Sarm1 enzyme activity inhibitor and application thereof

A compound represented by formula I:

• or a pharmaceutically acceptable salt or stereoisomer thereof,
• wherein,
• A represents CH or N;
• E represents CH or N;
• R1 is independently selected from the group consisting of hydrogen, halogen, CF3, CN, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, amino, CF3C(O)—NH—, CF3C(O)—N(CH3)—, C1-C6 alkylamino, C3-C6 cycloalkylamino, C6-C14 aryl, C5-C14 heteroaryl, C6-C14 arylamino, C6-C14 heteroarylamino, —OH, C6-C14 aryloxy, —CONH2, —SO2NH2, C1-C6 alkyl-C(O)NR5—, C3-C6 cycloalkyl-C(O)NR5—, C3-C6 heterocycloalkyl-C(O)NR5—, C1-C6 alkyl-OC(O)NR5—, C3-C6 cycloalkyl-OC(O)NR5—, C3-C6 heterocycloalkyl-OC(O)NR5—, C1-C6 alkyl-OC(O)NR5—(C1-C4 alkyl)-, C1-C6 alkyl-C(O)NR5—(C1-C4 alkyl)-, C3-C6 cycloalkyl-OC(O)NR5—(C1-C4 alkyl)-, C3-C6 cycloalkyl-C(O)NR5—(C1-C4 alkyl)-, (C6-C14 aryl)-(C1-C6 alkyl)-CO—N(R5)—(C6-C14 aryl)-(C3-C6 alkyl)-N(R5)—, and (C6-C14 aryl)-(C3-C6 alkenyl)-N(R5)—;
• wherein, in the above C1-C6 alkyl, one carbon atom can be replaced by a heteroatom selected from the group consisting of N, O and S atoms;
• preferably, R1 is independently selected from the group consisting of C1-C6 alkylamino, C3-C6 heterocycloalkylamino, C1-C6 alkylacylamino, 1-morpholinyl, and C1-C6 alkyl-OC(O)NR5—;
• X represents a cyclic structure, selected from the group consisting of C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C3-C6 heterocycloalkyl, C6-C14 aryl and C5-C14 heteroaryl, or X is absent;
• preferably, X is selected from the group consisting of phenyl, pyridyl, methoxy-substituted pyridyl, thiazolyl, cyclohexyl and cyclohexenyl, wherein the phenyl can be substituted by the following substituents:
• —SO2—NH2, —NH—COCH3, —NH2, —CO—NH2, —OCH3, halogen, C1-C4 alkyl, —SO2—N(BoC)CH3 or C1-C4 alkyl-NH—SO2—;
• R2 is independently selected from the group consisting of hydrogen, halogen, —NH2, —N(R5)—CO—R, —CO—N(R5)—R, —N(R5)—SO2—R, —SO2—N(R5)—R, —COOR, —COR, —(C1-C4 alkyl)-OR, —(C1-C4 alkyl)-N(CH3)2, NH—(C1-C4 alkyl)R—, —N(R5)—R, —NHCO—(C3-C6 cycloalkyl)-(C3-C6 heterocycloalkyl), —OR, —O—(C1-C4 alkyl)-R and R;
• R is selected from the group consisting of C1-C4 alkoxy, C1-C12 alkyl, —CONH2, —SO2—NH2, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, —(C1-C12 alkyl)-(C6-C14) aryl, C6-C14 aryl and C5-C14 heteroaryl, wherein the C1-C12 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C6-C14 aryl and C5-C14 heteroaryl are optionally substituted by 1, 2 or 3 halogens, and 1 to 4 —CH2— units in the C1-C12 alkyl are optionally replaced by O atom, S atom, —CO— or —NH—;
• R5 is selected from the group consisting of H, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, C1-C4 alkoxy, C6-C14 aryl and C5-C14 heteroaryl;
• R3 is independently selected from the group consisting of hydrogen, C1-C4 alkyl and C1-C4 alkoxycarbonyl;
• wherein the above C3-C6 heterocycloalkyl and C5-C14 heteroaryl contain 1 or 2 heteroatoms selected from the group consisting of N, O and S atoms;
• R1 and R2 can be connected through a carbon-carbon bond or an ether bond to form a 14- to 16-membered ring, which contains 1-4 heteroatoms selected from the group consisting of N, O and S, preferably, the ring contains 3-4 N atoms and 1-2 O or S atoms;
• m and n are positive integers selected from the group consisting of 1, 2 and 3.