Heteroaryl compounds as inhibitors of programmed necrosis pathway, composition and method using the same

A compound of Formula I:

• or a pharmaceutically acceptable salt, ester, solvate, isotope-labeled derivative, stereoisomer or tautomer thereof, wherein
• X is N or CR6;
• Z is
• or
• wherein the sulfonyl group in Formula I is connected to the carbon bearing R2 or R2a;
• wherein when Z is
• ring A is C6-10 aryl or 5-10 membered heteroaryl, wherein heteroaryl comprises 1 to 4 heteroatoms independently selected from N, O and S, wherein C6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted with 1 to 4 R7 groups;
• R1 is independently H, deuterium, C1-3 alkyl or C3-6 cycloalkyl, wherein C1-3 alkyl and C3-6 cycloalkyl are unsubstituted or substituted with 1 to 3 groups independently selected from halide and deuterium;
• R2 is independently H, deuterium, halide, amino, —OH, —CO2H, —CO2(C1-6 alkyl), —CN, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from —OH, halide and deuterium;
• R3 is independently H, deuterium, halide, amino, —OH, —CO2H, —CO2(C1-6 alkyl), —CN, C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycle, C1-6 alkoxy, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from —OH, C1-3 alkoxy, —NH(C1-3 alkyl), —N(C1-3 alkyl)2, cyclopropyl, halide and deuterium;
• or R3 is C6-10 aryl or 5-10 membered heteroaryl, wherein heteroaryl comprises 1 to 3 heteroatoms independently selected from N, O and S, wherein C6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted with 1 to 3 R8 groups;
• or R3 is L-BB, wherein L is —O—, —S—, —NH— or —CH2—, BB is C3-8 cycloalkyl or 3-8 membered heterocycle, wherein 3-8 membered heteroaryl comprises 1 to 3 heteroatoms independently selected from N, O and S, wherein C3-8 cycloalkyl and 3-8 membered heterocycle are unsubstituted or substituted with 1 to 3 R9 groups;
• each of R4, R5 and R6 is independently selected from the group consisting of H, deuterium, —CN, halide, —OH, amino, C1-6 alkyl, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, C3-6 cycloalkyl, C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl, wherein C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from halide and —OH;
• R7 is independently H, deuterium, —CN, halide, —OH, amino, C1-6 alkyl, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, C3-6 cycloalkyl, C1-8 alkoxy, C2-6 alkenyl, C2-6 alkynyl, —C(═O)NH2 or —CO2(C1-6 alkyl), wherein amino, C1-6 alkyl, C1-8 alkoxy, C2-6 alkenyl and C2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from halide, —OH, amino, acetyl and deuterium, or two adjacent R7 groups being connected to form a ring together with the atoms they are attached to;
• and
• each of R8 and R9 is independently selected from the group consisting of H, deuterium, —CN, halide, —OH, amino, C1-6 alkyl, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, C3-6 cycloalkyl, C1-8 alkoxy, C2-6 alkenyl, C2-6 alkynyl and —CO2(C1-6 alkyl), wherein amino, C1-6 alkyl, C3-6 cycloalkyl, C1-8 alkoxy, C2-6 alkenyl and C2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from halide, —OH, amino, acetyl and deuterium;
• wherein when Z is
• n is 1 or 2;
• Y is O, NR7a or CR7aR8a;
• ring A is C6-10 aryl or 5-10 membered heteroaryl, wherein heteroaryl comprises 1 to 4 heteroatoms independently selected from N, O and S, wherein C6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted with 1 to 4 R9a groups;
• R1 is independently H, deuterium, C1-6 alkyl or C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are unsubstituted or substituted with 1 to 3 groups independently selected from halide and deuterium;
• each of R2a and R3a is independently H, deuterium, halide, amino, —OH, —CO2H, —CO2(C1-6 alkyl), —CN, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from —OH, halide and cyclopropyl, or R2a and R3a forming ring B together with atoms connected to R2a or R3a;
• each of R4, R5 and R6 is independently selected from the group consisting of H, deuterium, —CN, halide, —OH, amino, C1-6 alkyl, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, C3-6 cycloalkyl, C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl, wherein C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from halide and —OH;
• R7a is H, deuterium, halide, amino, —OH, —CO2H, —CO2(C1-6 alkyl), —CN, C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, C2-6 alkenyl or C2-6 alkynyl, wherein C1-6 alkyl, C3-6 cycloalkyl, C1-6 alkoxy, C2-6 alkenyl and C2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from —OH, halide and cyclopropyl;
• R8a is H, deuterium, halide, amino, —OH, —CO2H, —CO2(C1-6 alkyl), —CN, —SOR20, —SO2R20, C1-6 alkyl, C3-6 cycloalkyl, 3-6 membered heterocycle comprising 1-3 heteroatoms independently selected from N, O and S, C1-6 alkoxy, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, C2-6 alkenyl, C2-6 alkynyl, —C(═O)NH2 or —CO2(C1-6 alkyl), wherein amino, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C2-6 alkenyl and C2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from —OH, C1-3 alkoxy, cyclopropyl, halide and deuterium,
• or R8a is C6-10 aryl or 5-10 membered heteroaryl, wherein heteroaryl comprises 1 to 3 heteroatoms independently selected from N, O and S, wherein C6-10 aryl and 5-10 membered heteroaryl are unsubstituted or substituted with 1 to 3 R10a groups;
• or R7a and Rea together with the carbon they attached to are C═O or C═CH2;
• or R7a and Rea form ring C together with atoms attached to R7a and R8a;
• each of ring B and ring C is independently selected from the group consisting of C3-8 cycloalkyl, 3-8 membered heterocycle, C4-8 cycloalkenyl and C4-8 heterocycloalkenyl, wherein C3-8 cycloalkyl, 3-8 membered heterocycle, C4-8 cycloalkenyl and C4-8 heterocycloalkenyl are unsubstituted or substituted with 1 to 3 R11a groups, wherein 3-8 membered heterocycle and C4-8 heterocycloalkenyl comprises 1 to 3 groups independently selected from the group consisting of heteroatom(s) of N, O and S, and hetero group(s) of —C(═O)N(R11a)—, —C(═O)O—, —C(═O)—, —C(═S)—, —S(═O)—, —S(═O)2— and —NHC(═O)NH—;
• each of R9a and R10a is independently selected from the group consisting of H, deuterium, —CN, halide, —OH, amino, C1-6 alkyl, —NH(C1-6 alkyl), —N(C1-6 alkyl)2, C3-6 cycloalkyl, C1-8 alkoxy, C2-6 alkenyl, C2-6 alkynyl and —CO2(C1-6 alkyl), wherein amino, C1-6 alkyl, C3-6 cycloalkyl, C1-8 alkoxy, C2-6 alkenyl and C2-6 alkynyl are unsubstituted or substituted with 1 to 3 groups independently selected from halide, —OH, amino, acetyl and deuterium;
• R11a is independently H, deuterium, C1-3 alkyl or C3-6 cycloalkyl, wherein C1-3 alkyl and C3-6 cycloalkyl are unsubstituted or substituted with 1 to 3 groups independently selected from halide and deuterium;
• and
• R20 is C1-6 alkyl or C3-6 cycloalkyl, wherein C1-6 alkyl and C3-6 cycloalkyl are unsubstituted or substituted with 1 to 3 groups independently selected from halide and deuterium.