Ulk1 inhibitor, preparation method therefor and use thereof

A compound of formula 1 or a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, a hydrate, an N-oxide, an isotope labeled compound, a metabolite, an ester, or a prodrug thereof:

• wherein X1 is CH or N;
• X2 is N or CR4;
• X3 is N or CR5;
• R1 is selected from H, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C10 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, and 5-10-membered heteroaryl, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C3-C10 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, or 5-10-membered heteroaryl is optionally substituted by one or more R6;
• R2 is selected from H, halogen, cyano, nitro, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, 5-10-membered heteroaryl, R70—, —SR7, —NR7R8, —NHCONR7R8, —NHCOR7, —CONR7R8, and —SO2R7, wherein each of the C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, or 5-10-membered heteroaryl is optionally substituted by one or more R6;
• R3 is selected from H, cyano, halogen, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, C2-C6 alkynyl, and C3-C10cycloalkyl;
• R4 is selected from H, halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, 5-10-membered heteroaryl, R70—, —NR7R8, and —NHCONR7R8, wherein each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, or 5-10-membered heteroaryl is optionally substituted by one or more R6;
• or, R2 and R4 together with the groups that they are attached to, form 3-12-membered monocyclic or spiro heterocycle, C6-C10 aromatic ring, or 5-10-membered heteroaromatic ring, wherein each of the 3-12-membered monocyclic or spiro heterocycle, C6-C10 aromatic ring, or 5-10-membered heteroaromatic ring is substituted by one or more R6;
• R5 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, and 5-10-membered heteroaryl;
• or, R1 and R5 together with the groups that they are attached to, form 5-6-membered heterocycle, benzene ring, or 5-6-membered heteroaromatic ring;
• each R6 is independently selected from halogen, cyano, nitro, amino, —NHCO(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C10 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, and 5-10-membered heteroaryl, wherein each of the C3-C10 cycloalkyl, 3-12-membered heterocyclyl, C6-C10 aryl, or 5-10-membered heteroaryl is optionally substituted by one or more halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy;
• R7, R8 are each independently selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, 3-12-membered heterocyclyl, and C6-C10 aryl, wherein each of the C1-C6 alkyl, C3-C10 cycloalkyl, 3-12-membered heterocyclyl, or C6-C10 aryl is optionally substituted by one or more R6;
• or R7 and R8 together with the groups that they are attached to, form 5-6-membered heterocycle or 5-6-membered heteroaromatic ring;
• R is selected from 3-12-membered heterocyclyl, 5-10-membered heteroaryl, and -L-R9, wherein each of the 3-12-membered heterocyclyl or 5-10-membered heteroaryl is optionally substituted by one or more R10;
• L is -(L1)m-(L2)n-(L3)p-;
• L1 is selected from —O—, —N(R12)—, —C(R12)(R13)—O—, —N(R12)CO—, and —S—;
• L2 is selected from C1-C6 alkylene, C1-C6 heteroalkylene, C3-C10 cycloalkylene, and 3-10-membered heterocyclylene;
• L3 is selected from —N(R12)—, —N(R12)C(O)—, and —C(O)—;
• m, n, and p are each independently selected from 0, 1, and 2, and m, n, and p are not simultaneously 0;
• R9 is selected from C3-C10 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclyl, each of the C3-C10 cycloalkyl, C6-C10 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl is optionally substituted by one or more R14;
• each R10 is independently selected from C1-C6 alkyl, oxo, 5-10-membered heteroaryl, 3-12-membered heterocyclyl, R11C(O)—, R11C(O)N(R12)—, and —NR12R13, wherein each of the C1-C6 alkyl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl is optionally substituted by one or more R15;
• R1 is selected from C1-C6 alkyl and C3-C10 cycloalkyl;
• R12 and R13 are each independently selected from H, C1-C6 alkyl, and C3-C10 cycloalkyl;
• each R14 is independently selected from H, halogen, cyano, oxo, C1-C6 alkyl, C1-C6 alkoxy, —CONR12R13, and R11C(O)—;
• and
• each R15 is independently selected from H, halogen, cyano, oxo, C1-C6 alkyl, C3-C10 cycloalkyl, and 3-12-membered heterocyclyl, wherein each of the C1-C6 alkyl, C3-C10 cycloalkyl, or 3-12-membered heterocyclyl is optionally substituted by one or more substituents selected from C1-C6 alkyl and oxo;
• with the proviso that:
• (1) when R9 is C3-C10 cycloalkyl, C6-C10 aryl, or 5-10-membered heteroaryl, then n is not 0;
• (2) when L is -(L1)m-(L2)n-(L3)p-, L1 is selected from —N(R12)—, m is 1, L2 is selected from C1-C6 alkylene, and n is 1, then L3 is not —N(R12)C(O)—;
• (3) when L is -(L1)m-(L2)n-(L3)p-, L1 is selected from —N(R12)—, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, and R9 is 3-12-membered heterocyclyl, then the 3-12-membered heterocyclyl is substituted by oxo;
• and
• (4) when L is -(L1)m-(L2)n-(L3)p-, L1 is selected from —N(R12)—, m is 1, L2 is selected from C1-C6 alkylene, n is 1, p is 0, and R9 is 5-10-membered heteroaryl, then R2 is not morpholinyl.