Prmt5 inhibitor, preparation method therefor, and pharmaceutical use thereof

A compound of formula (I), a stereoisomer or pharmaceutically acceptable salt thereof:

• wherein, X1 is CR6 or N;
• X2 is CR7 or N;
• X3 is CR8 or N;
• ring A is C3-10 cycloalkyl, 4-10 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl, and the C3-10 cycloalkyl or 4-10 membered heterocyclyl is further fused to C6-10 aryl or 5-10 membered heteroaryl, the C6-10 aryl or 5-10 membered heteroaryl is further fused to C3-10 cycloalkyl or 4-10 membered heterocyclyl;
• ring B is C4-12 cycloalkyl, 4-12 membered heterocyclyl, C6-10 aryl or 5-10 membered heteroaryl;
• each R1 is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-O—S(O)2R9, —C0-8 alkyl-S(O)rR9, —C0-8 alkyl-O—R10, —C0-8 alkyl-C(O)OR10, —C0-8 alkyl-C(O)SR10, —C0-8 alkyl-S—C(O)R11, —C0-8 alkyl-C(O)R11, —C0-8 alkyl-O—C(O)R11, —C0-8 alkyl-P(O)(R11)2, —C0-8 alkyl-NR12R13, —C0-8 alkyl-C(O)NR12R13 and —C0-8 alkyl-N(R12)—C(O)R11, and above groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuterioalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-O—S(O)2R9, —C0-8 alkyl-S(O)rR9, —C0-8 alkyl-O—R10, —C0-8 alkyl-C(O)OR10, —C0-8 alkyl-C(O)SR10, —C0-8 alkyl-S—C(O)R11, —C0-8 alkyl-C(O)R11, —C0-8 alkyl-O—C(O)R11, —C0-8 alkyl-P(O)(R11)2, —C0-8 alkyl-NR12R13, —C0-8 alkyl-C(O)NR12R13 and —C0-8 alkyl-N(R12)—C(O)R11;
• R2 is selected from the group consisting of hydrogen, deuterium, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —S(O)rR9, —O—R10, —C(O)OR10, —C(O)R11 and —C(O)NR12R13, and above groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuterioalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-O—S(O)2R9, —C0-8 alkyl-S(O)rR9, —C0-8 alkyl-O—R10, —C0-8 alkyl-C(O)OR10, —C0-8 alkyl-C(O)SR10, —C0-8 alkyl-S—C(O)R11, —C0-8 alkyl-C(O)R11, —C0-8 alkyl-O—C(O)R11, —C0-8 alkyl-P(O)(R11)2, —C0-8 alkyl-NR12R13, —C0-8 alkyl-C(O)NR12R13 and —C0-8 alkyl-N(R12)—C(O)R11;
• R3 and R4 are each independently selected from the group consisting of hydrogen, deuterium, hydroxy, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl and 3-12 membered heterocyclyl, or, R3 and R4, together with a nitrogen atom directly attached thereto, form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, and above groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, hydroxy, ═O, ═S, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuterioalkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy and —NR12R13;
• each R5 is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-O—S(O)2R9, —C0-8 alkyl-S(O)rR9, —C0-8 alkyl-O—R10, —C0-8 alkyl-C(O)OR10, —C0-8 alkyl-C(O)SR10, —C0-8 alkyl-S—C(O)R11, —C0-8 alkyl-C(O)R11, —C0-8 alkyl-O—C(O)R11, —C0-8 alkyl-P(O)(R11)2, —C0-8 alkyl-NR12R13, —C0-8 alkyl-C(O)NR12R13 and —C0-8 alkyl-N(R12)—C(O)R11, and above groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuterioalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, ═O, ═S, —C0-8 alkyl-SF5, —C0-8 alkyl-O—S(O)2R9, —C0-8 alkyl-S(O)rR9, —C0-8 alkyl-O—R10, —C0-8 alkyl-C(O)OR10, —C0-8 alkyl-C(O)SR10, —C0-8 alkyl-S—C(O)R11, —C0-8 alkyl-C(O)R11, —C0-8 alkyl-O—C(O)R11, —C0-8 alkyl-P(O)(R11)2, —C0-8 alkyl-NR12R13, —C0-8 alkyl-C(O)NR12R13 and —C0-8 alkyl-N(R12)—C(O)R11;
• R6, R7 and R8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, C1-10 alkyl, C1-10 haloalkyl, C1-10 deuterioalkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, —C0-8 alkyl-SF5, —C0-8 alkyl-O—S(O)2R9, —C0-8 alkyl-S(O)rR9, —C0-8 alkyl-O—R10, —C0-8 alkyl-C(O)OR10, —C0-8 alkyl-C(O)SR10, —C0-8 alkyl-S—C(O)R11, —C0-8 alkyl-C(O)R11, —C0-8 alkyl-O—C(O)R11, —C0-8 alkyl-P(O)(R11)2, —C0-8 alkyl-NR12R13, —C0-8 alkyl-C(O)NR12R13 and —C0-8 alkyl-N(R12)—C(O)R11;
• each R9 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C1-10 alkyl, C2-10 alkenyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl and —NR12R13, and above groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, ═O, C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and —NR12R13;
• each R10 is independently selected from the group consisting of hydrogen, deuterium, C1-10 alkyl, C2-10 alkenyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, and above groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, ═O, cyano, C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and —NR12R13;
• each R11 is independently selected from the group consisting of hydrogen, deuterium, hydroxy, C1-10 alkyl, C1-10 alkoxy, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and —NR12R13, and above groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, ═O, cyano, C1-10 alkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy and —NR12R13;
• each R12 and each R13 are independently selected from the group consisting of hydrogen, deuterium, hydroxy, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl and C1-10 alkanoyl, and above groups are independently optionally further substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, ═O, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 haloalkyl, C1-10 deuterioalkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C1-10 alkylamino, di-C1-10 alkylamino and C1-10 alkanoyl, or,
• R12 and R13, together with a nitrogen atom directly attached thereto, form a 4-10 membered heterocyclyl or 5-10 membered heteroaryl, and the 4-10 membered heterocyclyl or 5-10 membered heteroaryl is further optionally substituted by one or more substituents selected from the group consisting of deuterium, halogen, hydroxy, ═O, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C1-10 haloalkyl, C1-10 deuterioalkyl, C1-10 alkoxy, C3-12 cycloalkyl, C3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C6-10 aryl, C6-10 aryloxy, 5-10 membered heteroaryl, 5-10 membered heteroaryloxy, amino, mono-C1-10 alkylamino, di-C1-10 alkylamino and C1-10 alkanoyl;
• each r is independently 0, 1 or 2;
• m is 0, 1, 2, 3, 4, 5 or 6;
• and
• n is 0, 1, 2, 3, 4 or 5.