Compound containing structure of a heteroaromatic ring, pharmaceutical composition thereof and application thereof

A compound represented by formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, an isomer thereof or an isotopic compound thereof:

• wherein, represents a single bond or a double bond;
• both rings of
• are aromatic;
• A1 and A2 are independently N or CRb1;
• Rb1 is hydrogen or halogen;
• A3 is C or N;
• A4 is N, CR4 or NR4;
• A5 is NR, N, CR5, S or O;
• Ra1, Ra2 and Ra3 are independently hydrogen, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ORa-1, C(═O)Ra-2, —NRa-31Ra-32, —C(═O)ORa-4, —C(═O)NRa-1Ra-52, or, C1-6 alkyl substituted with one or more Ra1-1, Ra1-1 is independently halogen, hydroxyl or —OC1-6 alkyl;
• or, Ra2 and Ra3 together with the carbon atom to which they are attached form C3-7 cycloalkane, C3-7 cycloalkane substituted with one or more Ra2-1, “3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”, or, “3- to 8-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more Ra2-2;
• provided that when multiple substituents are present, the substituents are the same or different;
• Ra2-1 and Ra2-2 are independently halogen, ═O, hydroxyl, C1-6 alkyl, C1-6 alkyl substituted with one or more halogen, —OC1-6 alkyl, or, —OC1-6 alkyl substituted with one or more halogen;
• Ra-1, Ra-2, Ra-31, Ra-32, Ra-4, Ra-51 and Ra-52 are independently hydrogen, C1-6 alkyl, or, C1-6 alkyl substituted with one or more halogen;
• ring Y is C3-10 cycloalkyl, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”, C6-20 aryl, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, C4-8 cycloalkenyl, “5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N” fused with “5- to 6-membered heterocycloalkyl containing 1 to 3 heteroatoms independently
• selected from O, S and N”, or, “4- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N”;
• n is 0, 1, 2, 3, 4, 5 or 6;
• R2 is halogen, hydroxyl, cyano, oxo, C1-6 alkyl, C1-6 alkyl substituted with one or more R2-1 C2-6 alkenyl, C2-6 alkynyl, —OC1-6 alkyl, —SC1-6 alkyl, —OC1-6 alkyl substituted with one or more R2-2, —C(═O)R2a, —NR2b1R2b2, —C(═O)OR2c, —C(═O)NR2d1R2d2, C3-10 cycloalkyl, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”, C6-20 aryl, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, C4-8 cycloalkenyl, or, “4- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N”;
• or, when n is 2, 3, 4, 5 or 6, two optional R2 are connected, together with the atoms to which they are attached, independently form 3- to 8-membered carbon ring or “3- to 8-membered heterocycle containing 1 to 3 heteroatoms independently selected from O, S and N”;
• R2-1 and R2-2 are independently halogen, cyano, C1-6 alkyl-O—, hydroxyl, —C(═O)R22a, —NR22b1R22b2, —C(═O)OR22c, —C(═O)NR22d1R22d2, —S(O)2NR22e1R22e2 or —S(O)2R22f;
• R2a, R2b1, R2b2, R2c, R2d1, R2d2, R22a, R22b1, R22b2, R22c, R22d1, R22d2, R22e1, R22e2 and R22f are independently hydrogen, C1-6 alkyl, or, C1-6 alkyl substituted with one or more halogen;
• R1 is
• R11, R12, R13, R14, R15, R16, R17, R18, R19 and R20 are independently C1-6 alkyl, —OC1-6 alkyl, C1-6 alkyl substituted with one or more R1-1, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more R1-2, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-3, C6-20 aryl, C6-20 aryl substituted with one or more R1-4, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N” substituted with one or more R1-5, C4-8 cycloalkenyl, C4-8 cycloalkenyl substituted with one or more R1-6, “4- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N”, or, “4- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-7;
• R21 is hydrogen or C1-6 alkyl;
• R1-1, R1-2, R1-3, R1-4, R1-5, R1-6 and R1-7 are halogen, hydroxyl, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —OC1-6 alkyl, —SC1-6 alkyl, —OC1-6 alkyl substituted with one or more R1-1-1, —SC1-6 alkyl substituted with one or more R1-1-2, —C(═O)R1a, —NR1b1R1b2, —C(═O)OR1c, —C(═O)NR1d1R1d2, —S(O)2NR1e1R1e2, —S(O)2R1f, C3-10 cycloalkyl, C3-10 cycloalkyl substituted with one or more R1-1-3, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-1-4, C6-20 aryl, C6-20 aryl substituted with one or more R1-1-5, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N” substituted with one or more R1-1-6, C4-8 cycloalkenyl, C4-8 cycloalkenyl substituted with one or more R1-1-7, “4- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N”, or, “4- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R1-1-8;
• provided that when multiple substituents are present, the substituents are the same or different;
• R1-1-1, R1-1-2, R1-1-3, R1-1-4, R1-1-5, R1-1-6, R1-1-7 and R1-1-8 are independently azide, halogen, hydroxyl, cyano, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —OC1-6 alkyl, —C(═O)R11a, —NR11b1R11b2, —C(═O)OR11c, —C(═O)NR11d1R11d2, —S(O)2NR11e1R11e2, —S(O)2R11f, C3-10 cycloalkyl, or, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”;
• provided that when multiple substituents are present, the substituents are the same or different;
• R1a, R1b1, R1b2, R1c, R1d1, R1d2, R1e1, R1e2, R1f, R11a, R11b1, R11b2, R11c, R11d1, R11d2, R11e1, R11e2 and R11f are independently hydrogen or C1-6 alkyl;
• R3 is “5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, or, “5- to 6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N” substituted with one or more R3-1;
• R3-1 is halogen, hydroxyl, cyano, C1-6 alkyl, C1-6 alkyl substituted with one or more halogen, C1-6 alkyl substituted with one or more —OC1-6 alkyl, —OC1-6 alkyl, —SC1-6 alkyl, —OC1-6 alkyl substituted with one or more halogen, or, —SC1-6 alkyl substituted with one or more halogen;
• provided that when multiple substituents are present, the substituents are the same or different;
• R4 is hydrogen, halogen, C1-6 alkyl, or, C1-6 alkyl substituted with one or more R4-1;
• R4-1 is halogen, hydroxyl, C3-12 cycloalkyl, —OC1-6 alkyl or —SC1-6 alkyl;
• provided that when multiple substituents are present, the substituents are the same or different;
• R5 is
• L1 is a bond, C1-6 alkylene or C1-6 alkylene substituted with deuterium;
• Q1 is hydrogen, deuterium, halogen, cyano, C2-6 alkenyl, C2-6 alkynyl, hydroxyl, —OC1-6 alkyl, —C(═O)R5a, —NR5b1R5b2, —C(═O)OR5c, —C(═O)NR5d1R5d2, —OC1-6 alkyl substituted with one or more R5-1, C6-20 aryl, C6-20 aryl substituted with one or more R5-2, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N”, “5- to 12-membered heteroaryl containing 1 to 4 heteroatoms independently selected from O, S and N” substituted with one or more R5-3, C3-12 cycloalkyl, C3-12 cycloalkyl substituted with one or more R5-4, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “4- to 12-membered heterocycloalkyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R5-5, C4-8 cycloalkenyl, C4-8 cycloalkenyl substituted with one or more R5-6, “4- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N”, “4- to 8-membered heterocycloalkenyl containing 1 to 3 heteroatoms independently selected from O, S and N” substituted with one or more R5-7 or C1-6 alkyl substituted with one or more R5-8;
• provided that when multiple substituents are present, the substituents are the same or different;
• R5-1, R5-2, R5-3, R5-4, R5-5, R5-6, R5-7 and R5-8 are independently halogen, hydroxyl, oxo, cyano, C1-6 alkyl, C1-6 alkyl substituted with one or more halogen, C2-6 alkenyl, C2-6 alkynyl, —OC1-6 alkyl, —OC1-6 alkyl substituted with one or more halogen, —C(═O)R51a, —NR51b1R51b2, —C(═O)OR51c or —C(═O)NR51d1R51d2;
• provided that when multiple substituents are present, the substituents are the same or different;
• R5a, R5b1, R5b2, R5c, R5d1, R5d2, R51a, R51b1, R51b2, R51c, R51d1 and R51d2 are independently hydrogen, C1-6 alkyl, or C1-6 alkyl substituted with one or more halogen;
• or, R2 and R5 are connected together with the atoms to which they are attached independently form “5- to 12-membered heterocyclic olefin containing 1 to 3 heteroatoms independently selected from O, S and N”;
• or, Ra-3 and Ra-32, Ra-51 and Ra-52, R2b1 and R2b2, R2d1 and R2d2, R22b1 and R22b2, R22d1 and R22d2, R22e1 and R22e2, R1b1 and R1b2, R1d1 and R1d2, R1e1 and R1e2, R11b1 and R11b2, R11d1 and R11d2, R11e1 and R11e2, R5b1 and R5b2, R5d1 and R5d2, R51b1 and R51b2, R51d1 and R51d2 together with the N to which they are attached independently form “3- to 8-membered heterocycle containing 1 to 3 heteroatoms, wherein, one heteroatom is N, the other one or two heteroatoms independently selected from O, S and N”, or “3- to 8-membered heterocycle containing 1 to 3 heteroatoms, wherein, one heteroatom is N, the other one or two heteroatoms independently selected from O, S and N” substituted with one or more R1-2-1;
• R1-2-1 is independently hydrogen, C1-6 alkyl, or C1-6 alkyl substituted with one or more halogen;
• the compound represented by formula I is not one of the following compounds:
• N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-1-methyl-7-(4-(methylsulfonyl)piperazin-1-yl)-1H-indazole-5-sulfonamide;
• N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-methyl-1H-indazole-5-sulfonamide;
• N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide;
• N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(1-(isopropylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-methyl-1H-indazole-5-sulfonamide;
• N-(1-Cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazol-2-yl)-7-(4-(isopropylsulfonyl)piperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-5-sulfonamide.