Fused-ring compounds as Wee-1 inhibitors

Abstract

A class of fused ring compounds as Wee-1 inhibitors. Specifically, it relates to a compound represented by general formula (I) and a method for preparing the same, and the use of the compound of general formula (I) and its isomers, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates as Wee-1 inhibitors. The compound and its isomers, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates can be used to prepare drugs for treating or preventing diseases associated with Wee-1 protein kinase.

Description

[0001] This application claims priority to Chinese patent application No. 2021107574524, filed on July 5, 2021. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0002] The present invention relates to the field of medicinal chemistry, and more specifically, to a class of fused ring compounds with Wee1 kinase inhibitory effects, as well as a preparation method and the use of such compounds in preparing drugs for treating or preventing related diseases mediated by Wee1. Background Art

[0003] Wee-1 protein kinase is an important negative regulatory protein in cell cycle checkpoints. Cell cycle checkpoints include the G1 phase checkpoint, which transitions from G1 (cell resting phase) to S phase (DNA synthesis phase), the G2 phase checkpoint, which transitions from G2 (cell division preparation phase) to M phase (cell division phase), and the spindle checkpoint, which transitions from M phase metaphase (mid-cell division phase) to anaphase (late cell division phase). Wee-1 protein kinase plays a key role in the G2 phase checkpoint. Cellular entry into the M phase depends on the activity of CDK1 kinase. Wee-1 inhibits CDK1 activity by phosphorylating Tyr 15 of the CDK1 protein, preventing cells from entering the M phase (cell division phase). Polo kinase phosphorylates Wee-1, activating the degradation of the Wee-1 protein and promoting cell entry into the M phase. It can be seen that the activity of Wee-1 kinase determines the activity of the G2 checkpoint, thereby regulating the transition of cells from G2 to M phase [Cell Cycle, 2013.12(19): p.3159-64.].

[0004] Cell cycle checkpoints are primarily activated after DNA damage and play an important role in the repair of DNA in cells. Normal activation of cell cycle checkpoints blocks the cell cycle and promotes DNA repair. Inhibiting the function of checkpoints prevents DNA damage from being repaired and causes cell apoptosis. Compared to normal cells, many tumor cells rely primarily on the activation of the G2 checkpoint to repair DNA damage and avoid apoptosis due to impaired function of p53, an important protein in the G1 checkpoint. Therefore, inhibiting the G2 checkpoint can selectively kill tumor cells. The important role of Wee-1 kinase activity in the G2 checkpoint suggests that Wee-1 kinase determines the repair or death of tumor cells after DNA damage. Inhibiting Wee-1 activity can promote tumor cells with unrepaired DNA damage to enter the M phase and induce apoptosis [Curr Clin Pharmacol, 2010.5(3):p.186-91.].

[0005] Studies have shown that in addition to its role in the G2 checkpoint, Wee-1 is also involved in DNA synthesis, DNA homology repair, chromosomal histone post-translational modification, and other functions closely related to tumor occurrence and development [J Cell Biol, 2011. 194(4): p.567-79.]. Wee-1 expression is significantly elevated in a large number of tumors including liver cancer, breast cancer, cervical cancer, melanoma, and lung cancer [PLoS One, 2009.4(4): p.e5120.; Hepatology, 2003.37(3): p.534-43.; Mol Cancer, 2014.13: p.72.]. High Wee-1 expression is positively correlated with tumor development and poor prognosis, suggesting that Wee-1 kinase may be involved in tumor occurrence and development. Studies in in vitro cell models and in vivo animal models have shown that inhibiting Wee-1 activity while inducing DNA damage can significantly inhibit the growth of various tumors [Cancer Biol Ther, 2010.9(7): p.514-22.; Mol Cancer Ther, 2009.8(11): p.2992-3000.].

[0006] Therefore, the development of specific small molecule inhibitors of highly active Wee-1 kinase has important clinical value for tumor treatment, especially targeting tumors with impaired G1 checkpoint such as P53 loss. Summary of the Invention

[0007] The present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0008]

[0009] In the general formula (1):

[0010] X is CH or N;

[0011] Ring A is a (C5-C11) partially unsaturated cycloalkyl group or a (5-11 membered) partially unsaturated heterocycloalkyl group;

[0012] Each R 1 are independently -H, -D, halogen, -OH, -(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 、-S(O)2NR 8 R 9 、 (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl or (C3-C9)cycloalkyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ; or 2 adjacent R 1 The atoms to which they are attached can together form a (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9; or two R on the same carbon atom in ring A 1 The carbon atoms to which they are connected can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ;

[0013] Y 1 N or CR 4 ;

[0014] Y 2 N or CR 5 ;

[0015] Y 3 N or CR 6 ;

[0016] R 4 、R 5 and R 6 are each independently -H, -D, halogen, -OH, -(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 、-S(O)2NR 8 R9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl or (C3-C9) cycloalkyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ; or R 5 and R 6 The atoms to which they are attached can together form a (5-9 membered) heterocycloalkyl, a (5-9 membered) heteroaryl or a (C5-C9) cycloalkyl, which may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ;

[0017] Ring B is a (C5-C11) partially unsaturated cycloalkyl group or a (5-11 membered) partially unsaturated heterocycloalkyl group;

[0018] X 1 for

[0019] X 2 For chemical bonds,

[0020] X 3 CH, N or CR c ;

[0021] X 4 CH, N or CR d ;

[0022] X 5 NR a or CH-R b ;

[0023] Each R 2 are independently -H, -D, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 、-S(O)2NR 8 R 9 、 (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 alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ; or 2 adjacent R 2 The atoms to which they are attached can together form a (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ; or two R on the same carbon atom in ring B 2 The carbon atoms to which they are connected can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9; or R 2 and an adjacent R e The atoms to which they are attached can together form a (5-7 membered) heterocycloalkyl or (C3-C9) cycloalkyl, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ;

[0024] R a -H, -(CH2) m OR 8 、-(CH2) m NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl, (C3-C14) cycloalkyl or (3-15 membered) heterocycloalkyl, wherein the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl groups may be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -D, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ;

[0025] R b -H, -(CH2) n OR 8 、-(CH2) n NR 8 R 9 , (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C14)cycloalkyl or (3-15 membered)heterocycloalkyl, wherein R 8 、R 9 , alkyl, haloalkyl, cycloalkyl and heterocycloalkyl may be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -D, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ;

[0026] R c and R d are independently -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 、-S(O)2NR 8 R 9, (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 said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ;

[0027] R e is -H, -D, halogen, (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 said alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyl, aryl, heterocycloalkyl and heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R8 and -S(O)2NR 8 R 9 ;

[0028] R f and R g are independently -H, -D, -(CH2) n OR 8 、-(CH2) n NR 8 R 9 , -CN, (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 said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl can each be independently optionally substituted with 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ; or R f and R g The carbon atoms to which they are connected can together form a (4-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ; or R f and an adjacent R e The atoms to which they are attached can together form a (C3-C9) cycloalkyl or a (3-11 membered) heterocycloalkyl, wherein the cycloalkyl and heterocycloalkyl groups can each be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) p R 8 and -S(O)2NR 8 R 9 ;

[0029] R 3 is (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C5)alkenyl, (C2-C5)alkynyl or (C3-C6)cycloalkyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -D, halogen, R 7 、R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-S(O) pR 8 and -S(O)2NR 8 R 9 ;

[0030] R 7 is (C1-C5)haloalkyl, (C2-C5)alkenyl or (C2-C5)alkynyl;

[0031] R 8 and R 9 Each is independently -H, (C1-C6) alkyl, (C1-C3) haloalkyl or (C3-C14) cycloalkyl, or R on the same nitrogen atom 8 and R 9 The nitrogen atoms to which they are attached can together form a (3-11 membered) heterocycloalkyl group, which can be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 10 AND-OR 10 ;

[0032] R 10 is -H, (C1-C6)alkyl or (C3-C14)cycloalkyl; and

[0033] 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 m is an integer of 1, 2 or 3.

[0034] In another preferred embodiment, in the general formula (1), ring A is a (C5-C7) partially unsaturated cycloalkyl group or a (5-7 membered) partially unsaturated heterocycloalkyl group.

[0035] In another preferred embodiment, wherein in the general formula (1), ring A is:

[0036]

[0037]

[0038] In another preferred embodiment, wherein in the general formula (1), each R 1 are independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OR 8 、-CH2NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R8 、-SR 8 、-S(O)2R 8 、-S(O)2NR 8 R 9 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl or (C3-C6) cycloalkyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -N(CH3)2 and -CN; or 2 adjacent R 1 The atoms to which they are attached can together form a (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, which may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2 and -CN; or 2 R on the same carbon atom on ring A 1 Together with the carbon atoms to which they are attached, they can form a (4-7 membered) heterocycloalkyl group or a (C3-C6) cycloalkyl group, and the heterocycloalkyl group and cycloalkyl group may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2 and -CN.

[0039] In another preferred embodiment, wherein in the general formula (1), each R 1 Independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -OCF3, -N(CH3)2, -CN, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -NHC(O )CH3, -N(CH3)-C(O)CH3, -NHS(O)2CH3, -N(CH3)-S(O)2CH3, -SCH3, -S(O)2CH3 and -S(O)2NH2, -S(O)2NH(CH3), -S(O)2N(CH3)2, -CD3, -CD2CD3,

[0040] In another preferred embodiment, wherein in the general formula (1), R 4 、R 5 and R 6 Each independently represents -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OR 8 、-CH2NR8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-SR 8 、-S(O)2R 8 、-S(O)2NR 8 R 9 , (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C3-C6)cycloalkyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -N(CH3)2 and -CN; or R 5 and R 6 The atoms to which they are attached can together form an aryl group, a (5-6 membered) heterocycloalkyl group, a (5-6 membered) heteroaryl group or a (C5-C6) cycloalkyl group, wherein the aryl group, the heterocycloalkyl group, the heteroaryl group and the cycloalkyl group may be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2 and -CN;

[0041] In another preferred embodiment, wherein in the general formula (1), R 4 、R 5 and R 6 Each is independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -OCF3, -N(CH3)2, -CN, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -NHC(O)CH3, -N(CH3)-C(O)CH3, -NHS(O)2CH3, -N(CH3)-S(O)2CH3, -SCH3, -S(O)2CH3 and -S(O)2NH2, -S(O)2NH(CH3), -S(O)2N(CH3)2,

[0042] In another preferred embodiment, wherein in the general formula (1), the structural unit for:

[0043] In another preferred embodiment, wherein in the general formula (1), ring B is (C5-C8) partially unsaturated cycloalkyl or (5-8 membered) partially unsaturated heterocycloalkyl; and R e For: -H, -D, -F, -CH3, -OCH3, Or -CH2CH3.

[0044] In another preferred embodiment, wherein in the general formula (1), the structural unit for:

[0045]

[0046] In another preferred embodiment, wherein in the general formula (1), X 1 for:

[0047] In another preferred embodiment, wherein in the general formula (1), X 2 For: chemical bonds,

[0048] In another preferred embodiment, wherein in the general formula (1), when X 5 NR a When R a -H, -(CH2)2OR 8 、-(CH2)2NR 8 R 9 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C3-C6) cycloalkyl or (4-7 membered) heterocycloalkyl, wherein the alkyl, haloalkyl, cycloalkyl and heterocycloalkyl are independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -D, -F, -OH, -CH3, -CH2OCH3, -(CH2)2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2 and -CN.

[0049] In another preferred embodiment, wherein in the general formula (1), when X 5 NR a When R aFor: -H, -(CH2)2OCH3, -(CH2)2OH, -(CH2)2N(CH3)2,

[0050] In another preferred embodiment, wherein in the general formula (1), when X 5 CH-R b When R b -H, -(CH2)2OR 8 、-NR 8 R 9 、-(CH2)2NR 8 R 9 , (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C6)cycloalkyl or (4-7 membered)heterocycloalkyl, wherein R 8 、R 9 , alkyl, haloalkyl, cycloalkyl and heterocycloalkyl may independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -D, -F, -OH, -CH3, -CH2OCH3, -(CH2)2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2 and -CN.

[0051] In another preferred embodiment, wherein in the general formula (1), when X 5 CH-R b When R b For: -H, -N(CH3)2, -N(CD3)2, -(CH2)2OCH3, -(CH2)2OH, -(CH2)2N(CH3)2,

[0052] In another preferred embodiment, wherein in the general formula (1), X 3 is: CH, N or CR c , wherein the R c For: -H, -F, -Cl, -Br, -I, -OH, -CH3, -CH2OCH3, -(CH2)2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2, or -CN.

[0053] In another preferred embodiment, wherein in the general formula (1), X 4 is: CH, N or CR d, wherein the R d For: -H, -F, -Cl, -Br, -I, -OH, -CH3, -CH2OCH3, -(CH2)2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2, or -CN.

[0054] In another preferred embodiment, wherein in the general formula (1), each R 2 are independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OR 8 、-CH2NR 8 R 9 、-OR 8 、-NR 8 R 9 、-CN、-C(O)NR 8 R 9 、-NR 9 C(O)R 8 、-NR 9 S(O)2R 8 、-SR 8 、-S(O)2R 8 、-S(O)2NR 8 R 9 , (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, phenyl, (4-8 membered) heterocycloalkyl or (5-6 membered) heteroaryl, wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocycloalkyl and heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH3, -OCH3, -N(CH3)2 and -CN; or 2 adjacent R 2 The atoms to which they are attached can together form a (5-7 membered) heterocycloalkyl or (C3-C6) cycloalkyl group, which may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2 and -CN; or 2 R on the same carbon atom on the B ring 2The carbon atoms to which they are attached can together form a (4-7 membered) heterocycloalkyl group or a (C3-C6) cycloalkyl group, which may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2 and -CN; or R 2 and an adjacent R e Together with the atoms to which they are attached, they can form a (5-7 membered) heterocycloalkyl group or a (C3-C6) cycloalkyl group, which may be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2 and -CN.

[0055] In another preferred embodiment, wherein in the general formula (1), wherein in the general formula (1), each R 2 are independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -OCF3, -N(CH3)2, -CN, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -NHC(O)CH3, -N(CH3)-C(O)CH3, -NHS(O)2CH3, -N(CH3)-S(O)2CH3, -SCH3, -S(O)2CH3 and -S(O)2NH2, -S(O)2NH(CH3), -S(O)2N(CH3)2,

[0056] In another preferred embodiment, wherein in the general formula (1), the structural unit for:

[0057]

[0058]

[0059]

[0060]

[0061] In another preferred embodiment, wherein in the general formula (1), R 3is (C1-C4)alkyl, (C1-C4)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C3-C5)cycloalkyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl groups may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -D, -F, -CN,

[0062] In another preferred embodiment, wherein in the general formula (1), R 3 for:

[0063] In another specific embodiment of the present invention, the compound of formula (1) has one of the following structures:

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and / or excipient, and a compound of the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0071] Another object of the present invention is to provide the use of the compound represented by general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical compositions for preparing drugs for treating, regulating or preventing diseases related to Wee-1 protein; the disease is preferably cancer, and the cancer is blood cancer and solid tumor.

[0072] Another object of the present invention is to provide a method for treating, regulating or preventing diseases related to Wee-1 protein, comprising administering to a subject a therapeutically effective amount of a compound represented by the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates or the above-mentioned pharmaceutical composition; the disease is preferably cancer, and the cancer is blood cancer and solid tumor.

[0073] By synthesizing and carefully studying a variety of new compounds having Wee-1 inhibitory effects, the inventors found that among the compounds of general formula (1), the compounds unexpectedly have strong Wee-1 inhibitory activity.

[0074] It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0075] Synthesis of compounds

[0076] The following specifically describes the preparation methods of the compound of general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0077] The compounds of formula (1) described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein can be varied. The starting materials used in the synthesis of the compounds can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulae provided herein.

[0078] In one aspect, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of the compounds used, reaction temperatures, reaction times, etc., are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art. In one aspect, the present invention also provides a method for preparing the compound of formula (1), wherein the compound of formula (1) can be prepared using the following general reaction scheme 1:

[0079] General reaction scheme 1

[0080]

[0081] An embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein R 1 、R 2 、R 3 、R e 、X 1 、X 2 、X 3 、X 4 、X 5 , X, Y 1 、Y 2 、Y 3 , s, q, Ring A, and Ring B are as defined above, H represents hydrogen, N represents nitrogen, Z represents chlorine, bromine, or iodine, S represents sulfur, and O represents oxygen. As shown in General Reaction Scheme 1, compounds 1-1 and 1-2 undergo a substitution reaction under alkaline conditions to produce compound 1-3, compound 1-3 reacts under acidic conditions to produce compound 1-4, compound 1-4 reacts under alkaline conditions to produce 1-5, compound 1-5 reacts with compound 1-6 under alkaline conditions to produce compound 1-7, compound 1-7 reacts with m-CPBA to produce compound 1-8, and compound 1-8 and 1-9 undergo a substitution reaction to produce target compound 1-10.

[0082] Further forms of compounds

[0083] "Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a substance that does not cause undesirable biological effects or interact in a deleterious manner with any of its components when administered to a subject.

[0084] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain specific aspects, the pharmaceutically acceptable salt is obtained by reacting the compound of formula (1) with an acid, such as an inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, formic acid, acetic acid, propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and an acidic amino acid such as aspartic acid and glutamic acid.

[0085] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystallized forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water / organic solvent, using organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated forms are considered to be equivalent to the unsolvated forms.

[0086] In other embodiments, the compound of formula (1) is prepared in different forms, including but not limited to, amorphous, crushed and nano-particle forms. In addition, the compound of formula (1) includes crystalline forms and can also be polymorphic. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs generally have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.

[0087] In another aspect, compounds of formula (1) may have chiral centers and / or axial chirality and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially purified compounds are included within the scope of the present invention. The present invention is intended to include all such isomeric forms of these compounds.

[0088] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) and C-14( 14 C). For example, deuterated compounds can be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0089] the term

[0090] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. It should be noted that, throughout the specification and the appended claims, the singular forms "a," "an," and "an" include plural referents unless the context clearly indicates otherwise. Conventional methods, such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology, are employed unless otherwise indicated. Throughout this application, the use of "or" or "and" means "and / or," unless otherwise indicated.

[0091] Unless otherwise specified, for the convenience of compound naming, the definition of Ring B in this application assumes that Ring B is named as an independent group (not fused with other rings). In Formula (1), Ring B is fused with the adjacent group.

[0092] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. Preferred are lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t Bu.

[0093] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms. Preferably, the lower alkenyl group contains 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl.

[0094] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Preferably, the lower alkynyl group contains 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl.

[0095] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic). If the carbocyclic ring contains at least one double bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl group", or if the carbocyclic ring contains at least one triple bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl group". Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. The ring-forming carbon atoms of the cycloalkyl group may optionally be oxidized to form an oxo or sulfide group. Cycloalkyl groups also include cycloalkylene groups. In some embodiments, the cycloalkyl group contains 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl group contains 1 or 2 double bonds (partially unsaturated cycloalkyl groups). In some embodiments, the cycloalkyl group may be fused with an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, the cycloalkyl group may be fused with an aryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, cycloalkyl groups can be fused with aryl groups and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl groups and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.

[0096] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0097] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group. Aryl is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

[0098] Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.

[0099] Unless otherwise specified, "arylene" refers to a divalent aromatic radical as defined above. Examples of arylene radicals include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.

[0100] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl group is monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,

[0101] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0102] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and phosphorus. If the heterocycloalkyl contains at least one double bond, the partially unsaturated heterocycloalkyl may be referred to as a "heterocycloalkenyl", or if the heterocycloalkyl contains at least one triple bond, the partially unsaturated heterocycloalkyl may be referred to as a "heterocycloalkynyl". The heterocycloalkyl may include a monocyclic, bicyclic, spirocyclic or polycyclic (e.g., having two fused or bridged rings) ring system. In some embodiments, the heterocycloalkyl is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl may be optionally oxidized to form oxo or sulfide groups or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) 2, N-oxides, etc.), or the nitrogen atom may be quaternized. The heterocycloalkyl may be connected via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, heterocycloalkyl contains 0 to 3 double bonds. In some embodiments, heterocycloalkyl contains 0 to 2 double bonds. The definition of heterocycloalkyl also includes parts with one or more aromatic rings fused to the heterocycloalkyl ring (i.e., sharing a key with it), such as benzo derivatives of piperidine, morpholine, azacycloheptatriene or thienyl. The heterocycloalkyl containing fused aromatic rings can be connected via any ring-forming atoms, including the ring-forming atoms of the fused aromatic ring. Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanediyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazole ... oxazolo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactamyl, valerolactamyl, imidazolinyl, hydantoinyl, dioxolane, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyranonyl, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolinyl,

[0103] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

[0104] Unless otherwise specified, "oxo" refers to =0; for example, a carbonyl group substituted with an oxo group is a "carbonyl group." The group formed by sulfur being replaced by an oxo group is called "sulfinyl" The group formed by sulfur being substituted by two oxo groups is called "sulfonyl"

[0105] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group indicates that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0106] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0107] The substituent "-O-CH2-O-" refers to the substituent in which two oxygen atoms are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, for example:

[0108] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0109] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0110] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thiopyranyl are six-membered rings, while cyclopentyl, pyrrolyl, furanyl, and thiophenyl are five-membered rings.

[0111] The term "fragment" refers to a specific part or functional group of a molecule. A chemical fragment is generally considered to be a chemical entity contained in or attached to a molecule.

[0112] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed key Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0113] Unless otherwise stated, Indicates a single bond or a double bond.

[0114] Specific pharmaceutical and medical terms

[0115] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0116] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0117] "Active ingredient" refers to the compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0118] The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0119] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0120] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0121] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0122] Therapeutic uses

[0123] The compounds of formula (1) or pharmaceutical compositions of the present invention are generally useful for inhibiting Wee-1 kinase, and are therefore useful for treating one or more conditions associated with Wee-1 kinase activity. Therefore, in certain embodiments, the present invention provides a method for treating Wee-1 kinase-mediated conditions, comprising administering to a patient in need thereof a compound of formula (1) or a pharmaceutically acceptable composition thereof.

[0124] In some embodiments, a method for treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of formula (1), wherein the cancer includes, but is not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome, and myeloproliferative syndrome) and solid tumors (cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary, and soft tissue cancers and osteosarcoma, as well as stromal tumors).

[0125] Route of administration

[0126] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0127] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0128] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0129] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0130] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0131] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0132] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0133] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0134] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0135] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0136] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compounds of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, all of which are within the skill of a skilled physician.

[0137] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features. DETAILED DESCRIPTION

[0138] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0139] In all embodiments, 1 H-NMR was recorded on a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were by volume.

[0140] The present invention uses the following abbreviations: Ac2O represents acetic anhydride; (Boc)2O represents di-tert-butyl dicarbonate; CDCl3 represents deuterated chloroform; EtOAc represents ethyl acetate; Hexane represents n-hexane; HPLC represents high performance liquid chromatography; MeCN represents acetonitrile; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; Dioxane represents 1,4-dioxane; DMF represents N,N-dimethylformamide; DMP represents Dess-Martin periodinane; DMAP represents 4-(dimethylamino)pyridine; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; EtMgBr represents ethylmagnesium bromide; hr represents hour; IPA represents isopropyl alcohol; min represents minute; K2CO3 represents potassium carbonate; KOAc represents potassium acetate; KOH represents potassium hydroxide; K3P represents potassium hydroxide. O4 represents potassium phosphate; min represents minutes; MeOH represents methanol; MeMgBr represents methylmagnesium bromide; MS represents mass spectrometry; MsOH represents methanesulfonic acid; m-CPBA represents m-chloroperbenzoic acid; n-BuLi represents n-butyllithium; NMR represents nuclear magnetic resonance; Pd / C represents palladium on carbon; Pd(PPh3)4 represents tetrakistriphenylphosphine palladium; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0); PE represents petroleum ether; POBr3 represents phosphorus oxybromide; POCl3 represents phosphorus oxychloride; TEA represents triethylamine; TFA represents trifluoroacetic acid; T3P represents 1-propylphosphonic anhydride; XantPhos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; TLC represents thin layer chromatography; XPhos represents 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

[0141] Preparation Example 1-3 Synthesis of Intermediates A-1, A-2 and A-3

[0142]

[0143] Step 1: Synthesis of compound int_A-1-2:

[0144]

[0145] Int_A-1-1 (50 g, 284 mmol), methylamine hydrochloride (57.5 g, 851 mmol), and TEA (144 g, 1.42 mol, 197 mL) were dissolved in acetonitrile (600 mL). T3P (217 g, 341 mmol, 203 mL, 50% purity) was added dropwise at room temperature. After addition, the mixture was heated to 50°C and reacted for 16 hours. The reaction mixture was diluted with 1500 mL of ethyl acetate and washed with aqueous NaHCO3 (400 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product as a white solid (50 g, 264 mmol, yield: 93.1%). The crude product was used directly in the next reaction.

[0146] 1 H NMR: (400MHz, Chloroform-d) δ7.12-7.01(m,3H),6.10-5.71(m,1H),2.93(d,J=4.9Hz,3H),2.83(br s,2H),2.79-2.71(m,2H),1.84-1.65(m,4H)

[0147] MS(ESI):190[M+H] + .

[0148] Step 2: Synthesis of compound int_A-1-3:

[0149]

[0150] Int_A-1-2 (50 g, 264 mmol) was dissolved in THF (500 mL) and n-BuLi (2.5 M, 275 mL) was slowly added dropwise at -23°C under nitrogen. DMF (48.3 g, 660 mmol, 50.8 mL) was then slowly added dropwise at -23°C. HCl solution (6 M, 300 mL) was then slowly added dropwise at 20°C. The reaction mixture was diluted with 100 mL of water and extracted with ethyl acetate (500 mL*3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain a yellow solid (55 g, crude product). The crude product was used directly in the next reaction.

[0151] 1 H NMR: (400MHz, Chloroform-d) δ8.36-8.20(m,1H),7.46-7.32(m,2H),6.84(s,1 H),3.63-3.52(m,3H),2.99-2.92(m,3H),2.75-2.69(m,2H),2.01-1.90(m,2H)

[0152] MS(ESI):200[M+H] + .

[0153] Step 3: Synthesis of compound int_A-1-4:

[0154]

[0155] Int_A-1-3 (55 g, 276 mmol) and 20 g of palladium on carbon were suspended in methanol (800 mL) and stirred at 30°C overnight under hydrogen pressure (50 psi). The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 3 / 1) to give a yellow solid (38.5 g, yield: 69.3%).

[0156] 1 H NMR: (400MHz, DMSO-d6) δ7.71-7.62(m,1H),7.28-7.20(m,2H),3.42(dd,J=5.6,11.9Hz,1H),3.25(t,J=1 2.5Hz,1H),3.13-2.99(m,4H),2.87-2.69(m,2H),2.06-1.90(m,2H),1.75-1.61(m,1H),1.41-1.22(m,1H)

[0157] MS(ESI):202[M+H] + .

[0158] Step 4: Synthesis of compound int_A-1-5:

[0159]

[0160] Int_A-1-4 (3.1 g, 19.2 mmol) was dissolved in H2SO4 (300 mL). KNO3 (17.9 g, 177 mmol) was slowly added over 3 hours at 0°C. The mixture was then warmed to room temperature and stirred for 2 hours. TLC indicated the reaction was complete. The reaction solution was diluted with 500 mL of water, resulting in the precipitation of a large amount of solid. The precipitate was filtered and dried to yield a yellow solid (79 g, crude product). The crude product was used directly in the next reaction.

[0161] MS(ESI):247[M+H] + .

[0162] Step 5: Synthesis of compound int_A-1-6:

[0163]

[0164] Int_A-1-5 (4.9 g, 19.9 mmol) and palladium on carbon (2 g, 19.9 mmol, 10% purity) were suspended in methanol (100 mL) and reacted at 25°C under hydrogen pressure (50 psi) for 16 hours. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 1 / 2) to give a yellow solid (1.44 g, yield: 33.5%).

[0165] 1 H NMR: (400MHz, Chloroform-d) δ7.24(d,J=2.3Hz,1H),6.56(d,J=2.0Hz,1H),3.67(br s,2H),3.32-3.25(m,2H),3.19-3.13(m,3H),3.09-2.97(m,1H),2.81- 2.65(m,2H),2.07-1.90(m,2H),1.78-1.62(m,1H),1.37-1.23(m,1H).

[0166] MS(ESI):217[M+H] + .

[0167] Step 6: Synthesis of Intermediate A-1:

[0168]

[0169] int_A-1-6 (7 g, 32.4 mmol) was dissolved in anhydrous tetrahydrofuran (300 mL), and LiAlH4 (6.14 g, 162 mmol) was added at 0°C. Under nitrogen protection, the mixture was heated to 25°C and reacted for 2 hours. Water was slowly added to the reaction solution to quench the reaction, while maintaining the reaction temperature between 0 and 10°C. The reaction solution was diluted with 800 mL of ethyl acetate and washed with water (100 mL*3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and evaporated under reduced pressure to obtain a crude product. The crude product was subjected to column chromatography (SiO2, DCM / (MeOH+1% NH4OH) = 1 / 0 to 10 / 1) to obtain a yellow oil (6.25 g, yield: 95.5%).

[0170] 1H NMR: (400MHz, Chloroform-d) δ6.31 (s, 1H), 6.21 (s, 1H), 3.88 (d, J = 15.1Hz, 1H), 3.62-3.34 (br s,2H),3.26(d,J=15.1Hz,1H),2.98-2.69(m,4H),2.42(s,3H),2.03(t,J=10.7H z,1H),1.92(tdd,J=3.4,6.5,13.1Hz,1H),1.88-1.75(m,2H),1.34-1.17(m,1H).

[0171] MS(ESI):203[M+H] + .

[0172] Step 7: Synthesis of intermediates A-2 and A-3:

[0173]

[0174] int_A-1 (1.5 g, 7.41 mmol) was chirally separated by preparative supercritical fluid chromatography (prep SFC) (SFC chiral separation conditions: instrument: Waters SFC350; chromatographic column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: A: CO2, B: IPA (0.1% NH3H2O); gradient: B%: 50%-50%; flow rate: 200 mL / min; column temperature: 40°C), and the fractionated liquid was concentrated under reduced pressure and freeze-dried to obtain a yellow oily substance int_A-2 (peak 1, the configuration is speculated, 438 mg, yield: 29.20%) and a yellow oily substance int_A-3 (peak 2, the configuration is speculated, 450 mg, yield: 30.00%).

[0175] A-2: 1 H NMR: (400MHz, Chloroform-d) δ6.32 (s, 1H), 6.22 (s, 1H), 3.88 (d, J = 15.1Hz, 1H), 3.48 (br s, 2H), 3.26 (br d,J=15.1Hz,1H),2.93(dd,J=4.6,10.5Hz,1H),2.90-2.80(m,1H),2.79-2.64(m,2H),2.42(s,3H ),2.02(t,J=10.7Hz,1H),1.92(dtd,J=3.6,6.5,9.8Hz,1H),1.87-1.79(m,2H),1.36-1.15(m,1H)

[0176] MS(ESI):203[M+H] + .

[0177] A-3: 1 H NMR: (400MHz, Chloroform-d) δ6.32 (s, 1H), 6.22 (s, 1H), 3.87 (d, J = 15.3Hz, 1H), 3.47 (br s,2H),3.26(d,J=15.1Hz,1H),2.93(dd,J=4.8,10.6Hz,1H),2.89-2.80(m,1H),2.80-2.65(m,2 H),2.42(s,3H),2.02(t,J=10.7Hz,1H),1.97-1.88(m,1H),1.87-1.75(m,2H),1.35-1.17(m,1H)

[0178] MS(ESI):203[M+H] + .

[0179] Preparation Example 4-6 Synthesis of Intermediates A-73, A-74 and A-75

[0180]

[0181] Step 1: Synthesis of compound int_A-73-2:

[0182]

[0183] Dissolve Int_A-73-1 (100 g, 504.6 mmol) and methylamine (156.7 g, 1.51 mol, 30% purity) in ethanol (1200 mL) and heat to 80°C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product (213 g, 99.9% yield), which was used directly in the next reaction.

[0184] 1 H NMR: (400MHz, Chloroform-d). δ = 8.60 (dd, J = 0.9, 7.3Hz, 1H), 8.21 (dd, J = 0.8, 8.3Hz, 1H), 7.83-7.71 (m, 1H), 3.57 (s, 2H)

[0185] Step 2: Synthesis of compound int_A-73-3:

[0186]

[0187] Int_A-73-2 (50 g, 236.7 mmol) and palladium on carbon (25 g, 10% purity) were suspended in acetic acid (500 mL) and stirred at 30° C. under hydrogen pressure (50 psi) for 40 hours. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by column chromatography (SiO 2 , PE / EtOAc = 1 / 0 to 3 / 1) to give a yellow solid (90 g, yield: 29.4%).

[0188] 1 H NMR: (400MHz, Chloroform-d). δ = 7.98-7.89 (m, 1H), 7.33-7.21 (m, 2H), 3.65 (dd, J = 4.8, 11.6Hz, 1H), 3.34-3.26 (m, 3H),2.92-2.73(m,2H),2.68-2.57(m,1H),2.06(qdd,J=3.6,6.6,13.5Hz,1H),1.90-1.76(m,1H),1.70-1.54(m,1H)

[0189] Step 3: Synthesis of compound int_A-73-4:

[0190]

[0191] Int_A-73-3 (33 g, 153.3 mmol) was dissolved in DMF (500 mL). NaH (9.20 g, 230.0 mmol, 60% purity) was added to the solution under nitrogen at 0°C. The reaction mixture was allowed to react at 0°C for half an hour. MeI (32.64 g, 223.0 mmol, 14.32 mL) was slowly added dropwise to the reaction mixture, and the temperature was then raised to 25°C for 2 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was poured into 1000 mL of ice water, and the aqueous phase was extracted with ethyl acetate (1000 mL x 2). The organic phases were combined and washed with saturated brine (500 mL x 4), dried over magnesium sulfate, filtered, and concentrated to obtain the crude product. Column chromatography (SiO2, PE / EtOAc = 10 / 0 to 10 / 1) afforded a white solid (80 g, yield: 75.9%).

[0192] 1 H NMR: (400MHz, Chloroform-d).δ=7.99-7.88(m,1H),7.30-7.14(m,2H),3.32-3.21(m,2H),2.99-2 .85(m,2H),2.79-2.69(m,1H),2.27(td,J=3.3,13.1Hz,1H),2.09-1.93(m,2H),1.90-1.80(m,1H)

[0193] Step 4: Synthesis of compound int_A-73-5:

[0194]

[0195] Int_A-73-4 (40 g, 174.5 mmol) was dissolved in H2SO4 (400 mL). KNO3 (19.40 g, 191.9 mmol) was slowly added at 0°C under nitrogen protection. The mixture was stirred at 0°C for half an hour. TLC indicated the reaction was complete. The reaction solution was poured into 1000 mL of ice water, and the aqueous phase was extracted with ethyl acetate (1000 mL x 2). The organic phases were combined and washed with saturated brine (500 mL x 4), dried over magnesium sulfate, filtered, and concentrated to obtain a crude product (95 g, yield: 99.3%), which was used directly in the next reaction.

[0196] Step 5: Synthesis of compound int_A-73-6:

[0197]

[0198] int_A-73-5 (30 g, 109.4 mmol) and palladium on carbon (15 g, 10% purity) were suspended in methanol (500 mL) and reacted at 25°C under hydrogen pressure (25 psi) for 5 hours. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, PE / EtOAc = 10 / 0 to 10 / 7) to give a yellow solid (13.20 g, yield: 16.5%).

[0199] 1 H NMR (400MHz, Chloroform-d) δ = 7.31 (d, J = 2.3Hz, 1H), 6.67 (d, J = 2.3Hz, 1H), 3.90-3.50 (m, 2H), 3.36- 3.28(m,4H),2.91-2.81(m,1H),2.77-2.66(m,1H),2.34-2.25(m,1H),2.10-1.81(m,4H),1.45(s,3H)

[0200] Step 6: Synthesis of intermediate A-73:

[0201]

[0202] Int_A-73-6 (12 g, 49.12 mmol) was dissolved in anhydrous tetrahydrofuran (500 mL) and LiAlH4 (18.64 g, 491.2 mmol) was added at 0 ° C. Under nitrogen protection, the mixture was heated to 25 ° C and reacted for 16 hours. Na2SO4.10H2O (100 g) was slowly added to the reaction solution to quench the reaction, and the reaction temperature was maintained at 0-10 ° C. The reaction solution was filtered and the filter cake was washed with dichloromethane (500 mL). The filtrate was combined and concentrated under reduced pressure to obtain a crude product. The crude product was column chromatography ( 120g Silica Flash Column, Eluent of 0-10% MeOH / DCM) = 1 / 0 to 10 / 1) to give a yellow oil (9.4 g, yield: 88.5%).

[0203] 1 H NMR (400MHz, Chloroform-d) δ = 6.33 (s, 1H), 6.22 (dd, J = 0.7, 1.5Hz, 1H), 3.96 (d, J = 15.3Hz, 1H), 3.47 (br s,2H),3.21(d,J=15.3Hz,1H),2.94-2.81(m,1H),2.75-2.60(m,2H),2.43(s,3H),2.18-2.01 (m,2H),1.88-1.76(m,1H),1.57(ddd,J=3.2,5.4,12.6Hz,1H),1.51-1.37(m,1H),1.33(s,3H)

[0204] Step 6: Synthesis of intermediates A-74 and A-75:

[0205]

[0206] int_A-73 (10 g, 46.30 mmol) was chirally separated by preparative supercritical fluid chromatography (prep SFC) (SFC chiral separation conditions: instrument: Waters SFC350; chromatographic column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: A: CO2, B: ethanol (0.1% NH3H2O); gradient: B%: 50%-50%; flow rate: 200 mL / min; column temperature: 40°C), and the fractions were concentrated under reduced pressure and freeze-dried to obtain yellow oil A-74 (peak 1, configuration is speculated, 4.5 g, yield: 42.4%) and yellow oil A-75 (peak 2, configuration is speculated, 4.5 g, yield: 42.4%).

[0207] A-74:1 H NMR: (400MHz, Chloroform-d). δ = 6.23 (s, 1H), 6.13 (s, 1H), 3.86 (br d, J = 15.3Hz, 1H), 3.37 (br s,2H),3.11(d,J=15.3Hz,1H),2.86-2.71(m,1H),2.68-2.49(m,2H),2.33(s,3H),2.09-1.95 (m,2H),1.79-1.68(m,1H),1.54-1.42(m,1H),1.34(td,J=6.3,12.6Hz,1H),1.27-1.18(m,3H)

[0208] A-75: 1 H NMR: (400MHz, Chloroform-d). δ = 6.23 (s, 1H), 6.13 (s, 1H), 3.86 (br d, J = 15.3Hz, 1H), 3.37 (br s,2H),3.12(d,J=15.3Hz,1H),2.85-2.71(m,1H),2.68-2.50(m,2H),2.33(s,3H),2.10- 1.95(m,2H),1.79-1.62(m,1H),1.53-1.41(m,1H),1.39-1.29(m,1H),1.25-1.13(m,3H)

[0209] Using the above synthesis method and different starting materials, the target intermediates A-4 to A-72 and A-76 to A-153 in Table 1 can be obtained.

[0210] Table 1

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219] Preparation Example 7-9 Synthesis of Intermediates B-1, B-2 and B-3

[0220]

[0221] Step 1: Synthesis of compound int_B-1-2:

[0222]

[0223] To int_B-1-1 (90 g, 1.07 mol, 94.74 mL) and acrylonitrile (28.39 g, 534.97 mmol, 35.48 mL) were added tetrahydropyrrole (1.92 g, 26.96 mmol, 2.25 mL) and acetic acid (236.44 mg, 3.94 mmol, 225.18 uL). The mixture was heated to 120°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove the acetic acid to obtain a crude product (100 g, yield: 68.1%), which was used directly in the next reaction.

[0224] MS(ESI):138[M+H] + .

[0225] Step 2: Synthesis of compound int_B-1-3:

[0226]

[0227] To int_B-1-2 (40 g, 291.59 mmol) was added sulfuric acid (243.09 g, 2.48 mol, 132.11 mL). The mixture was heated to 40°C under nitrogen for 12 hours. The reaction mixture was cooled to room temperature, the pH was adjusted to 7-8 with aqueous ammonia, filtered, and dried under reduced pressure to obtain a crude product (20 g, yield: 25.4%), which was used directly in the next reaction.

[0228] MS(ESI):136[M+H] + .

[0229] Step 3: Synthesis of compound int_B-1-4:

[0230]

[0231] Dissolve int_B-1-3 (17 g, 125.77 mmol) in phosphorus oxychloride (84.08 g, 548.38 mmol, 50.96 mL) and slowly add N,N-dimethylaniline (15.24 g, 125.77 mmol, 15.94 mL). The mixture was heated to 100 ° C under nitrogen protection and reacted for 8 hours. The reaction solution was cooled to room temperature and poured into ice water for quenching. The aqueous phase was extracted with ethyl acetate (200 mL * 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient) to give a yellow solid (14 g, yield: 72.5%).

[0232] Step 4: Synthesis of compound int_B-1-5:

[0233]

[0234] Dissolve int_B-1-4 (14 g, 91.14 mmol) in toluene (420 mL) and slowly add tribromophosphine oxide (57.48 g, 200.51 mmol, 20.38 mL). Heat the mixture to 130°C under nitrogen for 16 hours. Cool the reaction mixture to room temperature, remove the solvent under reduced pressure, and adjust the pH to 7-8 with 1M aqueous sodium hydroxide. Pour the mixture into ice water, extract the aqueous phase with ethyl acetate (200 mL x 3), and dry the organic phase over anhydrous sodium sulfate and concentrate under reduced pressure to obtain a crude product (14.51 g). This crude product can be used directly in the next reaction.

[0235] MS(ESI):198[M+H] + .

[0236] Step 5: Synthesis of compound int_B-1-6:

[0237]

[0238] Dissolve int_B-1-5 (15.50 g, 78.26 mmol) in dichloromethane (150 mL) and slowly add m-CPBA (23.83 g, 117.39 mmol, 85% purity). The mixture was reacted at room temperature for 16 hours. The reaction solution was adjusted to pH 7-8 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with ethyl acetate (200 mL*3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-60% Ethylacetate / Petroleum ether gradient) to give a brown solid (10 g, yield: 59.7%).

[0239] Step 6: Synthesis of compound int_B-1-7:

[0240]

[0241] Dissolve int_B-1-6 (7 g, 32.70 mmol) in acetic anhydride (104.32 g, 1.02 mol, 95.71 mL). The mixture was heated to 120 ° C and reacted for 16 hours. The reaction solution was cooled to room temperature and the acetic anhydride was removed under reduced pressure. The pH value of the residue was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution. The aqueous phase was extracted with dichloromethane (100 mL * 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-30% Ethylacetate / Petroleum ether gradient) to give a yellow oil (7.1 g, yield: 84.8%).

[0242] MS(ESI):256[M+H] + .

[0243] Step 7: Synthesis of compound int_B-1-8:

[0244]

[0245] Dissolve int_B-1-7 (7.1 g, 27.72 mmol) in ethanol (75 mL) and add KOH (1.63 g, 29.11 mmol). The mixture was reacted at room temperature for 5 hours. 30 mL of water was added to the reaction solution, and the ethanol was removed under reduced pressure. The aqueous phase was extracted with dichloromethane (100 mL*3), and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient) to give a yellow oil (5.3 g, yield: 89.3%).

[0246] MS(ESI):214[M+H] + .

[0247] Step 8: Synthesis of compound int_B-1-9:

[0248]

[0249] Dissolve int_B-1-8 (5.3 g, 24.76 mmol) in dichloromethane (60 mL) and add DMP (21.00 g, 49.52 mmol). The mixture is reacted at room temperature for 5 hours. The reaction solution is filtered, and the filtrate is adjusted to pH 7-8 with saturated sodium bicarbonate aqueous solution. The aqueous phase is extracted with dichloromethane (150 mL*3). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product is purified by column chromatography ( Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient) to give a green oil (4 g, yield: 76.2%).

[0250] MS(ESI):212[M+H] + .

[0251] Step 9: Synthesis of Intermediate B-1:

[0252]

[0253] Dissolve int_B-1-9 (3 g, 14.15 mmol) in toluene (10 mL) and add EtMgBr (3 M, 14.15 mL) at 0 ° C under nitrogen protection. The mixture is warmed to room temperature and reacted for 1 hour. The reaction solution is quenched with saturated ammonium chloride solution, and the aqueous phase is extracted with ethyl acetate (150 mL * 3). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product is purified by column chromatography ( Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient) to give a gray solid (1.6 g, yield: 49.6%).

[0254] MS(ESI):242[M+H] + .

[0255] Step 10: Synthesis of intermediates B-2 and B-3:

[0256]

[0257] B-1 (1.6 g, 6.61 mmol) was chirally separated by preparative supercritical fluid chromatography (prep SFC) (SFC chiral separation conditions: instrument: Waters SFC350; chromatographic column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 um); mobile phase: A: CO2 B: iso-propanol (0.05% DEA); gradient: B%: 50%-50%; flow rate: 200 mL / min; column temperature: 40°C). The fractions were concentrated under reduced pressure and freeze-dried to obtain yellow oil B-3 (peak 1, configuration is speculated, 0.67 g, yield: 40.2%) and yellow oil B-2 (peak 2, configuration is speculated, 0.69 g, yield: 41.4%).

[0258] B-3: 1 HNMR: (400MHz, DMSO-d6) δ = 7.61 (d, J = 7.8Hz, 1H), 7.43 (d, J = 8.0Hz, 1H), 5.13 (s, 1H), 2.91-2.82 (m, 1H), 2.68 (ddd, J = 5.5, 8.5, 16 .6Hz,1H),2.15(ddd,J=5.5,8.3,13.5Hz,1H),2.01-1.93(m,1H),1.89-1.78(m,1H),1.71-1.60(m,1H),0.84(t,J=7.4Hz,3H).B-2: 1 HNMR: (400MHz, DMSO-d6) δ = 7.61 (d, J = 8.0Hz, 1H), 7.43 (d, J = 7.9Hz, 1H), 5.12 (br s,1H),2.91-2.81(m,1H),2.73-2.63(m,1H),2.19-2.11(m,1H),1.96(ddd,J=5. 5,8.5,13.5Hz,1H),1.89-1.78(m,1H),1.70-1.59(m,1H),0.84(t,J=7.4Hz,3H)

[0259] Preparation Example 10 Synthesis of Intermediate B-4

[0260]

[0261] Step 1: Synthesis of intermediate B-4:

[0262] Dissolve int_B-1-9 (1 g, 4.72 mmol) in tetrahydrofuran (10 mL) and add MeMgBr (3 M, 3.14 mL) at 0 ° C under nitrogen protection. The mixture is warmed to room temperature and reacted for 1 hour. The reaction solution is quenched with saturated ammonium chloride solution, and the aqueous phase is extracted with ethyl acetate (150 mL * 3). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product is purified by column chromatography ( Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient) to obtain a green oil (0.44 g, yield: 38.9%).

[0263] 1 HNMR: (400MHz, DMSO-d6) δ = 7.72-7.59 (m, 1H), 7.43 (d, J = 7.9Hz, 1H), 7.30 (d, J = 7.9Hz, 1H),5.25(s,1H),2.92-2.82(m,1H),2.75-2.66(m,1H),2.11-2.05(m,2H),1.41(s,3H)

[0264] MS(ESI):228[M+H] + .

[0265] Using the above synthesis method and different starting materials, the target intermediates B-5 to B-48 in Table 2 can be obtained.

[0266] Table 2

[0267]

[0268]

[0269]

[0270]

[0271] Example 1 Synthesis of Compound 6

[0272]

[0273] Step 1: Synthesis of compound int_6-3:

[0274]

[0275] Int_6-1 (13.5 g, 58.06 mmol), int_6-2 (10 g, 58.06 mmol), and DIPEA (18.72 g, 145.16 mmol) were dissolved in THF (300 mL), and the temperature was raised to reflux for overnight reaction. The reaction was monitored by LC-MS. After completion of the reaction, the reaction solution was concentrated and the residue was dissolved in ethyl acetate (200 mL). The organic phase was washed with water (150 mL) and saturated brine (100 mL), dried, and concentrated to give a yellow oil (21 g, yield 98%).

[0276] MS(ESI):369[M+H] + .

[0277] Step 2: Synthesis of compound int_6-4:

[0278]

[0279] Int_6-3 (21 g, 57 mmol) was dissolved in DCM (70 mL) and TFA (70 mL) was added. The mixture was allowed to react overnight at room temperature. The reaction was monitored by LC-MS and completed. The mixture was then concentrated and the residue was dissolved in EtOH (120 mL). Aqueous sodium hydroxide (6 M, 66 mL) was added dropwise under an ice bath. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LC-MS and completed. The reaction solution was then concentrated and the residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford a yellow solid (10 g, 79% yield).

[0280] MS(ESI):223[M+H] + .

[0281] Step 3: Synthesis of compound int_6-5:

[0282]

[0283] Int_6-4 (2.5 g, 10 mmol), B-4 (2.28 g, 10 mmol), CuI (1.9 g, 10 mmol), K2CO3 (2.07 g, 15 mmol), and N,N'-dimethylethylenediamine (970 mg, 11 mmol) were dissolved in dioxane (100 mL) under argon protection. The temperature was raised to 80°C and the reaction was allowed to proceed overnight. The reaction was monitored by LC-MS. After completion of the reaction, the product was filtered and the filtrate was concentrated. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a light yellow solid (1.95 g, 50% yield).

[0284] MS(ESI):370[M+H] + .

[0285] Step 4: Synthesis of compound int_6-6:

[0286]

[0287] Dissolve int_6-5 (390 mg, 1.0 mmol) in DCM (20 mL) and add m-CPBA (305 mg, 1.5 mmol, 85%). Allow to react at room temperature for 1 hour. LC-MS monitoring indicates completion of the reaction. The system is then washed with saturated sodium bicarbonate solution, the organic phase is dried, and spin-dried to afford the crude product (390 mg, 99% yield). The crude product can be used directly in the next step.

[0288] MS(ESI):386[M+H] + .

[0289] Step 5: Synthesis of compound 6:

[0290]

[0291] Int_6-6 (390 mg, 1.0 mmol) was dissolved in DMF (20 mL), and trifluoroacetic acid (0.3 mL, 4.0 mmol) and A-73 (242 mg, 1.2 mmol) were added. The mixture was allowed to react overnight at 80°C and monitored by LC-MS. The reaction was complete. DCM (50 mL) was added for dilution, followed by washing with water (20 mL x 2). The organic phase was dried and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford the compound as a light yellow solid (72 mg, 13.2% yield).

[0292] 1 H NMR(400MHz,cdcl3)δ8.79(d,J=2.7Hz,1H),7.76–7.69(m,2H),7.49(s,1H),7.16(s,1H),7.12(s,1H),5.74–5. 64(m,1H),5.02–4.99(m,1H),4.90(d,J=17.1Hz,1H),4.81(d,J=16.0Hz,1H),4.75–4.67(m,1H),4.15–4.01(m,1 H),3.37–3.26(m,1H),3.04(s,0H),2.98–2.84(m,1H),2.75(dt,J=16.8,8.2Hz,2H),2.49(d,J=5.0Hz,3H),2.3 9–2.29(m,2H),2.25–2.12(m,1H),1.61(s,3H),1.49–1.41(m,1H),1.35(d,J=1.7Hz,3H),1.25(d,J=1.7Hz,2H).

[0293] MS(ESI):538[M+H] + .

[0294] Example 2 Synthesis of Compound 16

[0295]

[0296] Step 1: Synthesis of compound int_16-1:

[0297]

[0298] Int_6-4 (2.5 g, 10 mmol), B-1 (2.22 g, 10 mmol), CuI (1.9 g, 10 mmol), K2CO3 (2.07 g, 15 mmol), and N,N'-dimethylethylenediamine (970 mg, 11 mmol) were dissolved in dioxane (100 mL) under argon protection. The temperature was raised to 80°C and the reaction was allowed to proceed overnight. The reaction was monitored by LC-MS. After completion of the reaction, the product was filtered and the filtrate was concentrated. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a light yellow solid (1.56 g, yield 40.7%).

[0299] MS(ESI):384[M+H] + .

[0300] Step 2: Synthesis of compound int_16-2:

[0301]

[0302] Dissolve int_16-1 (780 mg, 2.0 mmol) in DCM (20 mL) and add m-CPBA (710 mg, 3 mmol, 85%). Allow to react at room temperature for 1 hour. LC-MS monitoring indicates completion of the reaction. The system is then washed with saturated sodium bicarbonate solution, the organic phase is dried, and spin-dried to afford the crude product (780 mg, 99% yield). This crude product can be used directly in the next step.

[0303] MS(ESI):400[M+H] + .

[0304] Step 3: Synthesis of compound 16:

[0305]

[0306] Int_16-2 (780 mg, 1.95 mmol) was dissolved in DMF (20 mL), and trifluoroacetic acid (0.3 mL, 4.0 mmol) and A-73 (506.2 mg, 2.3 mmol) were added. The mixture was allowed to react overnight at 80°C. LC-MS monitoring indicated the reaction was complete. The mixture was diluted with DCM (50 mL) and washed with water (20 mL x 2). The organic phase was dried and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford the compound as a light yellow solid (216 mg, 20% yield).

[0307] MS(ESI):552[M+H] + .

[0308] Example 3 Synthesis of Compound 19

[0309]

[0310] Step 1: Synthesis of compound int_19-1:

[0311]

[0312] Int_6-4 (2.5 g, 10 mmol), B-2 (2.22 g, 10 mmol), CuI (1.9 g, 10 mmol), K2CO3 (2.07 g, 15 mmol), and N,N'-dimethylethylenediamine (970 mg, 11 mmol) were dissolved in dioxane (100 mL) under argon protection. The temperature was raised to 80°C and the reaction was allowed to proceed overnight. The reaction was monitored by LC-MS. After completion of the reaction, the reaction was filtered and the filtrate was concentrated. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a light yellow solid (1.6 g, yield 41%).

[0313] MS(ESI):384[M+H] + .

[0314] Step 2: Synthesis of compound int_19-2:

[0315]

[0316] Dissolve int_19-1 (780 mg, 2.0 mmol) in DCM (20 mL) and add m-CPBA (710 mg, 3 mmol, 85%). Allow to react at room temperature for 1 hour. LC-MS monitoring indicates completion of the reaction. The system is then washed with saturated sodium bicarbonate solution, the organic phase is dried, and spin-dried to afford a crude product (775 mg, 97% yield). This crude product can be used directly in the next reaction.

[0317] MS(ESI):400[M+H] + .

[0318] Step 3: Synthesis of compound 19:

[0319]

[0320] Int_19-2 (780 mg, 1.95 mmol) was dissolved in DMF (20 mL), and trifluoroacetic acid (0.3 mL, 4.0 mmol) and A-75 (506.2 mg, 2.3 mmol) were added. The mixture was allowed to react overnight at 80°C. LC-MS monitoring indicated the reaction was complete. The mixture was diluted with DCM (50 mL) and washed with water (20 mL x 2). The organic phase was dried and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford the compound as a light yellow solid (220 mg, 20% yield).

[0321] 1 H NMR(400MHz,cdcl3)δ8.78(s,1H),7.71(d,J=1.9Hz,2H),7.49(s,1H),7.13(s,1H),7.11(s,1H),5.73–5.61(m,1H),5.01(dt,J=10.2,1.3Hz,1H), 4.90(dt,J=17.4,1.6Hz,1H), 4.83(d,J=5.8Hz,1H), 4.69(dd,J=15.7,6. 7Hz,1H),4.00(d,J=15.2Hz,1H),3.26(d,J=15.2Hz,1H),3.08–3.00(m,1 H),2.97–2.70(m,4H),2.66(d,J=10.8Hz,1H),2.45(s,3H),2.37(td,J=8 .6,4.2Hz,1H),2.29–2.20(m,1H),2.14(dd,J=16.8,9.4Hz,2H),2.01(dq ,J=14.8,7.4Hz,2H),1.81(t,J=7.4Hz,1H),1.60(ddd,J=12.8,5.5,3.3H z,1H),1.44(td,J=12.6,5.7Hz,1H),1.33(s,3H),0.98(t,J=7.4Hz,3H).

[0322] MS(ESI):552[M+H] + .

[0323] Example 4 Synthesis of Compound 20

[0324]

[0325] Step 1: Synthesis of compound int_20-1:

[0326]

[0327] Int_6-4 (2.5 g, 10 mmol), B-3 (2.22 g, 10 mmol), CuI (1.9 g, 10 mmol), K2CO3 (2.07 g, 15 mmol), and N,N'-dimethylethylenediamine (970 mg, 11 mmol) were dissolved in dioxane (100 mL) under argon protection. The temperature was raised to 80°C and the reaction was allowed to proceed overnight. The reaction was monitored by LC-MS. After completion of the reaction, the product was filtered and the filtrate was concentrated. The residue was purified by column chromatography (DCM / MeOH = 100 / 1 to 20 / 1) to give a light yellow solid (1.65 g, yield 41%).

[0328] MS(ESI):384[M+H] + .

[0329] Step 2: Synthesis of compound int_20-2:

[0330]

[0331] Dissolve int_20-1 (780 mg, 2.0 mmol) in DCM (20 mL) and add m-CPBA (710 mg, 3 mmol, 85%). Allow to react at room temperature for 1 hour. LC-MS monitoring indicates completion of the reaction. The system is then washed with saturated sodium bicarbonate solution, the organic phase is dried, and spin-dried to afford the crude product (778 mg, 97% yield). This crude product can be used directly in the next reaction.

[0332] MS(ESI):400[M+H] + .

[0333] Step 3: Synthesis of compound 20:

[0334]

[0335] Int_20-2 (780 mg, 1.95 mmol) was dissolved in DMF (20 mL), and trifluoroacetic acid (0.3 mL, 4.0 mmol) and A-75 (506.2 mg, 2.3 mmol) were added. The mixture was allowed to react overnight at 80°C. The reaction was monitored by LC-MS. The mixture was diluted with DCM (50 mL) and washed with water (20 mL x 2). The organic phase was dried and evaporated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 100 / 1 to 10 / 1) to afford the compound as a light yellow solid (218 mg, 20% yield).

[0336] 1H NMR(400MHz,cdcl3)δ8.79(s,1H),7.72(d,J=1.6Hz,2H),7.44(d,J=22.9Hz,1H),7.11(s,2H),5.73–5.62(m,1H),5.01(dd,J=10.2,1.3Hz, 1H),4.93–4.80(m,2H),4.68(dd,J=15.7,6.7Hz,1H),3.98(d,J=15.3Hz,1H),3.24(d,J=15.2Hz,1H),3.04(ddd,J=16.4,9.0,4.5Hz,1H),2 .97–2.70(m,4H),2.64(d,J=10.8Hz,1H),2.44(s,3H),2.37(td,J=8.7,4.3Hz,1H),2.28–2.20(m,1H),2.14(t,J=9.4Hz,2H),2.01(dd,J=1 4.0,7.3Hz,1H),1.85(t,J=7.0Hz,2H),1.59(ddd,J=8.7,5.5,2.7Hz,1H),1.45(dt,J=12.6,6.3Hz,1H),1.33(s,3H),0.97(d,J=7.4Hz,3H).

[0337] MS(ESI):552[M+H] + .

[0338] Using the above synthesis method and different raw materials (different intermediates A, different intermediates B and other different intermediates), the target compounds 1-5, 7-15 and 17, 18, 21-166 in Table 3 can be obtained.

[0339] Table 3

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348] Example 5 In vitro inhibition test of recombinant protein Wee-1 enzyme activity by the compounds of the present invention

[0349] The HTRF method was used to determine the inhibitory effect of the compounds on the recombinant protein Wee-1 enzyme activity. The details are as follows.

[0350] DMSO or serially diluted compounds (up to 200 nM, 1:5 serial dilution) and recombinant proteins were incubated in kinase buffer at 37 degrees for 30 minutes. Fluorescein-PolyGAT and ATP were added, and the substrate was added to initiate the reaction. After 90 minutes of reaction at room temperature, the antibody and detection solution were added. After a further 60 minutes of incubation at room temperature, the fluorescence value was read (excitation wavelength: 340 nm, emission wavelengths 495 and 520 nm). The 520 nm / 495 nm fluorescence intensity ratio was calculated and compared with the DMSO group, and the compound inhibition percentage and IC were calculated. 50 The results are shown in Table 4 below.

[0351] Table 4 Inhibitory activity of the compounds of the present invention against recombinant protein Wee-1 (IC 50 , nM)

[0352] Compound <![CDATA[IC 50 ]]> Compound <![CDATA[IC 50 ]]> Compound <![CDATA[IC 50 ]]> Compound <![CDATA[IC 50 ]]> 1 +++ 2 +++ 3 +++ 4 +++ 5 +++ 6 +++ 7 +++ 8 +++ 9 +++ 10 +++ 11 +++ 12 +++ 13 +++ 14 +++ 15 +++ 16 +++ 17 +++ 18 +++ 19 +++ 20 +++ 21 +++ 22 +++ 23 +++ 24 +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 +++ 40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 +++ 49 +++ 50 +++ 51 +++ 52 +++ 53 +++ 54 +++ 55 +++ 56 +++ 57 +++ 58 +++ 59 +++ 60 +++ 61 +++ 62 +++ 63 +++ 64 +++ 65 +++ 66 +++ 67 +++ 68 +++ 69 +++ 70 +++ 71 +++ 72 +++ 73 +++ 74 +++ 75 +++ 76 +++ 77 +++ 78 +++ 79 +++ 80 +++

[0353] 81 +++ 82 ++ 83 ++ 84 ++ 85 ++ 86 ++ 87 ++ 88 +++ 89 +++ 90 +++ 91 +++ 92 +++ 93 +++ 94 +++ 95 +++ 96 +++ 97 +++ 98 +++ 99 +++ 100 +++ 101 +++ 102 +++ 103 +++ 104 +++ 105 +++ 106 +++ 107 +++ 108 +++ 111 +++ 112 +++ 113 +++ 114 +++ 115 +++ 116 +++ 117 +++ 118 +++ 119 +++ 120 +++ 121 +++ 122 +++ 123 +++ 124 +++ 125 +++ 126 +++ 127 ++ 128 ++ 129 ++ 130 +++ 131 +++ 132 +++ 133 +++ 134 +++ 135 +++ 136 +++ 137 +++ 138 +++ 139 +++ 140 +++ 141 +++ 142 +++ 143 +++ 144 +++ 145 +++ 146 +++ 147 +++ 148 +++ 149 +++ 150 +++ 151 +++ 152 +++ 153 +++ 154 +++ 155 +++ 156 +++ 157 +++ 158 +++ 159 +++ 160 +++ 161 +++ 162 +++ 163 +++ 164 +++ 165 +++ 166 +++

[0354] +++ indicates IC 50 Less than or equal to 10nM

[0355] ++ indicates IC 50 10nM to 50nM

[0356] + indicates IC 50 Greater than 50nM.

[0357] From the data in Table 4, it can be seen that the compounds of the present invention have good inhibitory activity on the enzyme activity of the recombinant protein Wee-1.

[0358] Example 6 In vitro antiproliferative activity of the compounds of the present invention on MIA PaCa-2 cells

[0359] 3000 MIA PaCa-2 cells were plated in 384-well plates and allowed to adhere overnight. DMSO or compound diluted 1:5 with a maximum concentration of 5 μM was then added. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was calculated. 50 The results are shown in Table 5 below.

[0360] Table 5 Antiproliferative activity of the compounds of the present invention on MIA PaCa-2 cells

[0361]

[0362] From the data in Table 5, it can be seen that the compounds of the present invention have weak anti-proliferative activity against MIA PaCa-2 cells.

[0363] Example 7 In vitro antiproliferative activity of the compound of the present invention combined with gemcitabine on MIA PaCa-2 cells

[0364] 3000 MIA PaCa-2 cells / well were plated in a 384-well plate and treated with 20 nM Gemcitabine. After overnight attachment, DMSO or a compound with a maximum concentration of 100 nM and a 1:5 dilution series was added. 72 hours after drug addition, cell survival was assessed by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was then calculated. 50 The results are shown in Table 6 below.

[0365] Table 6 In vitro antiproliferative activity of the compounds of the present invention combined with gemcitabine on MIA PaCa-2 cells

[0366]

[0367] From the data in Table 6, it can be seen that the compound of the present invention combined with gemcitabine has strong in vitro anti-proliferative activity against MIA PaCa-2 cells.

[0368] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound represented by the general formula (1) or a pharmaceutically acceptable salt or optical isomer thereof: In the general formula (1): X is CH or N; Ring A is a (C5-C7) partially unsaturated cycloalkyl group or a (5-7 membered) partially unsaturated heterocycloalkyl group; Each R 1 are independently -D, halogen, -OH, -(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl or (C3-C6)cycloalkyl; Y 1 N or CR 4 ; Y 2 N or CR 5 ; Y 3 N or CR 6 ; R 4 、R 5 and R 6 are each independently -H, -D, halogen, -OH, -(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl or (C3-C6)cycloalkyl; or R 5 and R 6 Together with the atoms to which they are attached, they can form a (5-6 membered) heterocycloalkyl, a (5-6 membered) heteroaryl or a (C5-C6) cycloalkyl; Ring B is a (C5-C8) partially unsaturated cycloalkyl group or a (5-8 membered) partially unsaturated heterocycloalkyl group; X 1 for X 2 For chemical bonds, X 3 CH, N or CR c ; X 4 CH, N or CR d ; X 5 NR a or CH-R b ; Each R 2 are independently -H, -D, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 , -CN, (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C6) cycloalkyl; or 2 adjacent R 2 The atoms to which they are attached can together form a (C3-C6) cycloalkyl group; or two R on the same carbon atom on the B ring 2 The carbon atoms to which they are connected can together form a (C3-C6) cycloalkyl group; or R 2 and an adjacent R e Together with the atoms to which they are attached, they can form a (C3-C6) cycloalkyl group; R a -H, -(CH2) m OR 8 、-(CH2) m NR 8 R 9 , (C1-C6) alkyl, (C1-C6) haloalkyl or (C3-C6) cycloalkyl, wherein the alkyl, haloalkyl and cycloalkyl groups may be optionally substituted with 1, 2, 3 or 4 of the following groups: -D, halogen, R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 and -CN; R b -H, -(CH2) n OR 8 、-(CH2) n NR 8 R 9 , (C1-C6)alkyl, (C1-C6)haloalkyl or (C3-C6)cycloalkyl; R c and R d are each independently halogen, -OH, -(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R e is -H, -D, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; R f and R g are independently -H, -D, -(CH2) n OR 8 、-(CH2) n NR 8 R 9 , -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or R f and R g Together with the carbon atoms to which they are connected, they can form a (C3-C6) cycloalkyl group; R 3 is (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C5)alkenyl, (C2-C5)alkynyl or (C3-C6)cycloalkyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 of the following groups: -D, halogen, R 7 、R 8 、-OH、-(CH2) n OR 8 、-(CH2) n NR 8 R 9 、-OR 8 、-NR 8 R 9 and -CN; R 7 is (C2-C5)alkenyl or (C2-C5)alkynyl; R 8 and R 9 Each is independently -H, (C1-C6)alkyl, (C1-C3)haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; q is an integer of 1, 2 or 3, s is an integer of 1, 2 or 3, n is an integer of 0, 1, 2 or 3, and m is an integer of 1, 2 or 3.

2. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), Ring A is:

3. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), each R 1 are independently -D, -F, -Cl, -Br, -I, -OH, -CH2OR 8 、-CH2NR 8 R 9 、-OR 9 、-NR 8 R 9 , -CN, (C1-C3)alkyl, (C1-C3)haloalkyl or (C3-C6)cycloalkyl.

4. The compound according to claim 3 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), each R 1 are independently: -D, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -OCF3, -N(CH3)2, -CN, -CD3, -CD2CD3, 5. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), R 4 、R 5 and R 6 Each independently represents -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OR 8 、-CH2NR 8 R 9 、-OR 8 、-NR 8 R 9 , -CN, (C1-C3)alkyl, (C1-C3)haloalkyl or (C3-C6)cycloalkyl; or R 5 and R 6 Together with the atoms to which they are attached, they can form a (5-6 membered) heterocycloalkyl, a (5-6 membered) heteroaryl or a (C5-C6) cycloalkyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), R 4 、R 5 and R 6 Each is independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -OCF3, -N(CH3)2, -CN, 7. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), the structural unit for:

8. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), ring B is a (C5-C8) partially unsaturated cycloalkyl group or a (5-8 membered) partially unsaturated heterocycloalkyl group; and R e For: -H, -D, -F, -CH3, -OCH3, Or -CH2CH3.

9. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), the structural unit for:

10. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), X 1 for:

11. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), X 2 For: chemical bonds, 12. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), when X 5 NR a When R a -H, -(CH2)2OR 8 、-(CH2)2NR 8 R 9 , (C1-C3) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl, wherein the alkyl, haloalkyl and cycloalkyl groups are independently optionally substituted with 1, 2, 3 or 4 of the following groups: -D, -F, -OH, -CH3, -CH2OCH3, -(CH2)2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2 and -CN.

13. The compound according to claim 12 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), when X 5 NR a When R a For: -H, -(CH2)2OCH3, -(CH2)2OH, -(CH2)2N(CH3)2, 14. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), when X 5 CH-R b When R b -H, -(CH2)2OR 8 、-NR 8 R 9 、-(CH2)2NR 8 R 9 , (C1-C3)alkyl, (C1-C3)haloalkyl or (C3-C6)cycloalkyl.

15. The compound according to claim 14 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), when X 5 CH-R b When R b For: -H, -N(CH3)2, -N(CD3)2, -(CH2)2OCH3, -(CH2)2OH, -(CH2)2N(CH3)2, 16. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), X 3 is: CH, N or CR c , wherein the R c For: -F, -Cl, -Br, -I, -OH, -CH3, -CH2OCH3, -(CH2)2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2 or -CN.

17. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), X 4 is: CH, N or CR d , wherein the R d For: -F, -Cl, -Br, -I, -OH, -CH3, -CH2OCH3, -(CH2)2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2 or -CN.

18. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), each R 2 are independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OR 8 、-CH2NR 8 R 9 、-OR 8 、-NR 8 R 9 , -CN, (C1-C3) alkyl, (C1-C3) haloalkyl or (C3-C6) cycloalkyl; or 2 adjacent R 2 The atoms to which they are attached can together form a (C3-C6) cycloalkyl group; or two R on the same carbon atom on the B ring 2 The carbon atoms to which they are connected can together form a (C3-C6) cycloalkyl group; or R 2 and an adjacent R e Together with the atoms to which they are attached, they can form a (C3-C6)cycloalkyl group.

19. The compound according to claim 18 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), each R 2 are independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -OCF3, -N(CH3)2, -CN, 20. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), the structural unit for:

21. The compound according to claim 1 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), R 3 is (C1-C4)alkyl, (C1-C4)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C3-C5)cycloalkyl, wherein the alkyl, haloalkyl, alkenyl, alkynyl and cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 of the following groups: -D, -F, -CN, 22. The compound according to claim 21 or a pharmaceutically acceptable salt or optical isomer thereof, wherein in the general formula (1), R 3 for:

23. A compound or a pharmaceutically acceptable salt or optical isomer thereof, wherein the compound has one of the following structures:

24. A pharmaceutical composition, characterized in that It contains a pharmaceutically acceptable excipient or carrier and the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or optical isomer thereof as an active ingredient.

25. Use of the compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt or optical isomer thereof, or the pharmaceutical composition according to claim 24, in the preparation of a medicament for treating or preventing cancer.

26. The use according to claim 25, wherein the cancer is a blood cancer or a solid tumor.

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