers thereof, wherein:
• R100 is selected from the group consisting of H, Cl, D, —CN, —NO2, —OR3a, —C(O)R3b,
• —S(O)2R3b, —S(O)R3b, C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl,
• C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6aryl,
• 3-7-membered heterocyclyl, and 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C1-C6alkyl, —OR3a, —C(O)R3b, —P(O)R3bR4b, —S(O)2R3b, —S(O)R3b, —NR3aR4a, —NR3aC(O)R4a,
• —NR3aC(O)OR4a, —NR3aC(O)NR4a, —NR3aS(O)2R4a, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• R1 is selected from the group consisting of
• R2 is selected from the group consisting of C1-C6alkyl, C3-C10cycloalkyl, 3-7-membered heterocyclyl, 5-membered heteroaryl, —NR2gR2h,
• wherein the C1-C6alkyl, C3-C10cycloalkyl, 3-7-membered heterocyclyl, and 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, oxo, —OR23a, —C(O)R23b, —P(O)R23bR24b, —S(O)2R23b, —S(O)R23b, —NR23aR24a,
• —NR23aC(O)R24a, —NR23aC(O)OR24a, —NR23aC(O)NR24a, —NR23aS(O)2R24a,
• —(CH2)1-4C3-C10cycloalkyl, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and
• 5-6-membered heteroaryl;
• X2 is N or CR2a;
• X3 is N or CR2c;
• X4 is N or CR2d;
• X5 is N or CR2e;
• X6 and X7 are independently N or CR2n, wherein at least one of X6 and X7 is N;
• R1z is H, D, halogen, —CN, —NO2, —SR7a, —OR7a, —C(O)R7b, —P(O)R7bR8b, —S(O)2R7b,
• —S(O)R7b, —NR7aR8a, —NR7aC(O)R8a NR7aC(O)OR8a NR7aC(O)NR8a NR7aS(O)2R8a,
• C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6aryl,
• 3-7-membered heterocyclyl, or 5-6-membered heteroaryl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and
• 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C1-C6alkyl, —OR7a,
• —C(O)R7b, —P(O)R7bR8b, —S(O)2Rb, —S(O)R7, —NR7aR8a, —NR7aC(O)R8a, —NR7aC(O)OR8a,
• —NR7aC(O)NR8a, —NR7aS(O)2R8a, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and
• 5-6 membered heteroaryl;
• each R11a, R11b R1c, R1d, R1e, R1f, R1g, and R1h is independently selected from H, D, halogen, —CN, —NO2, —SR11a, —OR11a, —C(O)R11b, —P(O)R11bR12b, —S(O)2R11b, —S(O)R11b, —NR11aR12a, —NR11aC(O)R12a, —NR11aC(O)OR12a, —NR11aC(O)NR12a, —NR11aS(O)2R12a,
• C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6aryl,
• 3-7-membered heterocyclyl, or 5-6-membered heteroaryl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and
• 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C1-C6alkyl, —OR11a,
• —C(O)R11b, —P(O)R11bR12b, —S(O)2R11b, —S(O)R11b, —NR11aR12a, —NR11aC(O)R12a,
• —NR11aC(O)OR12a, —NR11aC(O)NR12a, —NR11aS(O)2R12a, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• or
• two of the following groups, R1a, R1b, R1c, R1d, R1e, R1f, R1g, and R1h, when present, together with the atoms to which they are attached can form a C3-C10cycloalkyl or a
• 3-7-membered heterocyclyl;
• wherein the C3-C10cycloalkyl and 3-7-membered heterocyclyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C1-C6alkyl, —OR13a, —C(O)R113b, —P(O)R13bR14b, —S(O)2R13b,
• —S(O)R13b, —NR13aR14a, —NR3aC(O)R14a, —NR13aC(O)OR14a, —NR13aC(O)NR14a, and
• —NR13aS(O)2R14a;
• or
• two geminal groups R1a and R1b;
• R1c and R1d;
• R1e and R1f;
• or R1g and R1h, when present, can form an oxo group;
• R2a is H, D, halogen, —CN, —OR15a C1-C6alkyl, C3-C10cycloalkyl, —C(O)NR15aR16a,
• —C(O)OR15a, NR15aR16a, —NR15aC(O)R16a, NR16aC(O)OR16a, NR15aC(O)NR16a, or
• —NR15aS(O)2R16a wherein the C1-C6alkyl and C3-C10cycloalkyl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, halogen,
• —CN, —OR15a, —C(O)R15b, NR15aR16a C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• each R2b, R2c, R2d, R2e, and R2f is independently H, D, halogen, —CN, —NO2, —SR17a,
• —OR17a, —C(O)R17b, —P(O)R17bR18b, —S(O)2R17b, —S(O)R7, —NR17aR18a, —NR17aC(O)R18a,
• —NR17aC(O)R18a, —NR17aC(O)OR18a, —NR17aC(O)NR18a, —NR17aS(O)2R18a, C1-C6alkyl,
• C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, or 5-6 membered heteroaryl;
• wherein the C1-C6alkyl, C2-C6alkenyl,
• C4-C8cycloalkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and
• 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, —OR17a, —C(O)R17b,
• —P(O)R17bR18b, —S(O)2R17b, —S(O)R17b, —NR17aR18a, —NR17aC(O)R18a, —NR17aC(O)OR18a,
• —NR17aC(O)NR18a, —NR17aS(O)2R18a, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• or
• two adjacent R2b, R2c, R2d, R2e, and R2f together with the atoms to which they are attached can form C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and
• 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, —CN, C1-C6alkyl, —OR19a, and NR19aR20a,
• each R2j, R2k, R2m, and R2n is independently H, D, halogen, —CN, —NO2, —SR17a,
• —OR17a, —C(O)R17b, —P(O)R17bR18b, —S(O)2R17, —S(O)R1, —NR17aR18a, —NR17aC(O)R18a,
• —NR17aC(O)R18a, —NR17aC(O)OR18a, —NR17aC(O)NR18a, —NR17aS(O)2R18a, C1-C6alkyl,
• C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, or 5-6 membered heteroaryl;
• wherein the C1-C6alkyl, C2-C6alkenyl,
• C4-C8cycloalkenyl, C2-C6alkynyl, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and
• 5-6 membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, —OR17a, —C(O)R17b,
• —P(O)R17bR18b, —S(O)2R17b, —S(O)R17b, —NR17aR18a, —NR17aC(O)R18a, —NR17aC(O)OR18a,
• —NR17aC(O)NR18a, —NR17aS(O)2R18a, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• or
• two adjacent R2j, R2k, R2m, and R2n together with the atoms to which they are attached can form C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, 5-6-membered heteroaryl, wherein the C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of halogen, D, —CN, C1-C6alkyl, —OR19a, and NR19aR20a;
• each R2g and R2h is independently H, C1-C6alkyl, C3-C10cycloalkyl, 3-7-membered heterocyclyl, C6aryl, or 5-membered heteroaryl, wherein the 3-7-membered heterocyclyl and
• 5-membered heteroaryl are attached to the nitrogen at a carbon on the 3-7-membered heterocyclyl or 5-membered heteroaryl, and wherein the C1-C6alkyl, C3-C10cycloalkyl,
• 3-7-membered heterocyclyl, C6aryl, or 5-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C1-C6alkyl, —OR21a, —C(O)R21b, —P(O)R21bR22b, —S(O)2R21b, —S(O)R21b, —NR21aR22a,
• —NR21aC(O)R22a, —NR21aC(O)OR22a, —NR21aC(O)NR22a, —NR21aS(O)2R22a C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and 5-membered heteroaryl;
• R3a, R4a, R7a, R8a, R11a R12a, R13a R14a, R15a, R16a, R17a, R18a, R21a, R22a, R23a, and R24a are independently, at each occurrence, H, D, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl,
• C3-C10cycloalkyl, C4-C8cycloalkenyl, C6aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl;
• wherein the C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C10cycloalkyl,
• C4-C8cycloalkenyl, C6aryl, 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C1-C6alkyl, —OH, —O—C1-C6alkyl, —NH2, —NH(C1-C6alkyl),
• —N(C1-C6alkyl)2, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl;
• R3b, R4b, R7b, R8b, Rlb, R12b, R13b, R14b, R15b, R17b R18b, R21b, R22b, R23b, and R24b are independently, at each occurrence, H, D, —OH, —O(C1-C6alkyl), —NH2, —NH(C1-C6alkyl),
• —N(C1-C6alkyl)2, —NHS(O)2CH3, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C10cycloalkyl,
• C4-C8cycloalkenyl, C6aryl, 3-7-membered heterocyclyl, or 5-6-membered heteroaryl;
• wherein the C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C10cycloalkyl, C4-C8cycloalkenyl, C6aryl,
• 3-7-membered heterocyclyl, and 5-6-membered heteroaryl are independently unsubstituted or substituted with one or more substituents selected from the group consisting of D, —CN, halogen, C1-C6alkyl, —OH, —O—C1-C6alkyl, —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, C3-C10cycloalkyl, C6aryl, 3-7-membered heterocyclyl, and 5-6 membered heteroaryl,
• to thereby treat the disorder in a subject in need thereof.