Chemical compounds as inhibitors of interleukin-1 activity

A compound of formula Ig:

• or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or a tautomer thereof,
• wherein:
• X1 is O or S;
• R1 is selected from the group consisting of
• wherein represents a single bond or a double bond provided that the ring comprising one or more A2 is a non-aromatic ring;
• each A is independently CR5a1 or N;
• each A2 is independently CR5a2, C(R5a2)2, N, NR5a2, O, S, or S(O)2;
• R2 is
• X2 is N or CR5b1;
• R3 and R4 are H;
• each R5a1 is independently H, D, halogen, OH, CN, —NO2, —SR6, —OR6, —NHR6, —NR6R7, —NR6C(O)R6, —NR6C(O)OR6, —NR6C(O)NR6, C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH2—C3-C8cycloalkyl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH2—C3-C8cycloalkyl are optionally substituted with D, —CN, halogen, C1-C6alkyl, —OR6, —NH2, —NH(C1-C6alkyl), N(C1-C6alkyl)2, —NR6C(O)OR6, or —NR6C(O)R6;
• each R5a2 is independently H, D, halogen, OH, CN, —NO2, —SR6, —OR6, —C(O)R6, S(O)2R6, —C(O)OR6, —C(O)NR6, C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH2—C3-C8cycloalkyl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH2—C3-C8cycloalkyl are optionally substituted with D, —CN, halogen, C1-C6alkyl, —OR6, —NR6C(O)OR6, —NR6C(O)R6, —NR6C(O)NR6, —NR6C(O)R6, or —NR6S(O)2R6;
• or
• two R5a2 together with the atoms to which they are attached can form C3-C8cycloalkyl or heterocyclyl;
• wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O;
• wherein the C3-C8cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C1-C6alkyl, —OR6, —S(O)2—R6;
• —COR6, NR6C(O)OR6, —NR6C(O)R6, —NR6C(O)NR6, or —NR6S(O)2R6;
• or
• two geminal R5a2 can form an oxo group;
• R5b1 is H, D, halogen, —CN, —OR6, or C1-C6alkyl, C3-C8cycloalkyl, —C(O)NR6, —C(O)OR6;
• wherein the C1-C6alkyl, and C3-C8cycloalkyl, are optionally substituted with D, halogen, —CN, —OR6, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• each R5b2, R5b3, R5b4, R5b5, and R5b6 is independently H, D, halogen, OH, —CN, —NO2, —SR6, —OR6, —NHR6, —NR6R7, C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C3-C8cycloalkyl, or C2-C6alkynyl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C3-C8cycloalkyl, and C2-C6alkynyl are optionally substituted with D, halogen, —CN, —OR6, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• or
• two adjacent R5b2, R5b3, R5b4, R5b5, and R5b6 together with the atoms to which they are attached can form C3-C8cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein C3-C8cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with halogen, —CN, C1-C6alkyl, —OR6, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• and
• R6 and R7 are independently, at each occurrence, H, D, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C4-C8cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
• wherein the heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O;
• wherein the C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C4-C8cycloalkenyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with D, —CN, halogen, C1-C6alkyl, —OH, —O—C1-C6alkyl, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• or
• R6 and R7 together with the atom to which they are attached can form heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and 0;
• provided that when the ring comprising A and/or A1 is an imidazole, then at least one A2 is N, NR5a2, O, S, or S(O)2.

A compound of formula Ih:

• or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or a tautomer thereof,
• wherein:
• X1 is O or S;
• R1 is selected from the group consisting of
• wherein represents a single bond or a double bond provided that the ring comprising one or more A2 is a non-aromatic ring;
• each A is independently CR5a1 or N;
• each A2 is independently CR5a2, C(R5a2)2, N, NR5a2, O, S, or S(O)2;
• R2 is
• X2 is N or CR5b1;
• R3 and R4 are H;
• each R5a1 is independently H, D, halogen, —OH, —CN, —NO2, —SR6, —OR6, —NHR6, —NR6R7, —NR6C(O)R6, —NR6C(O)OR6, —NR6C(O)NR6, C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH2—C3-C8cycloalkyl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH2—C3-C8cycloalkyl are optionally substituted with D, —CN, halogen, C1-C6alkyl, —OR6, —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —NR6C(O)OR6, or —NR6C(O)R6;
• each R5a2 is independently H, D, halogen, OH, —CN, —NO2, —SR6, —OR6, —NHR6, —NR6R7, —C(O)R6, —S(O)2R6, —C(O)OR6, —C(O)NR6, C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH2—C3-C8cycloalkyl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH2—C3-C8cycloalkyl are optionally substituted with D, —CN, halogen, C1-C6alkyl, —OR6, —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —NR6C(O)OR6, or —NR6C(O)R6, —NR6C(O)NR6, —NR6C(O)R6, or —NR6S(O)2R6;
• or
• wherein at least one R5a2 is —NHR6, —NR6R7, C1-C6alkyl, or heterocyclyl containing N, wherein the C1-C6alkyl is substituted with —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2, and wherein the heterocyclyl is optionally substituted with D, —CN, halogen, C1-C6alkyl, —OR6, —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —NR6C(O)OR6, or —NR6C(O)R6, —NR6C(O)NR6, —NR6C(O)R6, or —NR6S(O)2R6;
• R5b1 is H, D, halogen, —CN, —OR6, or C1-C6alkyl, C3-C8cycloalkyl, —C(O)NR6, —C(O)OR6;
• wherein the C1-C6alkyl, and C3-C8cycloalkyl, are optionally substituted with D, halogen, —CN, —OR6, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• each R5b2, R5b3, R5b4, R5b5, and R5b6 is independently H, D, halogen, OH, —CN, —NO2, —SR6, —OR6, —NHR6, —NR6R7, C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C3-C8cycloalkyl, or C2-C6alkynyl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C3-C8cycloalkyl, and C2-C6alkynyl are optionally substituted with D, halogen, —CN, —OR6, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• or
• two adjacent R5b2, R5b3, R5b4, R5b5, and R5b6 together with the atoms to which they are attached can form C3-C8cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein C3-C8cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with halogen, —CN, C1-C6alkyl, —OR6, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• and
• R6 and R7 are independently, at each occurrence, H, D, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C4-C8cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
• wherein the heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O;
• wherein the C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C4-C8cycloalkenyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with D, —CN, halogen, C1-C6alkyl, —OH, —O—C1-C6alkyl, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• or
• R6 and R7 together with the atom to which they are attached can form heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and 0;
• provided that when the ring comprising A and/or A1 is an imidazole, then at least one A2 is N, NR5a2, O, S, or S(O)2.

A compound of formula Ie:

• or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, isomer, or a tautomer thereof,
• wherein:
• X1 is O or S;
• R1 is selected from the group consisting of
• wherein represents a single bond or a double bond provided that the ring comprising one or more A2 is a non-aromatic ring;
• each A is independently CR5a1 or N;
• each A2 is independently CR5a2, C(R5a2)2, N, NR5a2, O, S, or S(O)2;
• R2 is
• X2 is N or CR5b1;
• each Rb10, Rb11, Rb12, Rb13, Rb14, and Rb15 is independently H, —OH, or oxo;
• R3 and R4 are H;
• each R5a1 is independently H, D, halogen, OH, CN, —NO2, —SR6, —OR6, —NHR6, —NR6R7, —NR6C(O)R6, —NR6C(O)OR6, —NR6C(O)NR6, C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH2—C3-C8cycloalkyl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH2—C3-C8cycloalkyl are optionally substituted with D, —CN, halogen, C1-C6alkyl, —OR6, —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —NR6C(O)OR6, or —NR6C(O)R6;
• each R5a2 is independently H, D, halogen, OH, CN, —NO2, —SR6, —OR6, —NHR6, —NR6R7, —C(O)R6, —S(O)2R6, —C(O)OR6, —C(O)NR6, C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, or —CH2—C3-C8cycloalkyl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C2-C6alkynyl, C3-C8cycloalkyl, heterocyclyl, aryl, heteroaryl, and —CH2—C3-C8cycloalkyl are optionally substituted with D, —CN, halogen, C1-C6alkyl, —OR6, —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —NR6C(O)OR6, —NR6C(O)R6, NR6C(O)NR6, —NR6C(O)R6, or —NR6S(O)2R6;
• or
• two R5a2 together with the atoms to which they are attached can form C3-C8cycloalkyl or heterocyclyl;
• wherein the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, S, P and O;
• wherein the C3-C8cycloalkyl and heterocyclyl are optionally substituted with D, halogen, C1-C6alkyl, —OR6, —NH2, —NH(C1-C6alkyl), —N(C1-C6alkyl)2, —S(O)2—R6, —COR6, NR6C(O)OR6, —NR6C(O)R6, —NR6C(O)NR6, or —NR6S(O)2R6;
• or
• two geminal R5a2 can form an oxo group;
• R5b1 is H, D, halogen, —CN, —OR6, or C1-C6alkyl, C3-C8cycloalkyl, —C(O)NR6, —C(O)OR6;
• wherein the C1-C6alkyl, and C3-C8cycloalkyl, are optionally substituted with D, halogen, —CN, —OR6, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• each R5b2, R5b3, R5b4, R5b5, and R5b6 is independently H, D, halogen, OH, —CN, —NO2, —SR6, —OR6, —NHR6, —NR6R7, C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C3-C8cycloalkyl, or C2-C6alkynyl;
• wherein the C1-C6alkyl, C2-C6alkenyl, C4-C8cycloalkenyl, C3-C8cycloalkyl, and C2-C6alkynyl are optionally substituted with D, halogen, —CN, —OR6, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• or
• two adjacent R5b2, R5b3, R5b4, R5b5, and R5b6 together with the atoms to which they are attached can form C3-C8cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein C3-C8cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted with halogen, —CN, C1-C6alkyl, —OR6, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• and
• R6 and R7 are independently, at each occurrence, H, D, C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C4-C8cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
• wherein the heterocyclyl and heteroaryl contain 1-5 heteroatoms selected from the group consisting of N, S, P and O;
• wherein the C1-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, C3-C8cycloalkyl, C4-C8cycloalkenyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with D, —CN, halogen, C1-C6alkyl, —OH, —O—C1-C6alkyl, —NH2, —NH(C1-C6alkyl), or —N(C1-C6alkyl)2;
• or
• R6 and R7 together with the atom to which they are attached can form heterocyclyl or heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, S, P and 0;
• provided that when the ring comprising A and/or A1 is an imidazole, then at least one A2 is N, NR5a2, O, S, or S(O)2.