Pyrimidine compound as Wee-1 inhibitor

1 . A compound of general formula (1), or an isomer, 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, halogen, —CN, —S(O) 2 R 5 , —P(O)(R 6 ) 2 , —C(O)NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C3-C14) cycloalkyl, (C6-C14) aryl, 3- to 11-membered heterocycloalkyl, or 5- to 11-membered heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkynyl, (C3-C14) cycloalkyl, (C6-C14) aryl, 3- to 11-membered heterocycloalkyl, or 5- to 11-membered heteroaryl may be each independently and optionally substituted with 1, 2, 3, or 4 of the following groups: —H, halogen, R 8 , —OH, —(CH 2 ) n OR 8 —, —(CH 2 ) n NR 8 R 9 , —OR 8 , —NR 8 R 9 , —CN, —C(O)NR 8 R 9 , —NR 8 C(O)R 8 , —NR 9 S(O) 2 R 8 , —S(O) p R 8 , and —S(O) 2 NR 8 R 9 ;

Z is a chemical bond, —CH 2 —, —O—, or —NH—;

ring A is 5- to 14-membered heteroaryl or 3- to 14-membered heterocycloalkyl;

R 1 and R 2 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, R 8 , —OH, —(CH 2 ) n OR 8 , —(CH 2 ) n NR 8 R 9 , —OR 8 , —NR 8 R 9 , —CN, —C(O)NR 8 R 9 , —NR 8 C(O)R 8 , —NR 9 S(O) 2 R 8 , —S(O) p R 8 , and —S(O) 2 NR 8 R 9 ; or R 1 and R 2 , along with the S atom connected thereto, are capable of forming 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl may be optionally substituted with 1, 2, 3, or 4 of the following groups: —H, halogen, R 8 , —OR 8 , —NR 8 R 9 , and —CN;

each R 3 is independently —H, -D, halogen, R 8 , —OH, —(CH 2 ) n OR 8 , —(CH 2 ) n NR 8 R 9 , —OR 8 , —NR 8 R 9 , —CN, —C(O)NR 8 R 9 , —NR 8 C(O)R 8 , —NR 9 S(O) 2 R 8 , —S(O) p R 8 , —S(O) 2 NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, 3- to 11-membered heterocycloalkyl, or 5- to 11-membered heteroaryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C6-C14) aryl, 3- to 11-membered heterocycloalkyl, or 5- to 11-membered heteroaryl may be each independently and optionally substituted with 1, 2, 3, or 4 of the following groups: —H, halogen, R 8 , —OH, —(CH 2 ) n OR 8 , —(CH 2 ) n NR 8 R 9 , —OR 8 , —NR 8 R 9 , —CN, —C(O)NR 8 R 9 , —NR 8 C(O)R 8 , —NR 9 S(O) 2 R 8 , —S(O) p R 8 , and —S(O) 2 NR 8 R 9 ; or two adjacent R 3 , along with the atoms connected thereto, are capable of forming 5- to 9-membered heterocycloalkyl or (C5-C9) cycloalkyl, wherein the 5- to 9-membered heterocycloalkyl or the (C5-C9) cycloalkyl may be optionally substituted with 1, 2, 3, or 4 of the following groups: —H, halogen, R 8 , —OH, —(CH 2 ) n OR 8 , —(CH 2 ) n NR 8 R 9 , —OR 8 , —NR 8 R 9 , —CN, —C(O)NR 8 R 9 , —NR 8 C(O)R 8 , —NR 9 S(O) 2 R 8 , —S(O) p R 8 , and —S(O) 2 NR 8 R 9 ;

ring B is (C6-C14) aryl or 5- to 11-membered heteroaryl;

each R 4 is independently —H, halogen, R 8 , —OH, —(CH 2 ) n OR 8 , —OR 8 , —(CH 2 ) NR 8 R 9 , —NR 8 R 9 , —CN, —O(CH 2 ) m NR 8 R 9 , —N(R 9 )(CH 2 ) m NR 8 R 9 , —C(O)NR 8 R 9 , —NR 8 C(O)R 8 , —NR 9 S(O) 2 R 8 , —S(O) p R 8 , —S(O) 2 NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, —CH 2 -3- to 15-membered heterocycloalkyl, 3- to 15-membered heterocycloalkyl, 5- to 9-membered heteroaryl, or (C6-C10) aryl, wherein the (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, —CH 2 -3- to 15-membered heterocycloalkyl, 3- to 15-membered heterocycloalkyl, 5- to 9-membered heteroaryl, or (C6-C10) aryl may be optionally substituted with 1, 2, 3, or 4 of the following groups: —H, halogen, R 8 , —OH, —(CH 2 ) n OR 8 , —OR 8 , —(CH 2 ) n NR 8 R 9 , —NR 8 R 9 , —CN, —O(CH 2 ) m NR 8 R 9 , —N(R 9 )(CH 2 ) m NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, —CH 2 -3- to 15-membered heterocycloalkyl, 3- to 15-membered heterocycloalkyl, 5- to 9-membered heteroaryl, (C6-C10) aryl, and —R 7 ; or two adjacent R 4 , along with the atoms connected thereto, are capable of forming 5- to 9-membered heterocycloalkyl or (C5-C9) cycloalkyl, wherein the 5- to 9-membered heterocycloalkyl or (C5-C9) cloalkyl may be optionally substituted with 1, 2, 3, or 4 of the following groups: —H, halogen, R 8 , —OH, —(CH 2 ) n OR 8 , —OR 8 , —(CH 2 ) NR 8 R 9 , —NR 8 R 9 , —CN, —O(CH 2 ) m NR 8 R 9 , —N(R 9 )(CH 2 ) m NR 8 R 9 , —C(O)R 8 , —C(O)NR 8 R 9 , —NR 8 C(O)R 8 , —NR 9 S(O) 2 R 8 , —S(O) p R 8 , —S(O) 2 NR 8 R 9 ,

 (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C9) cycloalkyl, (C1-C6) alkoxy, —CH 2 -4- to 9-membered heterocycloalkyl, 4- to 9-membered heterocycloalkyl, 5- to 9-membered heteroaryl, and (C6-C10) aryl;

R 5 is (C1-C3) alkyl or (C3-C6) cycloalkyl;

R 6 is (C1-C3) alkyl or (C3-C6) cycloalkyl;

R 7 is 3- to 11-membered heterocycloalkyl, wherein the heterocycloalkyl may be optionally substituted with 1, 2, 3, or 4 of the following groups: —H, R 8 , —OR 8 , and —NR 8 R 9 ;

R 8 and R 9 are each independently —H, (C1-C6) alkyl or (C3-C14) cycloalkyl, or R 8 and R 9 on the same N atom, along with the N atom connected thereto, are capable of forming 3- to 11-membered heterocycloalkyl, wherein the 3- to 11-membered heterocycloalkyl may be optionally substituted with 1, 2, 3, or 4 of the following groups: —H, halogen, R 10 , and —OR 10 ;

R 10 is —H, (C1-C3) alkyl, or (C3-C6) cycloalkyl;

and

p is an integer of 0, 1, or 2, q is an integer of 1, 2, 3, or 4, r is an integer of 1, 2, or 3, s is an integer of 1, 2, 3, or 4, n is an integer of 0, 1, 2, or 3, and m is an integer of 1, 2, or 3.

2 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein, in general formula (1), Y is —H, —F, —Cl, —Br, —I, —CN, —S(O) 2 CH 3 , —P(O)(CH 3 ) 2 , —C(O)NH 2 , —C(O)NH(CH 3 ), —C(O)N(CH 3 ) 2 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C5) cycloalkyl, (C2-C3) alkynyl, or 5- to 6-membered heteroaryl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C5) cycloalkyl, (C2-C3) alkynyl, or 5- to 6-membered heteroaryl may be each independently and optionally substituted with 1, 2, 3, or 4 of the following groups: —H, —F, —CN, —CH 3 , and —OCH 3 .

3 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 2 , wherein, in general formula (1), Y is —H, —F, —Cl, —Br, —I, —CN, —S(O) 2 CH 3 , —P(O)(CH 3 ) 2 , —C(O)NH 2 , —C(O)NH(CH 3 ), —C(O)N(CH 3 ) 2 , —CH 3 , —CF 3 ,

4 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein, in general formula (1), ring A is 5- to 10-membered heteroaryl, or 5- to 10-membered heterocycloalkyl.

5 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 4 , wherein, in general formula (1), ring A is:

6 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 4 , wherein, in general formula (1), ring A is:

7 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein, in general formula (1), R 1 and R 2 are each independently (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, or (C3-C5) cycloalkyl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, or (C3-C5) cycloalkyl may be each independently and optionally substituted with 1, 2, 3, or 4 of the following groups: —H, -D, —F, —Cl, —Br, —I, —CH 3 , —OH, —CH 2 OCH 3 , —CH 2 N(CH 3 ) 2 , —OCH 3 , —N(CH 3 ) 2 , and —CN; or R 1 and R 2 , along with the S atom connected thereto, are capable of forming 4- to 6-membered heterocycloalkyl, wherein the 4- to 6-membered heterocycloalkyl may be optionally substituted with 1, 2, 3, or 4 of the following groups: —H, —F, —Cl, —Br, —I, —CH 3 , —OH, —OCH 3 , —N(CH 3 ) 2 , and —CN.

8 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 7 , wherein, in general formula (1), structure unit

is:

9 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein, in general formula (1), each R 3 is independently —H, -D, —F, —Cl, —Br, —I, —OH, —CH 2 OR 11 , —CH 2 NR 11 R 12 , —OR 11 , —NR 11 R 12 , —CN, —C(O)NR 11 R 12 , —NR 12 C(O)R 11 , —NR 12 S(O) 2 R 11 , —SR 11 , —S(O) 2 R 11 , —S(O) 2 NR 11 R 12 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, phenyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heteroaryl, wherein the (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, phenyl, 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heteroaryl may be each independently and optionally substituted with 1, 2, 3, or 4 of the following groups: —H, —F, —Cl, —Br, —I, —OH, —OCH 3 , —N(CH 3 ) 2 , and —CN; or two adjacent R 3 , along with the atoms connected thereto, are capable of forming 5- to 7-membered heterocycloalkyl or (C5-C7) cycloalkyl, wherein the 5- to 7-membered heterocycloalkyl or (C5-C7) cycloalkyl may be independently and optionally substituted with 1, 2, 3, or 4 of the following groups: —H, —F, —Cl, —Br, —I, —CH 3 , —OH, —CH 2 OCH 3 , —CH 2 N(CH 3 ) 2 , —OCH 3 , —N(CH 3 ) 2 , and —CN; and R 11 and R 12 are each independently —H, (C1-C3) alkyl or (C3-C6) cycloalkyl, or R 11 and R 12 on the same N atom, along with the N atom connected thereto, are capable of forming 4- to 6-membered heterocycloalkyl.

10 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 9 , wherein, in general formula (1), each R 3 is independently: —H, -D, —F, —Cl, —Br, —I, —OH, —CH 2 OCH 3 , —CH 2 N(CH 3 ) 2 , —OCH 3 , —N(CH 3 ) 2 , —CN, —C(O)NH 2 , —C(O)NH(CH 3 ), —C(O)N(CH 3 ) 2 , —NHC(O)CH 3 , —N(CH 3 )—C(O)CH 3 , —NHS(O) 2 CH 3 , —NCH 3 S(O) 2 CH 3 , —SCH 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 NH(CH 3 ), —S(O) 2 N(CH 3 ) 2 ,

11 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein, in general formula (1), structural unit is

is

12 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein, in general formula (1), ring B is (C6-C10) aryl or 5- to 10-membered heteroaryl.

13 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 12 , wherein, in general formula (1), ring B is:

14 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein, in general formula (1), each R 4 is independently —H, —F, —Cl, —Br, —I, —OH, —CH 2 OR 11 , —(CH 2 ) 2 OR 11 , —(CH 2 ) 3 OR 11 , —OR 11 , —CH 2 NR 11 R 12 , —(CH 2 ) 2 NR 11 R 12 , —(CH 2 ) 3 NR 11 R 12 , —NR 11 R 12 , —CN, —O(CH 2 ) 2 NR 11 R 12 , —N(R 12 )(CH 2 ) 2 NR 11 R 12 , —C(O)NR 11 R 12 , —NR 12 C(O)R 11 , —NR 12 S(O) 2 R 11 , —S(O) 2 R 11 , —SR 11 , —S(O) 2 NR 11 R 12 , (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, —CH 2 -4- to 11-membered heterocycloalkyl, 4- to 11-membered heterocycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered aryl, wherein the (C1-C4) alkyl, (C1-C4) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (C1-C4) alkoxy, —CH 2 -4- to 11-membered heterocycloalkyl, 4- to 11-membered heterocycloalkyl, 5- to 9-membered heteroaryl, or 5- to 9-membered aryl may be independently and optionally substituted with 1, 2, 3, or 4 of the following groups: —H, —F, —Cl, —Br, —I, —OH, —CH 2 OCH 3 , —(CH 2 ) 2 OCH 3 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —CH 2 N(CH 3 ) 2 , —(CH 2 ) 2 N(CH 3 ) 2 , —N(CH 3 ) 2 , —CN, —O(CH 2 ) 2 N(CH 3 ) 2 , —NH—(CH 2 ) 2 N(CH 3 ) 2 , —N(CH 3 )—(CH 2 ) 2 N(CH 3 ) 2 ,

or two adjacent R 4 on ring B, along with the atoms connected thereto, are capable of forming 5- to 7-membered heterocycloalkyl or (C5-C7) cycloalkyl, wherein the 5- to 7-membered heterocycloalkyl or (C5-C7) cycloalkyl may be independently and optionally substituted with 1, 2, 3, or 4 of the following groups: —H, —F, —Cl, —Br, —I, —OH, —CH 2 OCH 3 , —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —CH 2 N(CH 3 ) 2 , —(CH 2 ) 2 N(CH 3 ) 2 , —N(CH 3 ) 2 , —CN, —O(CH 2 ) 2 N(CH 3 ) 2 , —NH—(CH 2 ) 2 N(CH 3 ) 2 , —N(CH 3 )—(CH 2 ) 2 N(CH 3 ) 2 , —C(O)CH 3 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —S(O) 2 CH 3 , —SCH 3 , —S(O) 2 NH 2 , —S(O) 2 N(CH 3 ) 2 ,

and R 11 and R 12 are each independently —H, (C1-C3) alkyl or (C3-C6) cycloalkyl, or R 11 and R 12 on the same N atom, along with the N atom connected thereto, are capable of forming 4- to 6-membered heterocycloalkyl.

15 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 14 , wherein, in general formula (1), each R 4 is independently —H, —F, —Cl, —Br, —I, —OH, —CH 2 OCH 3 , —(CH 2 ) 2 OCH 3 , —(CH 2 ) 3 OCH 3 , —CH 2 OH, —(CH 2 ) 2 OH, —(CH 2 ) 3 OH, —CH 2 NH 2 , —(CH 2 ) 2 NH 2 , —(CH 2 ) 3 NH 2 , —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —OCF 3 , —OCF 2 H, —CH 2 N(CH 3 ) 2 , —(CH 2 ) 2 N(CH 3 ) 2 , —N(CH 3 ) 2 , —CN, —O(CH 2 ) 2 N(CH 3 ) 2 , —NH—(CH 2 ) 2 N(CH 3 ) 2 , —N(CH 3 )—(CH 2 ) 2 N(CH 3 ) 2 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —S(O) 2 CH 3 , —SCH 3 , —S(O) 2 NH 2 , —S(O) 2 N(CH 3 ) 2 ,

16 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 14 , wherein, in general formula (1), each R 4 is independently

17 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 14 , wherein, in general formula (1), two adjacent R 4 on ring B, along with the atoms connected thereto, are capable of forming 5- to 7-membered heterocycloalkyl, wherein the 5- to 7-membered heterocycloalkyl is:

or two adjacent R 4 on ring B, along with the atoms connected thereto, are capable of forming C5-7 cycloalkyl, wherein the 5- to 7-membered cycloalkyl is:

wherein the heterocycloalkyl and the cycloalkyl may be optionally substituted with 1, 2, 3, or 4 of the following groups: —H, —F, —Cl, —Br, —I, —OH, —CH 2 OCH 3 , —(CH 2 ) 2 OCH 3 , —(CH 2 ) 2 OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —CH 2 N(CH 3 ) 2 , —(CH 2 ) 2 N(CH 3 ) 2 , —N(CH 3 ) 2 , —CN, —O(CH 2 ) 2 N(CH 3 ) 2 , —NH—(CH 2 ) 2 N(CH 3 ) 2 , —N(CH 3 )—(CH 2 ) 2 N(CH 3 ) 2 , —C(O)CH 3 , —C(O)NH 2 , —C(O)N(CH 3 ) 2 , —S(O) 2 CH 3 , —SCH 3 , —S(O) 2 NH 2 , —S(O) 2 N(CH 3 ) 2 ,

18 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein, in general formula (1), structural unit

is:

19 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein, in general formula (1), structural unit

is:

20 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein, in general formula (1), structural unit

is:

21 . The compound, or the isomer, the crystalline form, the pharmaceutically acceptable salt, the hydrate or the solvate thereof according to claim 1 , wherein the compound has one of the following structures: