Fused ring compound as Wee-1 inhibitor

A compound of general formula (1) or a stereoisomer, a crystalline form, a pharmaceutically acceptable salt, a hydrate or a solvate thereof:

• wherein in general formula (1):
• X is CH or N;
• Y is —H, a halogen, —CN, —S(O)2R6, —P(O)(R7)2, —C(O)NR8R9, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C3-C14) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OH, —(CH2)˜OR8—, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• Z is a chemical bond, —CH2—, —O— or —NH—;
• ring A is (C6-C14) aryl, (5-14 membered) heteroaryl or (3-14 membered) heterocycloalkyl;
• R1 is
• R4a and R5a are each independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, -D, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• or R4a and R5a, together with the S atom to which they are attached, can form (4-7 membered) heterocycloalkyl, wherein the (4-7 membered) heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OR8, —NR8R9 and —CN;
• R4b and R5b are each independently (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, -D, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• or R4b and R5b, together with the P atom to which they are attached, can form (4-7 membered) heterocycloalkyl, wherein the (4-7 membered) heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OR8, —NR8R9 and —CN;
• R4c and R5c are each independently —H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, -D, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• or R4c and R5c, together with the carbon atom to which they are attached, can form (3-7 membered) cycloalkyl, wherein the (3-7 membered) cycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OR8, —NR8R9 and —CN;
• R4d is —H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, -D, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• and
• R5d is (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, or (C3-C6) cycloalkyl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, -D, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• or R4d and R5d, together with the atoms to which they are attached, can form (4-7 membered) heterocycloalkyl, wherein the (4-7 membered) heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OR8, —NR8R9 and —CN;
• R4e and R5e are each independently —H, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, -D, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• or R4e and R5e, together with the N atom to which they are attached, can form (4-7 membered) heterocycloalkyl, wherein the (4-7 membered) heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OR8, —NR8R9 and —CN;
• R4f and R5f are each independently —H, a halogen, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl or (C3-C6) cycloalkyl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, -D, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• or R4f and R5f together with the carbon atom to which they are attached, can form (3-7 membered) cycloalkyl, wherein the (3-7 membered) cycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OR8, —NR8R9 and —CN;
• R4g is (C1-C3) alkyl or (C3-C6) cycloalkyl, wherein the (C1-C3) alkyl or (C3-C6) cycloalkyl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, -D, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• each R3 is independently —H, -D, a halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8, —S(O)2NR8R9, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• or 2 adjacent R3, together with the atoms to which they are attached, can form (5-9 membered) heterocycloalkyl or (C5-C9) cycloalkyl, wherein the (5-9 membered) heterocycloalkyl or (C5-C9) cycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• ring B is (C5-C11) partially unsaturated cycloalkyl or (5-11 membered) partially unsaturated heterocycloalkyl;
• X1 is
• X2 is a chemical bond,
• X3 is CH, N or C—Rc;
• X4 is CH, N or C—Rd;
• X5 is N—Ra or CH—Rb;
• each R2 is independently —H, -D, a halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8, —S(O)2NR8R9, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• or 2 adjacent R2, together with the atoms to which they are attached, can form (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl, wherein the (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• or 2 R2 on the same carbon atom of ring B, together with the carbon atom to which they are attached, can form (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, wherein the (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• or R2 and an adjacent Re, together with the atoms to which they are attached, can form (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl, wherein the (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• Ra is —H, R8, —(CH2)mOR8, —(CH2)mNR8R9, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl or (3-15 membered) heterocycloalkyl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl or (3-15 membered) heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, -D, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• Rb is —H, R8, —(CH2)nOR8, —(CH2)nNR8R9, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl or (3-15 membered) heterocycloalkyl, wherein the R8, R9, (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl or (3-15 membered) heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, -D, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• Rc and Rd are each independently —H, a halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8, —S(O)2NR8R9, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• Re is —H, -D, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C1-C6) alkoxy, (C1-C6) haloalkoxy, (C3-C9) cycloalkyl, (C6-C14) aryl, (3-11 membered) heterocycloalkyl or (5-11 membered) heteroaryl may be each independently and optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R8, —OH, —(CH2)nOR8, —(CH2)nNR8R9, —OR8, —NR8R9, —CN, —C(O)NR8R9, —NR9C(O)R8, —NR9S(O)2R8, —S(O)pR8 and —S(O)2NR8R9;
• R6 is (C1-C3) alkyl or (C3-C6) cycloalkyl;
• R7 is (C1-C3) alkyl;
• R8 and R9 are each independently —H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R8 and R9 on the same nitrogen atom, together with the N atom to which they are attached, can form (3-11 membered) heterocycloalkyl, wherein the (3-11 membered) heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups:
• —H, halogen, R10 and —OR10;
• R10 is —H, (C1-C6) alkyl or (C3-C14) cycloalkyl;
• R11 and R12 are each independently —H, (C1-C3) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl, or R11 and R12 on the same nitrogen atom, together with the N atom to which they are attached, can form (4-6 membered) heterocycloalkyl;
• p is an integer of 0, 1 or 2;
• q is an integer of 1, 2, 3 or 4;
• s is an integer of 1, 2, 3 or 4;
• n is an integer of 0, 1, 2 or 3;
• and
• and m is an integer of 1, 2 or 3.