Fused ring compounds as wee-1 inhibitors

Abstract

This invention discloses fused-ring compounds as Wee-1 inhibitors. Specifically, this invention relates to a compound of general formula (1) and its preparation method, and the use of the compound of general formula (1) and its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as Wee-1 inhibitors in the preparation of antitumor drugs.

Description

[0001] This application claims priority to Chinese patent applications 2021101958215, filed on February 19, 2021, and 2022101226828, filed on February 9, 2022. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of medicinal chemistry, and more specifically, to fused-ring compounds with Wee1 kinase inhibitory activity, their preparation methods, and the use of such compounds in the preparation of antitumor drugs. Background Technology

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

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

[0005] Studies have shown that, in addition to its role at the G2 checkpoint, Wee-1 is also involved in DNA synthesis, DNA homology repair, and post-translational modifications of chromosomal histones—functions closely related to tumorigenesis 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 tumorigenesis 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, developing specific, highly active small molecule inhibitors of Wee-1 kinase is of significant clinical value for tumor therapy, especially for targeting tumors with impaired G1 checkpoints such as those lacking P53. Summary of the Invention

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

[0008]

[0009] In general formula (1):

[0010] X is CH or N;

[0011] Y represents -H, halogen, -CN, or -S(O)2R. 6 -P(O)(R 7 )2、-C(O)NR 8 R 9(C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)ynyl, (C3-C14)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)ynyl, (C3-C14)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl may each be independently and 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 ;

[0012] Z represents a chemical bond, -CH2-, -O-, or -NH-;

[0013] Ring A is (C6-C14) aryl, (5-14-membered) heteroaryl, or (3-14-membered) heterocyclic alkyl;

[0014] R 1 for

[0015] R 4a and R 5a Each of the following groups is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl groups may be independently 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 8R 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 4a and R 5a The S atom attached to it can collectively form a (4-7) heterocyclic alkyl group, wherein the (4-7) heterocyclic alkyl group may optionally be substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 -OR 8 -NR 8 R 9 and -CN;

[0016] R 4b and R 5b Each of the following groups is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl groups may be independently 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 ; or R 4b and R 5b The P atom attached to it can collectively form a (4-7) heterocyclic alkyl group, wherein the (4-7) heterocyclic alkyl group may optionally be substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 -OR 8 -NR8 R 9 and -CN;

[0017] R 4c and R 5c Each of the following groups is independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl may be independently 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 ; or R 4c and R 5c The carbon atoms attached to it can collectively form a (3-7-membered) cycloalkyl group, wherein the (3-7-membered) cycloalkyl group may optionally be substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 -OR 8 -NR 8 R 9 and -CN;

[0018] R 4d The group is -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl may each be independently and 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 -NR8 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 ; and R 5d It is (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl may each be independently and 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 ; or R 4d and R 5d The atoms bonded to them can collectively form a (4-7-membered) heterocyclic alkyl group, wherein the (4-7-membered) heterocyclic alkyl group may optionally be substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 -OR 8 -NR 8 R 9 and -CN;

[0019] R 4e and R 5eEach of the following groups is independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl may be independently 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 ; or R 4e and R 5e The N atom attached to it can collectively form a (4-7-membered) heterocyclic alkyl group, wherein the (4-7-membered) heterocyclic alkyl group may optionally be substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 -OR 8 -NR 8 R 9 and -CN;

[0020] R 4f and R 5f Each of the following groups is independently -H, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, or (C3-C6)cycloalkyl may be independently optionally substituted by 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 ; or R 4f and R 5f The carbon atoms attached to it can collectively form a (3-7-membered) cycloalkyl group, wherein the (3-7-membered) cycloalkyl group may optionally be substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 8 -OR 8 -NR 8 R 9 and -CN;

[0021] R 4g It is a (C1-C3)alkyl or (C3-C6)cycloalkyl, wherein the (C1-C3)alkyl or (C3-C6)cycloalkyl may each be optionally substituted by 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 ;

[0022] Each R 3 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 -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)ynyl, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl groups may each be independently and 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 two adjacent R 3 The atoms bonded to them can collectively form a (5-9 member) heterocyclic alkyl or (C5-C9) cycloalkyl group, wherein the (5-9 member) heterocyclic alkyl or (C5-C9) cycloalkyl group may optionally be 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 ;

[0023] The B ring is a (C5-C11) partially unsaturated cycloalkyl group or a (5-11) partially unsaturated heterocycloalkyl group;

[0024] X 1 for

[0025] X 2 For chemical bonds,

[0026] X 3 For CH, N or CR c ;

[0027] X 4 For CH, N or CR d ;

[0028] X 5 For NR a or CH-R b ;

[0029] Each R 2 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 and -S(O)2NR 8 R 9(C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl groups may each be independently and 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 2 The atoms bonded to them can collectively form a (5-7 member) heterocyclic alkyl or a (C3-C9) cycloalkyl group, wherein the (5-7 member) heterocyclic alkyl or (C3-C9) cycloalkyl group may optionally be 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 atoms on the same carbon atom of ring B. 2The carbon atoms bonded to them can collectively form a (4-7-membered) heterocyclic alkyl or (C3-C6) cycloalkyl group, wherein the (4-7-membered) heterocyclic alkyl or (C3-C6) cycloalkyl group may optionally be 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 bonded to them can collectively form a (5-7 member) heterocyclic alkyl or a (C3-C9) cycloalkyl group, wherein the (5-7 member) heterocyclic alkyl or (C3-C9) cycloalkyl group may optionally be 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 ;

[0030] R a -H, R 8 -(CH2) m OR 8 -(CH2) m NR 8 R9 (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C14)cycloalkyl, or (3-15)heterocyclic alkyl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C14)cycloalkyl, or (3-15)heterocyclic alkyl may optionally be 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 ;

[0031] R b -H, R 8 -(CH2) n OR 8 -(CH2) n NR 8 R 9 (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C14)cycloalkyl or (3-15)heteroalkyl, wherein R 8 R 9 (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C14)cycloalkyl, or (3-15)heterocyclic alkyl groups may optionally be 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 9S(O)2R 8 -S(O) p R 8 and -S(O)2NR 8 R 9 ;

[0032] R c and R d Each is 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)ynyl, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl groups may each be independently and 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)2NR8 R 9 ;

[0033] R e The group can be -H, -D, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl can each be independently and 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 ;

[0034] R f1 R f2 R g1 and R g2 Each is independently -H, -D, or -R. 8 -(CH2) n OR 8 -(CH2) n NR 8 R 9-CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C9)cycloalkyl, (C6-C14)aryl, (3-11-membered)heterocyclic alkyl, or (5-11-membered)heteroaryl may each be independently and 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 f2 and an adjacent R e The atoms bonded to them can collectively form (C3-C9) cycloalkyl or (3-11-membered) heterocycloalkyl groups, wherein each (C3-C9) cycloalkyl or (3-11-membered) heterocycloalkyl group may be independently and 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 ;

[0035] R 6 It is (C1-C3)alkyl or (C3-C6)cycloalkyl;

[0036] R 7 It is an (C1-C3) alkyl group;

[0037] R 8 and R 9 Each is independently -H, (C1-C6)alkyl or (C3-C14)cycloalkyl, or R on the same nitrogen atom. 8 and R 9 The N atoms attached to them can collectively form a (3-11-membered) heterocyclic alkyl group, wherein the (3-11-membered) heterocyclic alkyl group may optionally be substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, R 10 and -OR 10 ;

[0038] R 10 It is -H, (C1-C6)alkyl or (C3-C14)cycloalkyl;

[0039] R 11 and R 12 Each is independently -H, (C1-C3)alkyl, (C1-C3)haloalkyl, or (C3-C6)cycloalkyl, or R on the same nitrogen atom. 11 and R 12 The N atoms bonded to them can together form a (4-6 member) heterocyclic alkyl group; and

[0040] 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.

[0041] In another preferred embodiment, Z in the general formula (1) is -NH- or a chemical bond.

[0042] In another preferred embodiment, in the general formula (1), Y is -H, -F, -Cl, -Br, -I, -CN, -S(O)2CH3, -P(O)(CH3)2, -C(O)NH2, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl, (C2-C3)ynyl or (5-6-membered)heteroaryl; wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl, (C2-C3)ynyl or (5-6-membered)heteroaryl may each be independently and optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -CN, -CH3 and -OCH3.

[0043] In another preferred embodiment, in the general formula (1), Y is -H, -F, -Cl, -Br, -I, -CN, -S(O)2CH3, -P(O)(CH3)2, -C(O)NH2, -CH3, -CF3, Y is preferably -Br, -CN, -S(O)2CH3, -P(O)(CH3)2, -C(O)NH2, -CF3. Y is more preferably -CN.

[0044] In another preferred embodiment, wherein in the general formula (1), ring A is (C6-C10) aryl, (5-10) heteroaryl, or (5-10) heterocyclic alkyl.

[0045] In another preferred embodiment, in the general formula (1), ring A is Ring A is preferred Ring A is more preferred Ring A is more preferred

[0046] In another preferred embodiment, wherein in the general formula (1), when R 1 for When, R 4a and R 5a Each is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl may be independently optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -D, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, and -CN; or R 4a and R 5a The S atom attached thereto can together form a (4-6) heterocyclic alkyl group, wherein the (4-6) heterocyclic alkyl group may optionally be 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.

[0047] In another preferred embodiment, wherein in the general formula (1), when R 1 for At that time, structural unit for: Preferred Preferred More preferably

[0048] In another preferred embodiment, wherein in the general formula (1), when R 1 for When, R 4b and R 5b Each is independently (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl may be independently optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -D, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, and -CN; or R 4b and R 5b The P atom attached thereto can together form a (4-6) heterocyclic alkyl group, wherein the (4-6) heterocyclic alkyl group may optionally be 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.

[0049] In another preferred embodiment, wherein in the general formula (1), when R 1 for At that time, structural unit for: Preferred More preferably

[0050] In another preferred embodiment, wherein in the general formula (1), when R 1 for When, R 4c and R 5c Each of the following groups is independently -H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl groups may be independently optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -D, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, and -CN; or R 4c and R 5cThe carbon atoms attached thereto can collectively form a (3-6-membered) cycloalkyl group, wherein the (3-6-membered) cycloalkyl group may optionally be 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.

[0051] In another preferred embodiment, in the general formula (1), R 1 for At that time, structural unit for: Preferred

[0052] In another preferred embodiment, wherein in the general formula (1), when R 1 for When, R 4d The group is -H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl may each be independently and optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -D, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, and -CN; and R 5d It is a (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl may each be independently and optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -D, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, and -CN; or R 4d and R 5d The atoms attached to them can collectively form a (4-6) heterocyclic alkyl group, wherein the (4-6) heterocyclic alkyl group may optionally be 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.

[0053] In another preferred embodiment, in the general formula (1), R 1 for At that time, structural unit for: Preferred

[0054] In another preferred embodiment, wherein in the general formula (1), when R 1 for When, R 4e and R 5e Each of the following groups is independently -H, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl groups may be independently optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -D, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, and -CN; or R 4e and R 5e The N atom to which it is attached can together form a (4-6) heterocyclic alkyl group, wherein the (4-6) heterocyclic alkyl group may optionally be 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, in the general formula (1), R 1 for At that time, structural unit for: Preferred

[0056] In another preferred embodiment, wherein in the general formula (1), when R 1 for When, R 4f and R 5f Each of the following groups is independently -H, halogen, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, or (C3-C5)cycloalkyl groups may be independently optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -D, -F, -Cl, -Br, -I, -CH3, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -N(CH3)2, and -CN; or R 4f and R 5fThe carbon atom to which it is attached can together form a (3-6 member) cycloalkyl group, wherein the (3-6 member) cycloalkyl group may optionally be 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.

[0057] In another preferred embodiment, in the general formula (1), R 1 for At that time, structural unit for:

[0058] In another preferred embodiment, wherein in the general formula (1), when R 1 for When, R 4g It is a (C1-C3)alkyl or (C3-C5)cycloalkyl, wherein the (C1-C3)alkyl or (C3-C5)cycloalkyl may be independently and 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.

[0059] In another preferred embodiment, in the general formula (1), R 1 for At that time, structural unit for: Preferred

[0060] In another preferred embodiment, wherein in the general formula (1), each R 3 Independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OR 11 -CH2NR 11 R 12 -OR 11 -NR 11 R 12 -CN, -C(O)NR 11 R 12 -NR 12 C(O)R 11 -NR 12 S(O)2R 11 -SR 11 -S(O)2R 11 -S(O)2NR 11 R 12(C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, phenyl, (4-8)heterocyclic alkyl, or (5-6)heteroaryl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, phenyl, (4-8)heterocyclic alkyl, or (5-6)heteroaryl may each be independently and optionally substituted by 1, 2, 3, or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -N(CH3)2, and -CN; or two adjacent R groups. 3 The atoms to which they are attached can collectively form (5-7) heterocyclic alkyl or (C5-C7) cycloalkyl groups, wherein the (5-7) heterocyclic alkyl or (C5-C7) cycloalkyl groups may optionally be 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.

[0061] In another preferred embodiment, wherein in the general formula (1), each R 3 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, -NCH3S(O)2CH3, -SCH3, -S(O)2CH3 and -S(O)2NH2, -S(O)2NH(CH3), -S(O)2N(CH3)2 R 3 Preferred suffixes are -H, -D, -F, -Cl, -Br, -OCH3, and -OCF3. R 3 More preferably -H, -D, -F, -Cl, -OCH3, R 3 More preferably -H, -D, -F, -Cl, -OCH3, q is preferably 1 or 2; q is more preferably 1.

[0062] In another preferred embodiment, in the general formula (1), the structural unit for: Preferred

[0063] In another preferred embodiment, wherein in the general formula (1), ring B is a (C5-C8) partially unsaturated cycloalkyl or a (5-8) partially unsaturated heterocycloalkyl; and R e The values ​​are: -H, -D, -CH3, -OCH3, or -CH2CH3.

[0064] In another preferred embodiment, in the general formula (1), the structural unit for:

[0065] In another preferred embodiment, in the general formula (1), X 1 for: Preferred More preferably More preferably

[0066] In another preferred embodiment, in the general formula (1), X 2 For: chemical bonds, Preferably chemical bonds, More preferably, chemical bonds, More preferably, chemical bonds or

[0067] In another preferred embodiment, wherein in the general formula (1), when X 5 For NR a When, R a -H, -(CH2)2OR 11 -(CH2)2NR 11 R 12 (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C6)cycloalkyl, or (4-7-membered)heterocyclic alkyl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C6)cycloalkyl, or (4-7-membered)heterocyclic alkyl may optionally be 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.

[0068] In another preferred embodiment, wherein in the general formula (1), when X 5 For NR a When, R a For: -H, -(CH2)2OCH3, -(CH2)2OH, -(CH2)2N(CH3)2, Preferably -(CH2)2OH, -(CH2)2N(CH3)2, More preferably -(CH2)2OH, -(CH2)2N(CH3)2, More preferably More preferably

[0069] In another preferred embodiment, wherein in the general formula (1), when X 5 CH-R b When, R b -H, -(CH2)2OR 11 -NR 11 R 12 -(CH2)2NR 11 R 12 (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C6)cycloalkyl or (4-7)heteroalkyl, wherein R 11 R 12 (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C6)cycloalkyl, or (4-7)heterocyclic alkyl groups may optionally be 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.

[0070] In another preferred embodiment, wherein in the general formula (1), when X 5 CH-R b When, R b are: -H, -N(CH3)2, -N(CD3)2, -(CH2)2OCH3, -(CH2)2OH, -(CH2)2N(CH3)2, Preferably -N(CH3)2, -N(CD3)2 or More preferably, it is -N(CH3)2.

[0071] In another preferred embodiment, in the general formula (1), X 3 For: CH, N or CR c Wherein 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; preferably -H, -F, -Cl, -CH3, -OCH3, -OCF3, -N(CH3)2 or -CN; more preferably -H, -F, -CH3, Or -OCH3.

[0072] In another preferred embodiment, in the general formula (1), X 4 For: CH, N or CR d Wherein 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; preferably -H, -F, -Cl, -CH3, -OCH3, -OCF3, -N(CH3)2 or -CN; more preferably -H, -F, -CH3, Or -OCH3.

[0073] In another preferred embodiment, wherein in the general formula (1), each R 2 Independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OR 11 -CH2NR 11 R 12 -OR 11 -NR 11 R 12 -CN, -C(O)NR 11 R 12 -NR 12 C(O)R 11 -NR 12 S(O)2R11 -SR 11 -S(O)2R 11 -S(O)2NR 11 R 12 (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, phenyl, (4-8)heterocyclic alkyl, or (5-6)heteroaryl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, phenyl, (4-8)heterocyclic alkyl, or (5-6)heteroaryl may each be independently and optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -F, -Cl, -Br, -I, -CH3, -OH, -OCH3, -N(CH3)2, and -CN; or 2 adjacent R 2 The atoms bonded to them can collectively form a (5-7 member) heterocyclic alkyl or (C3-C6) cycloalkyl group, wherein the (5-7 member) heterocyclic alkyl or (C3-C6) cycloalkyl group may optionally be 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 two R groups on the same carbon atom of ring B. 2 The carbon atoms bonded to them can collectively form (4-7-membered) heterocyclic alkyl or (C3-C6) cycloalkyl groups, wherein the (4-7-membered) heterocyclic alkyl or (C3-C6) cycloalkyl groups may optionally be 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 The atoms to which they are attached can collectively form (5-7 member) heterocyclic alkyl or (C3-C6) cycloalkyl, wherein the (5-7 member) heterocyclic alkyl or (C3-C6) cycloalkyl can optionally be 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.

[0074] In another preferred embodiment, wherein in the general formula (1), each R 2Independently: -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -CH2N(CH3)2, -OCH3, -OCF3, -NH2, -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, -NCH3S(O)2CH3, -SCH3, -S(O)2CH3 and -S(O)2NH2, -S(O)2NH(CH3), -S(O)2N(CH3)2 Preferred suffixes are -H, -D, -F, -Cl, -OH, -OCH3, -OCF3, -NH2, -N(CH3)2, and -CN. More preferably -H, -F, -OH, -NH2, s is preferably 1 or 2; s is more preferably 1; s is more preferably 2.

[0075] In another preferred embodiment, in the general formula (1), the structural unit for:

[0076] In some embodiments of the present invention, the present invention provides compounds of general formula (2) or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0077]

[0078] Among them, A, B, Y, Z, R 1 R 2 R 3 R e X 1 X 2 X 3 X 4 X 5 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0079] In some embodiments of the present invention, the present invention provides compounds as described in general formula (3a) or general formula (3b), or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0080]

[0081] Among them, A, B, Y, R 1 R 2 R 3 R e X 1 X 2 X 3 X 4 X 5 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0082] In some embodiments of the present invention, the present invention provides compounds of formula (4a), formula (4b) or formula (4c) or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0083]

[0084] Among them, B, Y, Z, R 1 R 2 R 3 R e X 1 X 2 X 3 X 4 X 5 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0085] In some embodiments of the present invention, the present invention provides compounds of formula (5a), formula (5b) or formula (5c) or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0086]

[0087] Where A, Y, Z, R 1 R 2 R 3 R e X 1 X 2 X 3 X 4 X 5 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0088] In some embodiments of the present invention, the present invention provides compounds of formula (6a), formula (6b) or formula (6c) or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0089]

[0090] Where A, Y, Z, R 1 R 2 R 3 R e X 2 X 5 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0091] In some embodiments of the present invention, the present invention provides compounds of general formula (7a), general formula (7b), general formula (7c), general formula (7d), general formula (7e) or general formula (7f), or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0092]

[0093] Among them, Y, Z, and R 1 R 2 R 3 R e X 2 X 5 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0094] In various embodiments, the representative compounds of the present invention have one of the following structures:

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, a diluent and / or an excipient, and a compound of general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0106] Another object of the present invention is to provide the use of the compound of general formula (1) of the present invention, or any isomer thereof, crystal form thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for the treatment, regulation or prevention of diseases related to Wee-1 protein.

[0107] Another object of the present invention is to provide a method for treating, modulating or preventing diseases mediated by the Wee-1 protein, comprising administering to a subject a therapeutically effective amount of a compound of general formula (1) of the present invention, or any isomer thereof, crystal form thereof, pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition thereof.

[0108] Through the synthesis and careful study of various new compounds involving Wee-1 inhibition, the inventors discovered that the compound of general formula (1) unexpectedly possesses strong Wee-1 inhibitory activity.

[0109] It should be understood that the foregoing general description of the invention and the following detailed description are exemplary and illustrative, and are intended to provide further explanation of the claimed invention.

[0110] Compound Synthesis

[0111] The preparation method of the compound of general formula (1) of the present invention is described in detail below, but these specific methods do not constitute any limitation on the present invention.

[0112] The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with the methods described herein. Furthermore, the solvents, temperatures, and other reaction conditions mentioned herein can be varied. Starting materials used for the synthesis of the compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds with different substituents can be synthesized using known techniques and starting materials, including those discovered 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 rdThe method described in Ed. (Wiley 1999) can be used to prepare compounds by employing appropriate reagents and by introducing different groups into the molecular formulas provided herein.

[0113] On the one hand, the compounds described herein are prepared according to methods known in the art. However, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to the explanations below. The compounds of the present invention can also be conveniently prepared by combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art. On the other hand, the present invention also provides a method for preparing the compound of general formula (1), wherein the compound of general formula (1) can be prepared by the following general reaction procedures 1, 2, 3 or 4:

[0114] General reaction process 1

[0115]

[0116] Compounds of general formula (1) can be prepared according to general reaction procedure 1, wherein R 1 R 2 R 3 R e X 1 X 2 X 3 X 4 X 5 X, Y, Z, s, q, ring A, and ring B are as defined above. H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, and O represents oxygen. As shown in the general reaction flow 1, compounds 1-1 and 1-2 undergo a substitution reaction under basic conditions to generate compound 1-3. Compound 1-3 reacts with m-CPBA to generate compound 1-4. Compounds 1-4 and 1-5 undergo a substitution reaction to generate the target compound 1-6.

[0117] General reaction process 2

[0118]

[0119] Compounds of general formula (1) can be prepared according to general reaction procedure 2, wherein R 1 R 2 R 3 R e X 1 X 2 X 3 X 4 X 5X, Y, s, q, ring A, and ring B are as defined above. H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, and O represents oxygen. As shown in the general reaction flow 2, compounds 2-1 and 2-2 undergo a substitution reaction under basic conditions to generate compound 2-3. Compound 2-3 reacts with m-CPBA to generate compound 2-4. Compounds 2-4 and 2-5 undergo a substitution reaction to generate the target compound 2-6.

[0120] General reaction process 3

[0121]

[0122]

[0123] Compounds of general formula (1) can be prepared according to general reaction procedure 3, wherein R 1 R 2 R 3 R e X 1 X 2 X 3 X 4 X 5 The X, Y, Z, s, q, A ring, and B ring are as defined above. H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, O represents oxygen, B represents boric acid, borate ester, or trifluoroborate, and L represents... 1 This indicates bromine or iodine. As shown in the general reaction flow 3, compounds 3-1 and 3-2 undergo a substitution reaction under alkaline conditions to generate compound 3-3. Compound 3-3 and YB undergo a coupling reaction to generate the target compound 3-4. Compound 3-4 reacts with m-CPBA to generate compound 3-5. Compounds 3-5 and 3-6 undergo a substitution reaction to generate the target compound 3-7.

[0124] General reaction process 4

[0125]

[0126] Compounds of general formula (1) can be prepared according to general reaction procedure 4, wherein R 1 R 2 R 3 R e X 1 X 2 X 3 X 4 X 5 The X, Y, s, q, A ring, and B ring are defined as above, where H represents hydrogen, N represents nitrogen, Cl represents chlorine, S represents sulfur, O represents oxygen, and L represents... 2This indicates bromine or chlorine. As shown in the general reaction flow 4, compounds 4-1 and 4-2 undergo a substitution reaction under alkaline conditions to generate compound 4-3. Compound 4-3 reacts with m-CPBA to generate compound 4-4. Compounds 4-4 and 4-5 undergo a substitution reaction to generate the target compound 4-6.

[0127] Further forms of the compound

[0128] "Pharmaceutical acceptable" here means that a substance, such as a carrier or diluent, will not destroy the biological activity or properties of a compound and is relatively non-toxic. For example, when given to an individual, a substance will not cause unwanted biological effects or interact with any of its components in a harmful manner.

[0129] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the administered organism and does not diminish the compound's biological activity and properties. In some specific respects, pharmaceutically acceptable salts are obtained by reacting compounds of general formula (1) with acids, such as inorganic acids like hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, and phosphoric acid; organic acids like 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, and p-toluenesulfonic acid; and acidic amino acids like aspartic acid and glutamic acid.

[0130] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. A hydrate is formed when the solvent is water, or an alcohol is formed when the solvent is ethanol. Solvates of compounds of general formula (1) are readily prepared or formed according to the methods described herein. For example, hydrates of compounds of general formula (1) are readily prepared by recrystallization from a mixture of water and organic solvents, including but not limited to tetrahydrofuran, acetone, ethanol, or methanol. Furthermore, the compounds mentioned herein can exist in both solvated and non-solvated forms. In summary, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solvated form.

[0131] In other specific embodiments, compounds of general formula (1) are prepared in various forms, including but not limited to amorphous, pulverized, and nano-particle forms. Furthermore, compounds of general formula (1) include crystalline forms and can also be polymorphic. Polymorphs comprise different lattice arrangements of the same elemental composition of the compound. Polymorphs typically have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability, and solubility. Different factors such as recrystallization solvents, crystallization rates, and storage temperatures may cause a single crystal form to dominate.

[0132] In another aspect, compounds of general formula (1) may possess a chiral center and / or axial chirality, and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, 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 diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of this invention. This invention means including all such isomeric forms of these compounds.

[0133] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting 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, deuterium can be used to replace hydrogen atoms to form deuterated compounds. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs generally have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0134] the term

[0135] Unless otherwise specified, the terms used in this application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, unless otherwise clearly indicated, the singular form "a" includes the plural meaning. Unless otherwise specified, conventional methods such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used. In this application, unless otherwise specified, "or" or "and" refers to "and / or".

[0136] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 6 carbon atoms. Lower alkyl groups containing 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and 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, etc. i Pr、 n Pr、 i Bu、 n Bu or t Bu.

[0137] Unless otherwise specified, "alkylene" means a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

[0138] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight-chain or branched groups with 1 to 14 carbon atoms. Lower alkenyl groups containing 1 to 4 carbon atoms are preferred, such as vinyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl.

[0139] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight-chain and branched groups with 1 to 14 carbon atoms. Lower alkynyl groups containing 1 to 4 carbon atoms are preferred, such as ethynyl, 1-propynyl or 1-butynyl.

[0140] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic, or polycyclic). A partially unsaturated cycloalkyl group may be referred to as "cycloalkenyl" if the carbon ring contains at least one double bond, or as "cycloynyl" if the carbon ring contains at least one triple bond. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocyclic groups. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. The cycloforming carbon atom of the cycloalkyl group may optionally be oxidized to form an oxo or thio 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). In some embodiments, the cycloalkyl group may be fused with aryl, heteroaryl, cycloalkyl, and heterocyclic alkyl groups. In some embodiments, the cycloalkyl group may be fused with aryl, cycloalkyl, and heterocyclic alkyl groups. In some embodiments, the cycloalkyl group may be fused with aryl and heterocyclic alkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclohepttrienyl, norcamphenyl, norpinel, norcarel, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, and so on.

[0141] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the remainder of the molecule via an ether oxygen atom. Representative alkoxy groups are those having 1-6 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, particularly those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, etc. i- PrO, n- PrO, i- BuO、 n- BuO or t- BuO.

[0142] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, which can be monocyclic or polycyclic, such as a monocyclic aryl ring fused with one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrene.

[0143] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), which may be monocyclic or polycyclic. For example, a monocyclic heteroaryl ring may be fused with one or more carbocyclic aromatic groups or other monocyclic heterocyclic alkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolinyl, furanyl, thiopheneyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrroleyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothiaphenyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrole[3,2-b]pyridinyl, 1H-pyrrole[2,3-c]pyridinyl, 1H-pyrrole[3,2-c]pyridinyl, 1H-pyrrole[2,3-b]pyridinyl,

[0144] Unless otherwise specified, "heterocyclic alkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenyl groups as part of a ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen, and phosphorus. If a heterocyclic alkyl contains at least one double bond, then a partially unsaturated heterocyclic alkyl may be referred to as a "heterocyclic alkenyl," or if a heterocyclic alkyl contains at least one triple bond, then a partially unsaturated heterocyclic alkyl may be referred to as a "heterocyclic ynyl." Heterocyclic alkyl can include monocyclic, bicyclic, spirocyclic, or polycyclic (e.g., having two fused or bridging rings) ring systems. In some embodiments, a heterocyclic alkyl is a monocyclic group having one, two, or three heteroatoms independently selected from nitrogen, sulfur, and oxygen. The cyclic carbon atom and heteroatom of a heterocyclic alkyl may optionally be oxidized to form an oxo or thio ion group or other oxidized bond (e.g., C(O), S(O), C(S), or S(O)₂, N-oxide, etc.), or the nitrogen atom may be quaternized. Heterocyclic alkyl may be linked via cyclic carbon atoms or cyclic heteroatoms. In some embodiments, the heterocyclic alkyl group contains 0 to 3 double bonds. In some embodiments, the heterocyclic alkyl group contains 0 to 2 double bonds. The definition of heterocyclic alkyl group also includes a portion having one or more aromatic rings fused with (i.e., sharing bonds with) the heterocyclic alkyl ring, such as benzo[a] derivatives of piperidine, morpholine, aziridine-heptadiene, or thiophene. Heterocyclic alkyl groups containing fused aromatic rings can be linked via any cyclizing atom, including the cyclizing atom of the fused aromatic ring. Examples of heterocyclic alkyl groups include, but are not limited to, azirrobutyl, azirroheptyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxoperazinyl, pyranyl, pyrrolidinyl, quininyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, scopolamine, 4,5,6,7-tetrahydrothiazo[5,4-c]pyridinyl, and 4,5,6,7-tetrahydro-1H-imidazolium. Azo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolyl, butyrolactam, valproic acid, imidazolinone, hydantoin, dioxolane, phthalimide, pyrimidin-2,4(1H,3H)-diketoyl, 1,4-dioxane, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide, thiomorpholin-S,S-oxide, piperazine, pyranyl, pyridinone, 3-pyrrololinyl, thiaranyl, pyranone, tetrahydrothiophene, 2-azaspiro[3,3]heptyl, indololinyl,

[0145] Unless otherwise specified, "halogen" (or halogenated group) means fluorine, chlorine, bromine or iodine. The term "halogenated" (or "halogen substituted") appearing before the group name indicates that the group is partially or completely halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0146] "Optional" or "optionally" means that the event or condition described below may, but is not required, occur, and the description includes both the scenario where said event or condition occurs and the scenario where said event or condition does not occur.

[0147] The substituent "-O-CH2-O-" indicates that the two oxygen atoms in the substituent are connected to two adjacent carbon atoms of a heterocyclic alkyl, aryl, or heteroaryl group. For example:

[0148] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a single bond.

[0149] When one of the variables is selected as a chemical bond, it means that the two groups connected are directly linked. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0150] The term "membered ring" includes any ring structure. The term "membered" refers to the number of skeleton atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thioranyl are six-membered rings, while cyclopentyl, pyrroleyl, furanyl, and thiophenyl are five-membered rings.

[0151] The term "fragment" refers to a specific part or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to a molecule.

[0152] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key Or straight dashed key

[0153] Unless otherwise stated, use Indicates a single bond or a double bond.

[0154] Specific pharmaceutical and medical terms

[0155] The term “acceptable,” as used herein, means that a prescription component or active ingredient does not have an excessively harmful effect on health for general therapeutic purposes.

[0156] The terms “treatment,” “treatment process,” or “therapy” as used herein include alleviating, suppressing, or improving symptoms or conditions of a disease; suppressing the development of complications; improving or preventing underlying metabolic syndromes; suppressing the development of a disease or symptom, such as controlling the progression of a disease or condition; reducing a disease or symptom; alleviating a disease or symptom; reducing complications arising from a disease or symptom; or preventing or treating signs arising from a disease or symptom. As used herein, a compound or pharmaceutical composition, when administered, may improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether administered regularly or intermittently, continuously or intermittently, it may be attributable to or related to the administration.

[0157] "Active ingredient" refers to the compound represented by general formula (1), and pharmaceutically acceptable inorganic or organic salts of compounds of general formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality), and thus appear as racemates, racemic mixtures, single enantiomers, diastereomers, and single diastereomers. The asymmetric centers that may exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomer mixtures, as well as pure or partially pure compounds, are included within the scope of the present invention. The present invention means including all such isomeric forms of these compounds.

[0158] The terms “compound,” “composition,” “agent,” or “medicine or medicament” may be used interchangeably here, and all refer to a compound or composition that, when applied to an individual (human or animal), can induce a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0159] The term “administered, administering, or administration” here refers to the direct application of the compound or composition described herein, or the application of a prodrug, derivative, or analog of the active compound.

[0160] While the numerical ranges and parameters used to define the broader scope of this invention are approximate values, the relevant values ​​in the specific embodiments have been presented as precisely as possible. However, any value inevitably contains standard deviations due to individual test methods. Here, "approximately" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "approximately" may mean that the actual value falls within the acceptable standard error of the mean, as determined by those skilled in the art. Except for experimental examples, or unless explicitly stated otherwise, it is understood that all ranges, quantities, values, and percentages used herein (e.g., to describe material usage, duration, temperature, operating conditions, quantity ratios, and others similar) are modified with "approximately". Therefore, unless otherwise stated, the numerical parameters disclosed in this specification and the accompanying claims are approximate values ​​and are subject to change as needed. At a minimum, these numerical parameters should be understood as the indicated significant digits and values ​​obtained using general rounding.

[0161] Unless otherwise defined in this specification, scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the art. Furthermore, unless conflicting with the context, singular nouns used herein include their plural forms, and vice versa.

[0162] Therapeutic uses

[0163] The present invention provides that compounds or pharmaceutical compositions of general formula (1) of the present invention are generally used to inhibit Wee1 kinase and are therefore used to treat one or more conditions associated with Wee1 kinase activity. Therefore, in some embodiments, the present invention provides a method for treating Wee1 kinase-mediated conditions, the method comprising the step of administering a compound of the present invention, or a pharmaceutically acceptable composition thereof, to a patient in need.

[0164] In some embodiments, a method for treating cancer is provided, comprising administering to an individual in need an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of general formula (1). In some embodiments, the compound of general formula (1) may be used in combination with other cancer treatment agents. In some embodiments, the compound of general formula (1) may be used in combination with gemcitabine. In some embodiments, the cancer is mediated by Wee1 kinase. In other embodiments, the cancer is a hematologic malignancy and a solid tumor, including, but not limited to, hematologic 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).

[0165] route of administration

[0166] The compounds of this invention and their pharmaceutically acceptable salts can be formulated into various preparations, comprising, within a safe and effective range, the compounds of this invention or their pharmaceutically acceptable salts and pharmacologically acceptable excipients or carriers. "Safe and effective range" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective range of the compound is determined based on the age, condition, and duration of treatment of the patient.

[0167] "Pharmaceutically acceptable excipients or carriers" refers to one or more compatible solid or liquid fillers or gelling substances that 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 and with the compounds of the present invention without significantly reducing the efficacy of the compounds. 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, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as... Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0168] When applying the compounds of this invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0169] 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 components: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silica; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (c) humectants, such as glycerin; (d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain complex silicates, and sodium carbonate; (e) slowing agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, such as kaolin; and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. Buffers may also be included in capsules, tablets, and pills.

[0170] Solid dosage forms such as tablets, sugar pills, capsules, pellets, and granules can be prepared using coatings and shells, such as casings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compound from such compositions can be delayed in a portion of the digestive tract. Examples of encapsulating components that can be used are polymeric substances and waxes. If necessary, the active compound may also be formed into microcapsules with one or more of the excipients described above.

[0171] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, e.g., ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0172] In addition to these inert diluents, the composition may also contain auxiliaries such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and fragrances.

[0173] In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0174] 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.

[0175] Dosage forms of the compounds of the present invention for topical administration include ointments, powders, patches, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be necessary.

[0176] The compounds of this invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using the pharmaceutical composition, a safe and effective amount of the compound of this invention is applied to the mammal (such as a human) requiring treatment, wherein the dose administered is a pharmaceutically considered effective dose. For a person weighing 60 kg, the daily dose is typically 1–2000 mg, preferably 50–1000 mg. Of course, the specific dosage should also consider factors such as the route of administration and the patient's health condition, which are all within the scope of a skilled physician's expertise.

[0177] The features mentioned above in this invention, or the features mentioned in the embodiments, can be combined arbitrarily. All features disclosed in this specification can be used in any compositional form, and each feature disclosed in the specification can be replaced by any alternative feature that provides the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the disclosed features are merely general examples of equivalent or similar features. Detailed Implementation

[0178] The following description will elaborate on the specific aspects, characteristics, and advantages of the aforementioned compounds, methods, and pharmaceutical compositions, making the content of this invention readily apparent. It should be understood that the detailed descriptions and examples described below are specific embodiments and are for reference only. After reading this description, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by this application.

[0179] In all embodiments, 1 H-NMR was recorded using a Varian Mercury 400 NMR spectrometer, and chemical shifts are expressed as δ (ppm). Unless otherwise specified, the silica gel used for separation was 200-300 mesh, and all eluent ratios were by volume.

[0180] The following abbreviations are used in this invention: (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; DMAP represents 4-(dimethylamino)pyridine; DMSO represents dimethyl sulfoxide; hr represents hours; IPA represents isopropanol; min represents minutes; K₂CO₃ represents potassium carbonate; KOAc represents potassium acetate; K₃PO₄ represents potassium phosphate. min represents minutes; MeOH represents methanol; MS represents mass spectrometry; MsOH represents methanesulfonic acid; m-CPBA represents m-chloroperoxybenzoic acid; n-BuLi represents n-butyllithium; NMR represents nuclear magnetic resonance; Pd / C represents palladium on carbon; Pd(PPh3)4 represents tetratetraphenylphosphine palladium; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium(0); PE represents petroleum ether; TFA represents trifluoroacetic acid; T3P represents 1-propylphosphonic anhydride; XantPhos represents 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene); TLC represents thin-layer chromatography; XPhos represents 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl.

[0181] Example 1: Synthesis of Compound 1

[0182]

[0183] Step 1: Synthesis of compound int_1-9-2:

[0184]

[0185] Int_1-9-1 (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 the addition was complete, the mixture was heated to 50 °C and reacted for 16 hours. The reaction solution was diluted with 1500 mL of ethyl acetate and washed with NaHCO3 aqueous solution (400 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to give a crude product as a white solid (50 g, yield: 93.1%). The crude product could be used directly in the next reaction step.

[0186] 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)

[0187] MS(ESI): 190[M+H] + .

[0188] Step 2: Synthesis of compound int_1-9-3:

[0189]

[0190] Int_1-9-2 (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 protection. Then, DMF (48.3 g, 660 mmol, 50.8 mL) was slowly added dropwise at -23 °C. Next, HCl solution (6 M, 300 mL) was slowly added dropwise at 20 °C. The reaction mixture was diluted with 100 mL of water, extracted with ethyl acetate (500 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to give a yellow solid (55 g, crude product). The crude product can be used directly in the next reaction step.

[0191] 1H 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)

[0192] MS(ESI):200[M+H] + .

[0193] Step 3: Synthesis of compound int_1-9-4:

[0194]

[0195] 55 g (276 mmol) of int_1-9-3 and 20 g of palladium on carbon were suspended in methanol (800 mL) and stirred overnight at 30 °C under hydrogen pressure (50 psi). The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (SiO2, PE / EtOAc = 1 / 0 to 3 / 1) to give a yellow solid (38.5 g, yield: 69.3%).

[0196] 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)

[0197] MS(ESI):202[M+H] + .

[0198] Step 4: Synthesis of compound int_1-9-5:

[0199]

[0200] Int_1-9-4 (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. After addition, the mixture was brought to room temperature and stirred for 2 hours. TLC analysis showed 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 obtain a yellow solid (79 g, crude product). The crude product can be used directly in the next reaction step.

[0201] MS(ESI):247[M+H] + .

[0202] Step 5: Synthesis of compound int_1-9-6:

[0203]

[0204] Int_1-9-5 (4.9, 19.9 mmol) and palladium on carbon (2 g, 19.9 mmol, 10% purity) were suspended in methanol (100 mL) and reacted under hydrogen pressure (50 psi) at 25 °C for 16 h. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (SiO2, PE / EtOAc = 1 / 0 to 1 / 2) to give a yellow solid (1.44 g, yield: 33.5%).

[0205] 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).

[0206] MS(ESI):217[M+H] + .

[0207] Step 6: Synthesis of compounds int_1-9:

[0208]

[0209] Int_1-9-6 (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. The reaction was quenched by slowly adding water to the reaction solution, while maintaining the temperature of the reaction solution at 0–10 °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 distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, DCM / (MeOH + 1% NH4OH) = 1 / 0 to 10 / 1) to give a yellow oil (6.25 g, yield: 95.5%).

[0210] 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=10.7Hz, 1H), 1.92 (tdd, J=3.4, 6.5, 13.1Hz, 1H), 1.88-1.75 (m, 2H), 1.34-1.17 (m, 1H).

[0211] MS(ESI):203[M+H] + .

[0212] Step 7: Synthesis of compound int_1-2:

[0213]

[0214] Int_1-1 (3.46 g, 20 mmol) was dissolved in dichloromethane (100 mL), and DIPEA (5.2 g, 40 mmol), DMAP (1.22 g, 10 mmol), and (Boc)₂O (4.8 g, 22 mmol) were added. The reaction was allowed to proceed overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction solution was diluted with dichloromethane (100 mL), washed with water (200 mL), washed with 2N dilute hydrochloric acid (100 mL), washed with sodium bicarbonate aqueous solution (100 mL), washed with water (100 mL), and finally washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product as a light brown gel (4.0 g, yield: 73%). The crude product can be used directly in the next reaction.

[0215] ESI-MS m / z: 273 [M+H] + .

[0216] Step 8: Synthesis of compound int_1-4:

[0217]

[0218] Int_1-2 (4 g, 14.6 mmol), int_1-3 (1.36 g, 14.6 mmol), cesium carbonate (7.14 g, 161 mmol), Pd2(dba)3 (668 mg, 0.73 mmol), and Xantphos (845 mg, 1.46 mmol) were dissolved in 1,4-dioxane (120 mL), and the mixture was reacted overnight at 85 °C. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a pale yellow solid product (2.7 g, yield: 65%).

[0219] ESI-MS m / z: 286 [M+H] +

[0220] Step 9: Synthesis of compounds int_1-5:

[0221]

[0222] Int_1-4 (2.4 g, 8.41 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added. The reaction was allowed to proceed overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a grayish-yellow solid (1.6 g, yield: 100%). The crude product can be used directly in the next reaction step.

[0223] ESI-MS m / z: 186 [M+H] +

[0224] Step 10: Synthesis of compounds int_1-7:

[0225]

[0226] Int_1-6 (2 g, 10.8 mmol) and int_1-5 (3.2 g, 10.8 mmol) were dissolved in isopropanol (5 mL), and DIPEA (5.57 g, 43.1 mmol, 7.51 mL) was added. The reaction mixture was heated to 50 °C and reacted overnight. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature, and a white solid precipitated. The solid was filtered to obtain the product. The product was dried to obtain a white solid (1.2 g, yield: 33%).

[0227] 1H NMR: (400MHz, DMSO-d6).δ9.80(s,1H),8.70(s,1H),7.58(t,J=7.9Hz,1H),7.16(d,J=7.8Hz,1H),6.44(d,J=7.9Hz,1H),3.41(s,6H),2.49(s,3H)

[0228] ESI-MS m / z: 335 [M+H] +

[0229] Step 11: Synthesis of compounds int_1-8:

[0230]

[0231] Int_1-7 (334 mg, 1.0 mmol) was dissolved in dichloromethane (40 mL), and m-CPBA (85%, 240 mg, 1.2 mmol) was added at room temperature. The mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product (335 mg, crude product). The crude product can be used directly in the next reaction step.

[0232] ESI-MS m / z: 351 [M+H] +

[0233] Step 12: Synthesis of Compound 1:

[0234]

[0235] Int_1-8 (335 mg, 0.95 mmol) was dissolved in DMF (20 mL), and int_1-9 (242 mg, 1.2 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain a white solid (160 mg, yield: 34%).

[0236] 1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.70(d,J=8.0Hz,1H),7.59(s,1H),7.48(s,1H) ,7.26(s,1H),7.07(d,J=8.6Hz,2H),6.57(dd,J=8.0,0.7Hz,1H),3.92(d,J=15.2Hz,1H),3. 36(s,6H),3.32(d,J=15.2Hz,1H),3.05-2.89(m,2H),2.79(ddt,J=24.3,17.0,8.9Hz,2H), 2.44(s,3H),2.08(t,J=10.4Hz,1H),1.99-1.78(m,3H),1.37-1.18(m,1H).LC-MS:489[M+H] +

[0237] The HPLC preparation method is as follows:

[0238] Instrument: Agilent 1260 Infinity 2

[0239] Column: Waters Xbridge Prep C1819*250mm, 5µm OBD

[0240] Column temperature: 25℃

[0241] Detection wavelength: 205nm / 254nm

[0242] Mobile phase A: H2O (0.1% FA)

[0243] Mobile phase B:MeCN

[0244] Flow rate: 20 mL / min

[0245] Gradient: 0.00 min – 1.00 min: 5% B → 5% B

[0246] 1.01min–20.00min:5%B→40%B

[0247] 20.00min–20.01min:40%B→95%B

[0248] 20.01min–24.00min:95%B→95%B

[0249] 24.00min–24.01min:95%B→5%B

[0250] 24.01min–27.00min:5%B→5%B

[0251] Example 2: Synthesis of Compound 2

[0252]

[0253] Step 1: Synthesis of compound int_1-9-2:

[0254]

[0255] Int_1-9-1 (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 the addition was complete, the mixture was heated to 50 °C and reacted for 16 hours. The reaction solution was diluted with 1500 mL of ethyl acetate and washed with NaHCO3 aqueous solution (400 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to give a crude product as a white solid (50 g, 264 mmol, yield: 93.1%). The crude product could be used directly in the next reaction step.

[0256] 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)

[0257] MS(ESI): 190[M+H] + .

[0258] Step 2: Synthesis of compound int_1-9-3:

[0259]

[0260] Int_1-9-2 (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 protection. Then, DMF (48.3 g, 660 mmol, 50.8 mL) was slowly added dropwise at -23 °C. Next, HCl solution (6 M, 300 mL) was slowly added dropwise at 20 °C. The reaction mixture was diluted with 100 mL of water, extracted with ethyl acetate (500 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to give a yellow solid (55 g, crude product). The crude product can be used directly in the next reaction step.

[0261] 1H 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)

[0262] MS(ESI):200[M+H] + .

[0263] Step 3: Synthesis of compound int_1-9-4:

[0264]

[0265] 55 g (276 mmol) of int_1-9-3 and 20 g of palladium on carbon were suspended in methanol (800 mL) and stirred overnight at 30 °C under hydrogen pressure (50 psi). The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (SiO2, PE / EtOAc = 1 / 0 to 3 / 1) to give a yellow solid (38.5 g, yield: 69.3%).

[0266] 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)

[0267] MS(ESI):202[M+H] + .

[0268] Step 4: Synthesis of compound int_1-9-5:

[0269]

[0270] Int_1-9-4 (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. After addition, the mixture was brought to room temperature and stirred for 2 hours. TLC analysis showed 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 obtain a yellow solid (79 g, crude product). The crude product can be used directly in the next reaction step.

[0271] MS(ESI):247[M+H] + .

[0272] Step 5: Synthesis of compound int_1-9-6:

[0273]

[0274] Int_1-9-5 (4.9, 19.9 mmol) and palladium on carbon (2 g, 19.9 mmol, 10% purity) were suspended in methanol (100 mL) and reacted under hydrogen pressure (50 psi) at 25 °C for 16 h. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (SiO2, PE / EtOAc = 1 / 0 to 1 / 2) to give a yellow solid (1.44 g, yield: 33.5%).

[0275] 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).

[0276] MS(ESI):217[M+H] + .

[0277] Step 6: Synthesis of compounds int_1-9:

[0278]

[0279] Int_1-9-6 (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. The reaction was quenched by slowly adding water to the reaction solution, while maintaining the temperature of the reaction solution at 0–10 °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 distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, DCM / (MeOH + 1% NH4OH) = 1 / 0 to 10 / 1) to give a yellow oil (6.25 g, yield: 95.5%).

[0280] 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).

[0281] MS(ESI):203[M+H] + .

[0282] Step 7: Synthesis of compounds int_1-9A and int_1-9B:

[0283]

[0284] Int_1-9 (1.5 g, 7.41 mmol) was chirally separated using preparative supercritical fluid chromatography (prep SFC) (SFC chiral separation conditions: instrument: Waters SFC350; column: DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 μm); mobile phase: A: CO2, B: IPA (0.1% NH3H2O); gradient: B%: 50%-50%; flow rate: 200 mL / min; column temperature: 40 °C). The fractions were concentrated under reduced pressure and lyophilized to obtain yellow oily int_1-9A (peak 1,438 mg, yield: 29.20%) and yellow oily int_1-9B (peak 2,450 mg, yield: 30.00%).

[0285] int_1-9A: 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)

[0286] MS(ESI):203[M+H] + .

[0287] int_1-9B: 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)

[0288] MS(ESI):203[M+H] + .

[0289] Step 8: Synthesis of compound int_1-2:

[0290]

[0291] Int_1-1 (3.46 g, 20 mmol) was dissolved in dichloromethane (100 mL), and DIPEA (5.2 g, 40 mmol), DMAP (1.22 g, 10 mmol), and (Boc)₂O (4.8 g, 22 mmol) were added. The reaction was allowed to proceed overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction solution was diluted with dichloromethane (100 mL), washed with water (200 mL), washed with 2N dilute hydrochloric acid (100 mL), washed with sodium bicarbonate aqueous solution (100 mL), washed with water (100 mL), and finally washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product as a light brown gel (4.0 g, yield: 73%). The crude product can be used directly in the next reaction.

[0292] ESI-MS m / z: 273 [M+H] + .

[0293] Step 9: Synthesis of compound int_1-4:

[0294]

[0295] Int_1-2 (4 g, 14.6 mmol), int_1-3 (1.36 g, 14.6 mmol), cesium carbonate (7.14 g, 161 mmol), Pd2(dba)3 (668 mg, 0.73 mmol), and Xantphos (845 mg, 1.46 mmol) were dissolved in 1,4-dioxane (120 mL), and the mixture was reacted overnight at 85 °C. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a pale yellow solid product (2.7 g, yield: 65%).

[0296] ESI-MS m / z: 286 [M+H] +

[0297] Step 10: Synthesis of compounds int_1-5:

[0298]

[0299] Int_1-4 (2.4 g, 8.41 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added. The reaction was allowed to proceed overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a grayish-yellow solid (1.6 g, yield: 100%). The crude product was used directly in the next reaction step.

[0300] ESI-MS m / z: 186 [M+H] +

[0301] Step 11: Synthesis of compounds int_1-7:

[0302]

[0303] Int_1-6 (2 g, 10.8 mmol) and int_1-5 (3.2 g, 10.8 mmol) were dissolved in isopropanol (5 mL), and DIPEA (5.57 g, 43.1 mmol, 7.51 mL) was added. The reaction mixture was heated to 50 °C and reacted overnight. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature, and a white solid precipitated. The solid was filtered to obtain the product. The product was dried to obtain a white solid (1.2 g, yield: 33%).

[0304] 1H NMR: (400MHz, DMSO-d6).δ9.80(s,1H),8.70(s,1H),7.58(t,J=7.9Hz,1H),7.16(d,J=7.8Hz,1H),6.44(d,J=7.9Hz,1H),3.41(s,6H),2.49(s,3H)

[0305] ESI-MS m / z: 335 [M+H] +

[0306] Step 12: Synthesis of compounds int_1-8:

[0307]

[0308] Int_1-7 (334 mg, 1.0 mmol) was dissolved in dichloromethane (40 mL), and m-CPBA (85%, 240 mg, 1.2 mmol) was added at room temperature. The mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product (335 mg, crude product). The crude product can be used directly in the next reaction step.

[0309] ESI-MS m / z: 351 [M+H] +

[0310] Step 13: Synthesis of Compound 2:

[0311]

[0312] Int_1-8 (100 mg, 0.28 mmol) was dissolved in DMF (5 mL), and int_1-9A (57 mg, 0.28 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography to give a white solid (70 mg, yield: 50%).

[0313] 1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.70(d,J=8.0Hz,1H),7.59(s,1H),7.48(s, 1H),7.26(s,1H),7.07(d,J=8.6Hz,2H),6.57(dd,J=8.0,0.7Hz,1H),3.92(d,J=15.2Hz ,1H),3.36(s,6H),3.32(d,J=15.2Hz,1H),3.05-2.89(m,2H),2.79(ddt,J=24.3,17.0, 8.9Hz,2H),2.44(s,3H),2.08(t,J=10.4Hz,1H),1.99-1.78(m,3H),1.37-1.18(m,1H).

[0314] LC-MS: 489 [M+H] +

[0315] The HPLC preparation method is as follows:

[0316] Instrument: Agilent 1260 Infinity 2

[0317] Column: Waters Xbridge Prep C1819*250mm, 5µm OBD

[0318] Column temperature: 25℃

[0319] Detection wavelength: 205nm / 254nm

[0320] Mobile phase A: H2O (0.1% FA)

[0321] Mobile phase B:MeCN

[0322] Flow rate: 20 mL / min

[0323] Gradient: 0.00 min – 1.00 min: 5% B → 5% B

[0324] 1.01min–20.00min:5%B→40%B

[0325] 20.00min–20.01min:40%B→95%B

[0326] 20.01min–24.00min:95%B→95%B

[0327] 24.00min–24.01min:95%B→5%B

[0328] 24.01min–27.00min:5%B→5%B

[0329] Example 3: Synthesis of Compound 3

[0330]

[0331] Step 1: Synthesis of compound int_1-9-2:

[0332]

[0333] Int_1-9-1 (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 the addition was complete, the mixture was heated to 50 °C and reacted for 16 hours. The reaction solution was diluted with 1500 mL of ethyl acetate and washed with NaHCO3 aqueous solution (400 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to give a crude product as a white solid (50 g, 264 mmol, yield: 93.1%). The crude product could be used directly in the next reaction step.

[0334] 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)

[0335] MS(ESI): 190[M+H] + .

[0336] Step 2: Synthesis of compound int_1-9-3:

[0337]

[0338] Int_1-9-2 (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 protection. Then, DMF (48.3 g, 660 mmol, 50.8 mL) was slowly added dropwise at -23 °C. Next, HCl solution (6 M, 300 mL) was slowly added dropwise at 20 °C. The reaction mixture was diluted with 100 mL of water, extracted with ethyl acetate (500 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to give a yellow solid (55 g, crude product). The crude product can be used directly in the next reaction step.

[0339] 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)

[0340] MS(ESI):200[M+H] + .

[0341] Step 3: Synthesis of compound int_1-9-4:

[0342]

[0343] 55 g (276 mmol) of int_1-9-3 and 20 g of palladium on carbon were suspended in methanol (800 mL) and stirred overnight at 30 °C under hydrogen pressure (50 psi). The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (SiO2, PE / EtOAc = 1 / 0 to 3 / 1) to give a yellow solid (38.5 g, yield: 69.3%).

[0344] 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)

[0345] MS(ESI):202[M+H] + .

[0346] Step 4: Synthesis of compound int_1-9-5:

[0347]

[0348] Int_1-9-4 (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. After addition, the mixture was brought to room temperature and stirred for 2 hours. TLC analysis showed 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 obtain a yellow solid (79 g, crude product). The crude product can be used directly in the next reaction step.

[0349] MS(ESI):247[M+H] + .

[0350] Step 5: Synthesis of compound int_1-9-6:

[0351]

[0352] Int_1-9-5 (4.9, 19.9 mmol) and palladium on carbon (2 g, 19.9 mmol, 10% purity) were suspended in methanol (100 mL) and reacted under hydrogen pressure (50 psi) at 25 °C for 16 h. The palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (SiO2, PE / EtOAc = 1 / 0 to 1 / 2) to give a yellow solid (1.44 g, yield: 33.5%).

[0353] 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).

[0354] MS(ESI):217[M+H] + .

[0355] Step 6: Synthesis of compounds int_1-9:

[0356]

[0357] Int_1-9-6 (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. The reaction was quenched by slowly adding water to the reaction solution, while maintaining the temperature of the reaction solution at 0–10 °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 distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, DCM / (MeOH + 1% NH4OH) = 1 / 0 to 10 / 1) to give a yellow oil (6.25 g, yield: 95.5%).

[0358] 1 H 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).

[0359] MS(ESI):203[M+H] + .

[0360] Step 7: Synthesis of compounds int_1-9A and int_1-9B:

[0361]

[0362] Int_1-9 (1.5 g, 7.41 mmol) was chirally separated using preparative supercritical fluid chromatography (prep SFC) (SFC chiral separation conditions: instrument: Waters SFC350; column: DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 μm); mobile phase: A: CO2, B: IPA (0.1% NH3H2O); gradient: B%: 50%-50%; flow rate: 200 mL / min; column temperature: 40 °C). The fractions were concentrated under reduced pressure and lyophilized to obtain yellow oily int_1-9A (peak 1,438 mg, yield: 29.20%) and yellow oily int_1-9B (peak 2,450 mg, yield: 30.00%).

[0363] int_1-9A: 1H 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)

[0364] MS(ESI):203[M+H] + .

[0365] int_1-9B: 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)

[0366] MS(ESI):203[M+H] + .

[0367] Step 8: Synthesis of compound int_1-2:

[0368]

[0369] Int_1-1 (3.46 g, 20 mmol) was dissolved in dichloromethane (100 mL), and DIPEA (5.2 g, 40 mmol), DMAP (1.22 g, 10 mmol), and (Boc)₂O (4.8 g, 22 mmol) were added. The reaction was allowed to proceed overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction solution was diluted with dichloromethane (100 mL), washed with water (200 mL), washed with 2N dilute hydrochloric acid (100 mL), washed with sodium bicarbonate aqueous solution (100 mL), washed with water (100 mL), and finally washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product as a light brown gel (4.0 g, yield: 73%). The crude product can be used directly in the next reaction.

[0370] ESI-MS m / z: 273 [M+H] + .

[0371] Step 9: Synthesis of compound int_1-4:

[0372]

[0373] Int_1-2 (4 g, 14.6 mmol), int_1-3 (1.36 g, 14.6 mmol), cesium carbonate (7.14 g, 161 mmol), Pd2(dba)3 (668 mg, 0.73 mmol), and Xantphos (845 mg, 1.46 mmol) were dissolved in 1,4-dioxane (120 mL), and the mixture was reacted overnight at 85 °C. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a pale yellow solid product (2.7 g, yield: 65%).

[0374] ESI-MS m / z: 286 [M+H] +

[0375] Step 10: Synthesis of compounds int_1-5:

[0376]

[0377] Int_1-4 (2.4 g, 8.41 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added. The reaction was allowed to proceed overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a grayish-yellow solid (1.6 g, yield: 100%). The crude product can be used directly in the next reaction step.

[0378] ESI-MS m / z: 186 [M+H]+

[0379] Step 11: Synthesis of compounds int_1-7:

[0380]

[0381] Int_1-6 (2 g, 10.8 mmol) and int_1-5 (3.2 g, 10.8 mmol) were dissolved in isopropanol (5 mL), and DIPEA (5.57 g, 43.1 mmol, 7.51 mL) was added. The reaction mixture was heated to 50 °C and reacted overnight. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature, and a white solid precipitated. The solid was filtered to obtain the product. The product was dried to obtain a white solid (1.2 g, yield: 33%).

[0382] 1 H NMR: (400MHz, DMSO-d6).δ9.80(s,1H),8.70(s,1H),7.58(t,J=7.9Hz,1H),7.16(d,J=7.8Hz,1H),6.44(d,J=7.9Hz,1H),3.41(s,6H),2.49(s,3H)

[0383] ESI-MS m / z: 335 [M+H] +

[0384] Step 12: Synthesis of compounds int_1-8:

[0385]

[0386] Int_1-7 (334 mg, 1.0 mmol) was dissolved in dichloromethane (40 mL), and m-CPBA (85%, 240 mg, 1.2 mmol) was added at room temperature. The mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product (335 mg, crude product). The crude product can be used directly in the next reaction step.

[0387] ESI-MS m / z: 351 [M+H] +

[0388] Step 13: Synthesis of Compound 3:

[0389]

[0390] Int_1-8 (100 mg, 0.28 mmol) was dissolved in DMF (5 mL), and int_1-9B (57 mg, 0.28 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase chromatography to give a white solid (75 mg, yield: 55%).

[0391] 1 H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.70(d,J=8.0Hz,1H),7.59(s,1H),7.48(s, 1H),7.26(s,1H),7.07(d,J=8.6Hz,2H),6.57(dd,J=8.0,0.7Hz,1H),3.92(d,J=15.2Hz ,1H),3.36(s,6H),3.32(d,J=15.2Hz,1H),3.05-2.89(m,2H),2.79(ddt,J=24.3,17.0, 8.9Hz,2H),2.44(s,3H),2.08(t,J=10.4Hz,1H),1.99-1.78(m,3H),1.37-1.18(m,1H).

[0392] LC-MS: 489 [M+H] +

[0393] The HPLC preparation method is as follows:

[0394] Instrument: Agilent 1260 Infinity 2

[0395] Column: Waters Xbridge Prep C1819*250mm, 5µm OBD

[0396] Column temperature: 25℃

[0397] Detection wavelength: 205nm / 254nm

[0398] Mobile phase A: H2O (0.1% FA)

[0399] Mobile phase B:MeCN

[0400] Flow rate: 20 mL / min

[0401] Gradient: 0.00 min – 1.00 min: 5% B → 5% B

[0402] 1.01min–20.00min:5%B→40%B

[0403] 20.00min–20.01min:40%B→95%B

[0404] 20.01min–24.00min:95%B→95%B

[0405] 24.00min–24.01min:95%B→5%B

[0406] 24.01min–27.00min:5%B→5%B

[0407] Example 4 Synthesis of Compound 64

[0408]

[0409] Step 1: Synthesis of compound int_64-1-2:

[0410]

[0411] Int_1-9-1 (50 g, 324 mmol) was dissolved in methanol (500 mL), and SOCl2 (77.2 g, 649 mmol, 47.1 mL) was added dropwise at 0 °C. After the addition was complete, the mixture was allowed to rise to room temperature and reacted for 16 hours. TLC analysis showed that the reaction was complete. The reaction solution was concentrated by vacuum distillation to obtain a crude product as a white solid (53.4 g, yield: 97.2%). The crude product can be used directly in the next reaction step.

[0412] 1 H NMR: (400MHz, METHANOL-d4) δ6.92 (d, J=2.0Hz, 2H), 6.47 (t, J=2.3Hz, 1H), 3.89-3.80 (m, 3H)

[0413] Step 2: Synthesis of compound int_64-1-4:

[0414]

[0415] Int_64-1-2 (54.3 g, 315 mmol) was dissolved in DMF (500 mL). Under nitrogen protection, K2CO3 (87.1 g, 630 mmol) and Int_64-1-3 (89.4 g, 662 mmol, 67.2 mL) were added. The mixture was heated to 60 °C and reacted for 16 hours. TLC showed that the reaction was complete. The reaction solution was diluted with 800 mL of water, extracted with ethyl acetate (800 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered, concentrated under reduced pressure, and subjected to column chromatography (SiO2, PE / THF = 10 / 1 to 5 / 1) to give a yellow solid (23.1 g, yield: 32.3%).

[0416] 1 H NMR: (400MHz, Chloroform-d) δ7.15 (ddd, J=1.3, 2.2, 6.7Hz, 2H), 6.62 (t, J=2.3Hz, 1H), 6.12 (s, 1H), 5.88 ( tdd,J=6.7,10.3,17.1Hz,1H),5.23-5.04(m,2H),4.02(t,J=6.7Hz,2H),3.90(s,3H),2.53(q,J=6.7Hz,2H)

[0417] Step 3: Synthesis of compound int_64-1-5:

[0418]

[0419] Int_64-1-4 (16 g, 72 mmol) was dissolved in THF (150 mL) and H2O (37 mL). LiOH·H2O (15.1 g, 360 mmol) was added at 0 °C, and the mixture was stirred at 30 °C for 16 hours. TLC analysis showed the reaction was complete. The reaction solution was diluted with 200 mL of water and 200 mL of ethyl acetate, and the pH was adjusted to 2–3 with 4N hydrochloric acid solution. Extraction was performed with ethyl acetate (100 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain the crude product (12.1 g, yield: 80.7%). The crude product can be used directly in the next reaction step.

[0420] 1 H NMR: (400MHz, METHANOL-d4) δ7.04(t,J=2.1Hz,2H),6.57(t,J=2.3Hz,1H),5.92(tdd,J =6.7,10.3,17.1Hz,1H),5.26-5.03(m,2H),4.01(t,J=6.6Hz,2H),2.51(q,J=6.5Hz,2H)

[0421] Step 4: Synthesis of compound int_64-1-6:

[0422]

[0423] Int_64-1-5 (12 g, 57.6 mmol) was dissolved in DCM (120 mL). At 0 °C, (COCl)₂ (11.0 g, 86.5 mmol, 7.57 mL) and two drops of DMF were slowly added. The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to give a yellow solid (16.8 g, crude product). The crude product can be used directly in the next reaction step.

[0424] Step 5: Synthesis of compound int_64-1-8:

[0425]

[0426] Int_64-1-6 (18.3 g, 68.5 mmol) was dissolved in ethyl acetate (120 mL) and H2O (60 mL), and K2CO3 (31.6 g, 228 mmol) was added. The mixture was cooled to 0 °C, and an ethyl acetate solution (50 mL) of int_64-1-7 (16.8 g, crude product) was added. The reaction mixture was allowed to react at room temperature for 16 hours. TLC analysis showed that the reaction was complete. The reaction mixture was diluted with 200 mL of water, extracted with ethyl acetate (100 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, PE / THF = 1 / 0 to 4 / 1) to obtain a yellow oil (24 g, yield: 41.1%).

[0427] The mixture was suspended in methanol (100 mL) and reacted under hydrogen pressure (50 psi) at 25 °C for 16 hours. Palladium on carbon was removed by filtration, and the filtrate was concentrated under reduced pressure and subjected to column chromatography (SiO2, PE / EtOAc = 1 / 0 to 1 / 2) to give a yellow solid (1.44 g, yield: 33.5%).

[0428] MS(ESI):308[M+H] + .

[0429] Step 6: Synthesis of compound int_64-1-9:

[0430]

[0431] Int_64-1-8 (10.3 g, 13.8 mmol) was dissolved in acetonitrile (180 mL). Under nitrogen protection, cesium neopentanoate (6.45 g, 27.6 mmol) and dichloropentamethylcenzolide (216 mg, 345 μmol) were added. The reaction mixture was reacted at 25 °C for 7 hours under nitrogen protection. LC-MS analysis showed that the reaction was complete. The reaction mixture was filtered and concentrated. The crude product was dissolved in 200 mL of ethyl acetate and 200 mL of water, extracted with ethyl acetate (200 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain the crude product. The crude product was dissolved in 200 mL of ethyl acetate, filtered, and the filter cake was washed with ethyl acetate (20 mL x 3). The filtrate was concentrated to obtain the crude product. The crude product was dispersed and diluted in 50 mL of dichloromethane, filtered, and the filter cake was washed with dichloromethane (5 mL x 3). The filter cake was dried to obtain the product (3.5 g, crude product). The product can be used directly in the next reaction.

[0432] 1 H NMR: (400MHz, METHANOL-d4) δ6.91(d,J=2.4Hz,1H),6.39(d,J=2.4Hz,1H),4.47-4.34(m,1H),4.17-4.00(m, 1H),3.47(dd,J=4.3,10.9Hz,1H),3.18-2.99(m,2H),2.10-1.98(m,1H),1.74-1.60(m,1H),1.74-1.60(m,1H)

[0433] MS(ESI): 206[M+H] + .

[0434] Step 7: Synthesis of compound int_64-1-10:

[0435]

[0436] Int_64-1-9 (4.00 g, 19.5 mmol) and K₂CO₃ (5.39 g, 39.0 mmol) were dissolved in acetonitrile (40 mL), and benzyl bromide (4.00 g, 23.4 mmol, 2.78 mL) was added. The reaction mixture was reacted at 40 °C for 16 hours under nitrogen protection. LC-MS analysis showed the reaction was complete. The reaction mixture was filtered and concentrated. The crude product was dissolved in 200 mL of water and extracted with ethyl acetate (200 mL * 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. The crude product was subjected to column chromatography (SiO₂, PE / EtOAc = 1 / 1 to 1 / 3) to give a yellow solid (5.2 g, yield: 89.0%).

[0437] 1H NMR: (400MHz, Chloroform-d) δ7.47-7.29 (m, 5H), 6.61 (d, J = 2.5Hz, 1H), 6.52 (br d,J=4.5Hz,1H),5.11-5.03(m,2H),4.49-4.38(m,1H),4.18-4.05(m,1H),3.55-3.43(m,1H),3.26-3.14(m,2H),2.04-1.97(m,1H),1.75(br dd,J=3.1,12.2Hz,1H)

[0438] MS(ESI): 296[M+H] + .

[0439] Step 8: Synthesis of compound int_64-1-11:

[0440]

[0441] Int_64-1-10 (5.20 g, 17.6 mmol) was dissolved in DMF (50 mL). Under nitrogen protection, sodium hydride (1.06 g, 26.4 mmol, 60% purity) was added at 0 °C. The reaction solution was reacted at 0 °C for 0.5 h, and then iodomethane (2.75 g, 19.4 mmol, 1.21 mL) was added. The reaction solution was then heated to 20 °C and reacted for 1 h. LC-MS analysis showed that the reaction was complete. The reaction solution was slowly quenched in 100 mL of ice water and extracted with ethyl acetate (100 mL * 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. The crude product was subjected to column chromatography (SiO2, PE / EtOAc = 2 / 1 to 1 / 1) to give the product (4.8 g, yield: 88.1%).

[0442] 1 H NMR: (400MHz, Chloroform-d) δ7.46-7.31(m,5H),7.28(d,J=2.5Hz,1H),6.57(d,J=2.6Hz,1H),5.11-5.03(m,2H),4.55- 4.33(m,1H),4.23-4.00(m,1H),3.43-3.30(m,2H),3.29-3.19(m,1H),3.15(s,3H),2.04-1.96(m,1H),1.81-1.68(m,1H)

[0443] MS(ESI): 310[M+H] + .

[0444] Step 9: Synthesis of compound int_64-1-12:

[0445]

[0446] int_64-1-11 (4.80 g, 15.5 mmol) was dissolved in ethanol (50 mL), and Pd / C (991 mg, 931 μmol, 10% purity) was added. The reaction solution was reacted at 20 °C for 16 hours under a hydrogen atmosphere (15 Psi). LC-MS analysis showed that the reaction was complete. The reaction solution was distilled under reduced pressure to give the product (3.1 g, yield: 89.4%).

[0447] 1 H NMR: (400MHz, METHANOL-d4) δ6.90 (d, J=2.3Hz, 1H), 6.36 (d, J=2.5Hz, 1H), 4.45-4.33 (m, 1H), 4.09 (ddd, J=1.9, 11.0, 12.7Hz, 1H), 3.56-3. 44(m,1H),3.27(d,J=11.3Hz,1H),3.24-3.15(m,1H),3.12(s,3H),2.04(tdd,J=2.2,4.8,13.4Hz,1H),1.73-1.60(m,1H)MS(ESI):220[M+H] + .

[0448] Step 10: Synthesis of compound int_64-1-13:

[0449]

[0450] Int_64-1-12 (3g, 13.7mmol) and triethylamine (4.15g, 41.1mmol, 5.71mL) were dissolved in dichloromethane (20mL) and tetrahydrofuran (20mL), and Tf₂O (4.63g, 16.42mmol, 2.71mL) was added dropwise at 0℃. The reaction solution was heated to 20℃ and reacted for 3 hours. LC-MS showed that the reaction was complete. The reaction solution was slowly poured into 75mL of ice water to quench the reaction, and extracted with ethyl acetate (100mL*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. The crude product was subjected to column chromatography (…). 40g The product (4 g, yield: 83.2%) was obtained by reacting Silica Flash Column, Eluent of 0-80% Ethyl acetate / Petroleum ether gradient.

[0451] 1H NMR (400MHz, Chloroform-d) δ = 7.51 (d, J = 2.4Hz, 1H), 6.87 (d, J = 2.4Hz, 1H), 4.59-4.50 (m, 1 H),4.24-4.14(m,1H),3.53-3.27(m,4H),3.18(s,4H),2.15-2.04(m,1H),1.89-1.72(m,2H)

[0452] MS(ESI): 352[M+H] + .

[0453] Step 11: Synthesis of compound int_64-1-15:

[0454]

[0455] int_64-1-13 (3g, 8.54mmol) and int_64-1-14 (1.86g, 10.3mmol, 1.72mL) were dissolved in toluene (40mL), and Pd2(dba)3 (782mg, 854umol), BINAP (532mg, 854umol), and Cs2CO3 (5.56g, 17.1mmol) were added. Under nitrogen protection, the reaction solution was heated to 100℃ and reacted for 16 hours. LC-MS analysis showed that the reaction was complete. The reaction solution was distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (…). 40g The product (2g, yield: 61.2%) was obtained by reacting Silica Flash Column, Eluent of 0-70% Ethyl acetate / Petroleum ether gradient.

[0456] MS(ESI): 383[M+H] + .

[0457] Step 12: Synthesis of compound int_64-1-16:

[0458]

[0459] int_64-1-15 (2g, 5.23mmol) was dissolved in dichloromethane (40mL), and dioxane hydrochloride solution (4M, 1.31mL) was slowly added dropwise at 0℃. Under nitrogen protection, the reaction mixture was heated to 20℃ and reacted for 2 hours. LC-MS analysis showed the reaction was complete. The reaction mixture was distilled under reduced pressure to obtain the crude product. The crude product was then subjected to column chromatography (…). 20g The product (0.9 g, yield: 78.9%) was obtained by reacting 0–80% Ethyl acetate / Petroleum ether gradient (1% NH3·H2O) with Silica Flash Column, Eluent of 0–80% Ethyl acetate / Petroleum ether gradient.

[0460] 1 H NMR (400MHz, DMSO-d6) δ = 6.68 (d, J = 2.2Hz, 1H), 6.12 (d, J = 2.2Hz, 1H), 5.11 (s, 2H), 4.37-4.28 (m, 1H), 4. 07-3.94(m,1H),3.49-3.38(m,1H),3.23-3.03(m,3H),2.99(s,3H),1.99-1.89(m,1H),1.59-1.46(m,1H)

[0461] MS(ESI):219[M+H] + .

[0462] Step 13: Synthesis of compound int_64-1:

[0463]

[0464] int_64-1-16 (0.9 g, 4.12 mmol) was dissolved in tetrahydrofuran (30 ml), and lithium aluminum hydride (782 mg, 20.6 mmol) was slowly added at 0 °C. Under nitrogen protection, the reaction solution was heated to 20 °C and reacted for 16 hours. LC-MS analysis showed the reaction was complete. The reaction solution was quenched at 0 °C with Na₂SO₄·H₂O (50 g), filtered, and the filtrate was concentrated to obtain the crude product. The crude product was subjected to column chromatography (…). 12g Silica Flash Column, Eluent of 0-10% MeOH / DCM (1% NH3·H2O) to give product (0.7g, yield: 83.1%).

[0465] 1H NMR (400MHz, Chloroform-d) δ = 6.01 (d, J = 2.0Hz, 1H), 5.98 (d, J = 2.0Hz, 1H), 4.46-4.35 (m, 1H), 4.20 (ddd, J = 2.4, 10.6, 12.8Hz, 1H), 3.91 (d, J = 15.4Hz, 1H),3.62-3.42(m,2H),3.23(d,J=15.4Hz,1H),3.10-2.91(m,2H),2.45(s,4 H),2.05-1.97(m,1H),1.86(tdd,J=2.2,4.2,12.9Hz,1H),1.72-1.55(m,1H)

[0466] MS(ESI):205[M+H] + .

[0467] Step 14: Synthesis of compound int_1-2:

[0468]

[0469] Int_1-1 (3.46 g, 20 mmol) was dissolved in dichloromethane (100 mL), and DIPEA (5.2 g, 40 mmol), DMAP (1.22 g, 10 mmol), and (Boc)₂O (4.8 g, 22 mmol) were added. The reaction was allowed to proceed overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction solution was diluted with dichloromethane (100 mL), washed with water (200 mL), washed with 2N dilute hydrochloric acid (100 mL), washed with sodium bicarbonate aqueous solution (100 mL), washed with water (100 mL), and finally washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product as a light brown gel (4.0 g, yield: 73%). The crude product can be used directly in the next reaction.

[0470] ESI-MS m / z: 273 [M+H] + .

[0471] Step 15: Synthesis of compound int_1-4:

[0472]

[0473] Int_1-2 (4 g, 14.6 mmol), int_1-3 (1.36 g, 14.6 mmol), cesium carbonate (7.14 g, 161 mmol), Pd2(dba)3 (668 mg, 0.73 mmol), and Xantphos (845 mg, 1.46 mmol) were dissolved in 1,4-dioxane (120 mL), and the mixture was reacted overnight at 85 °C. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a pale yellow solid product (2.7 g, yield: 65%).

[0474] ESI-MS m / z: 286 [M+H] +

[0475] Step 16: Synthesis of compound int_1-5:

[0476]

[0477] Int_1-4 (2.4 g, 8.41 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added. The reaction was allowed to proceed overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a grayish-yellow solid (1.6 g, yield: 100%). The crude product can be used directly in the next reaction step.

[0478] ESI-MS m / z: 186 [M+H] +

[0479] Step 17: Synthesis of compounds int_1-7:

[0480]

[0481] Int_1-6 (2 g, 10.8 mmol) and int_1-5 (3.2 g, 10.8 mmol) were dissolved in isopropanol (5 mL), and DIPEA (5.57 g, 43.1 mmol, 7.51 mL) was added. The reaction mixture was heated to 50 °C and reacted overnight. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature, and a white solid precipitated. The solid was filtered to obtain the product. The product was dried to obtain a white solid (1.2 g, yield: 33%).

[0482] 1H NMR: (400MHz, DMSO-d6).δ9.80(s,1H),8.70(s,1H),7.58(t,J=7.9Hz,1H),7.16(d,J=7.8Hz,1H),6.44(d,J=7.9Hz,1H),3.41(s,6H),2.49(s,3H)

[0483] ESI-MS m / z: 335 [M+H] +

[0484] Step 18: Synthesis of compounds int_1-8:

[0485]

[0486] Int_1-7 (334 mg, 1.0 mmol) was dissolved in dichloromethane (40 mL), and m-CPBA (85%, 240 mg, 1.2 mmol) was added at room temperature. The mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product (335 mg, crude product). The crude product can be used directly in the next reaction step.

[0487] ESI-MS m / z: 351 [M+H] +

[0488] Step 19: Synthesis of Compound 64:

[0489]

[0490] Int_1-8 (335 mg, 0.95 mmol) was dissolved in DMF (20 mL), and int_64-1 (245 mg, 1.2 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain a white solid (165 mg, yield: 35%).

[0491] 1H NMR (400MHz, Chloroform-d) δ8.35 (s, 1H), 7.71 (d, J = 7.8Hz, 1H), 7.54 (dd, J = 19.7, 11. 9Hz,2H),7.40(s,1H),6.84(d,J=17.9Hz,2H),6.58(d,J=7.8Hz,1H),4.45(d,J=10.8Hz ,1H),4.23(t,J=11.7Hz,1H),4.05(d,J=15.5Hz,1H),3.43(d,J=33.4Hz,1H),3.36(s,6 H), 3.16 (d, J = 10.3Hz, 3H), 2.52 (s, 3H), 1.94 (d, J = 13.0Hz, 1H), 1.67 (d, J = 12.8Hz, 1H).

[0492] LC-MS: 491 [M+H] +

[0493] Example 5: Synthesis of Compound 95

[0494]

[0495] Step 1: Synthesis of compound int_1-2:

[0496]

[0497] Int_1-1 (3.46 g, 20 mmol) was dissolved in dichloromethane (100 mL), and DIPEA (5.2 g, 40 mmol), DMAP (1.22 g, 10 mmol), and (Boc)₂O (4.8 g, 22 mmol) were added. The reaction was allowed to proceed overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction solution was diluted with dichloromethane (100 mL), washed with water (200 mL), washed with 2N dilute hydrochloric acid (100 mL), washed with sodium bicarbonate aqueous solution (100 mL), washed with water (100 mL), and finally washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate. The organic phase was filtered and distilled under reduced pressure to obtain a crude product as a light brown gel (4.0 g, yield: 73%). The crude product can be used directly in the next reaction.

[0498] ESI-MS m / z: 273 [M+H] + .

[0499] Step 2: Synthesis of compound int_1-4:

[0500]

[0501] Int_1-2 (4 g, 14.6 mmol), int_1-3 (1.36 g, 14.6 mmol), cesium carbonate (7.14 g, 161 mmol), Pd2(dba)3 (668 mg, 0.73 mmol), and Xantphos (845 mg, 1.46 mmol) were dissolved in 1,4-dioxane (120 mL), and the mixture was reacted overnight at 85 °C. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a pale yellow solid product (2.7 g, yield: 65%).

[0502] ESI-MS m / z: 286 [M+H] +

[0503] Step 3: Synthesis of compounds int_1-5:

[0504]

[0505] Int_1-4 (2.4 g, 8.41 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (10 mL) was added. The reaction was allowed to proceed overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a grayish-yellow solid (1.6 g, yield: 100%). The crude product can be used directly in the next reaction step.

[0506] ESI-MS m / z: 186 [M+H] +

[0507] Step 4: Synthesis of compound int_95-2:

[0508]

[0509] Dissolve int_95-1 (2 g, 8.35 mmol) and int_1-5 (1.55 g, 8.35 mmol) in isopropanol (5 mL), add DIPEA (4.32 g, 33.4 mmol, 5.83 mL), heat the reaction solution to 80 °C, and react overnight. LC-MS monitoring showed the reaction was complete. Cool the reaction solution to room temperature, evaporate to dryness, and purify by column chromatography to obtain a pale yellow solid (1.5 g, yield: 46.3%). ESI-MS m / z: 388 [M+H] +

[0510] Step 5: Synthesis of compound int_95-3:

[0511]

[0512] Int_95-2 (100 mg, 0.26 mmol), cyclopropylboronic acid (45 mg, 0.52 mmol), and potassium phosphate (166 mg, 0.78 mmol) were dissolved in a mixed solvent of toluene (7.5 mL) and water (0.5 mL). The mixture was purged three times with argon gas. Palladium acetate (7 mg, 0.03 mmol) and tricyclohexylphosphine (17 mg, 0.06 mmol) were then added. The mixture was heated to 100 °C and stirred for 16 hours under argon protection. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, evaporated to dryness, and purified by column chromatography to give a pale yellow solid (61 g, yield: 67.1%).

[0513] ESI-MS m / z: 350 [M+H] +

[0514] Step 6: Synthesis of compound int_95-4:

[0515]

[0516] Int_95-3 (500 mg, 1.43 mmol) was dissolved in dichloromethane (40 mL), and m-CPBA (85%, 348.6 mg, 1.72 mmol) was added at room temperature. The mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product (335 mg, crude product). The crude product can be used directly in the next reaction step.

[0517] ESI-MS m / z: 366 [M+H] +

[0518] Step 7: Synthesis of Compound 95:

[0519]

[0520] Int_95-4 (100 mg, 0.273 mmol) was dissolved in DMF (5 mL), and int_1-9 (57 mg, 0.28 mmol) and trifluoroacetic acid (456 mg, 4.0 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase chromatography to give a white solid (75 mg, yield: 55%).

[0521] ESI-MS m / z: 504 [M+H] +

[0522] Example 6 Synthesis of Compound 137

[0523]

[0524] Step 1: Synthesis of compound int_137-3:

[0525]

[0526] Int_137-1 (3 g, 12.7 mmol), int_137-2 (4.94 g, 63.3 mmol), triethylamine (3.86 g, 38.1 mmol), and Pd(PPh3)4 (733.8 mg, 0.635 mmol) were dissolved in acetonitrile (100 mL), and the mixture was reacted overnight at 70 °C. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to give a pale yellow solid product (1.8 g, yield: 60%).

[0527] ESI-MS m / z: 234 [M+H] +

[0528] Step 2: Synthesis of compound int_137-5:

[0529]

[0530] Int_137-3 (2 g, 8.5 mmol) and int_137-4 (1.42 g, 8.5 mmol) were dissolved in isopropanol (5 mL), and DIPEA (4.39 g, 34 mmol, 5.6 mL) was added. The reaction solution was heated to 50 °C and reacted overnight. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to give a yellow solid (1.3 g, yield: 48%).

[0531] ESI-MS m / z: 320 [M+H] +

[0532] Step 3: Synthesis of compound int_137-6:

[0533]

[0534] Int_137-5 (500 mg, 1.57 mmol) was dissolved in dichloromethane (40 mL), and m-CPBA (85%, 381.7 mg, 1.88 mmol) was added at room temperature. The mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product (500 mg, crude product). The crude product can be used directly in the next reaction step.

[0535] ESI-MS m / z: 336 [M+H] +

[0536] Step 4: Synthesis of Compound 137:

[0537]

[0538] Int_137-6 (100 mg, 0.298 mmol) was dissolved in DMF (5 mL), and int_1-9 (60 mg, 0.298 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase chromatography to give a white solid (65 mg, yield: 46%).

[0539] 1 H NMR (400MHz, DMSO-d6): δ9.93(s,1H),9.74(s,1H),8.58(s,1H),7.91(s,2H),7.67(t,J=6.3Hz,1H),7.08(s,2H),3.70(s,1H),3.12(dd,J=25.9,9 .8Hz,1H),2.88(dd,J=10.9,4.8Hz,1H),2.67(q,J=19.8,16.3Hz,3H),2. 29(s,3H),1.96-1.75(m,4H),1.63(d,J=13.5Hz,6H),1.28-1.05(m,1H).

[0540] LC-MS: 474 [M+H] +

[0541] Example 7 Synthesis of Compound 138

[0542]

[0543] Step 1: Synthesis of compound int_137-3:

[0544]

[0545] Int_137-1 (3 g, 12.7 mmol), int_137-2 (4.94 g, 63.3 mmol), triethylamine (3.86 g, 38.1 mmol), and Pd(PPh3)4 (733.8 mg, 0.635 mmol) were dissolved in acetonitrile (100 mL), and the mixture was reacted overnight at 70 °C. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to give a pale yellow solid product (1.8 g, yield: 60%).

[0546] ESI-MS m / z: 234 [M+H] +

[0547] Step 2: Synthesis of compound int_137-5:

[0548]

[0549] Int_137-3 (2 g, 8.5 mmol) and int_137-4 (1.42 g, 8.5 mmol) were dissolved in isopropanol (5 mL), and DIPEA (4.39 g, 34 mmol, 5.6 mL) was added. The reaction solution was heated to 50 °C and reacted overnight. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to give a yellow solid (1.3 g, yield: 48%).

[0550] ESI-MS m / z: 320 [M+H] +

[0551] Step 3: Synthesis of compound int_137-6:

[0552]

[0553] Int_137-5 (500 mg, 1.57 mmol) was dissolved in dichloromethane (40 mL), and m-CPBA (85%, 381.7 mg, 1.88 mmol) was added at room temperature. The mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product (500 mg, crude product). The crude product can be used directly in the next reaction step.

[0554] ESI-MS m / z: 336 [M+H] +

[0555] Step 4: Synthesis of Compound 138:

[0556]

[0557] Int_137-6 (100 mg, 0.298 mmol) was dissolved in DMF (5 mL), and int_1-9A (60 mg, 0.298 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase chromatography to obtain a white solid (60 mg, yield: 42.5%).

[0558] 1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.74(s,1H),8.58(s,1H),7.91(s,2H),7.67(t,J =6.3Hz,1H),7.08(s,2H),3.70(s,1H),3.12(dd,J=25.9,9.8Hz,1H),2.88(dd,J=10.9,4.8Hz,1H),2. 67(q,J=19.8,16.3Hz,3H),2.29(s,3H),1.96-1.75(m,4H),1.63(d,J=13.5Hz,6H),1.28-1.05(m,1H).

[0559] LC-MS: 474 [M+H] +

[0560] Example 8 Synthesis of Compound 139

[0561]

[0562] Step 1: Synthesis of compound int_137-3:

[0563]

[0564] Int_137-1 (3 g, 12.7 mmol), int_137-2 (4.94 g, 63.3 mmol), triethylamine (3.86 g, 38.1 mmol), and Pd(PPh3)4 (733.8 mg, 0.635 mmol) were dissolved in acetonitrile (100 mL), and the mixture was reacted overnight at 70 °C. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to give a pale yellow solid product (1.8 g, yield: 60%).

[0565] ESI-MS m / z: 234 [M+H] +

[0566] Step 2: Synthesis of compound int_137-5:

[0567]

[0568] Int_137-3 (2 g, 8.5 mmol) and int_137-4 (1.42 g, 8.5 mmol) were dissolved in isopropanol (5 mL), and DIPEA (4.39 g, 34 mmol, 5.6 mL) was added. The reaction solution was heated to 50 °C and reacted overnight. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, filtered, and distilled under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography to give a yellow solid (1.3 g, yield: 48%).

[0569] ESI-MS m / z: 320 [M+H] +

[0570] Step 3: Synthesis of compound int_137-6:

[0571]

[0572] Int_137-5 (500 mg, 1.57 mmol) was dissolved in dichloromethane (40 mL), and m-CPBA (85%, 381.7 mg, 1.88 mmol) was added at room temperature. The mixture was stirred at room temperature for half an hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product (500 mg, crude product). The crude product can be used directly in the next reaction step.

[0573] ESI-MS m / z: 336 [M+H] +

[0574] Step 4: Synthesis of Compound 139:

[0575]

[0576] Int_137-6 (100 mg, 0.298 mmol) was dissolved in DMF (5 mL), and int_1-9B (60 mg, 0.298 mmol) and trifluoroacetic acid (456.8 mg, 4.0 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 10 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase chromatography to give a white solid (70 mg, yield: 50%).

[0577] 1H NMR (400MHz, DMSO-d6) δ9.93(s,1H),9.74(s,1H),8.58(s,1H),7.91(s,2H),7.67(t,J=6.3Hz,1H),7.08(s,2H),3.70(s,1H),3.12(dd,J=25.9,9 .8Hz,1H),2.88(dd,J=10.9,4.8Hz,1H),2.67(q,J=19.8,16.3Hz,3H),2. 29(s,3H),1.96-1.75(m,4H),1.63(d,J=13.5Hz,6H),1.28-1.05(m,1H).

[0578] LC-MS: 474 [M+H] +

[0579] Synthesis of compounds 4-63, 65-94, 96-136, and 140-296 in Examples 9-296

[0580] Using the above synthetic method and different raw materials, the target compounds 4-63, 65-94, 96-136, and 140-296 in Table 1 can be obtained.

[0581] The LC-MS analysis method is as follows:

[0582] Instrument: Agilent LC:1260 InfinityII + MS:G6125B

[0583] Chromatographic column: Welch: Core-shell 2.7um 4.3*50mm

[0584] Column temperature: 30℃

[0585] Wavelength: 254nm / 214nm

[0586] Mobile phase A: H2O (0.1% formic acid)

[0587] Mobile phase B: Acetonitrile (0.1% formic acid)

[0588] gradient:

[0589] Time (min) Flow rate (mL / min) Mobile phase B% Mobile phase A% 0 2 5 95 0.1 2 5 95 2.2 2 95 5 2.7 2 95 5 2.71 2 5 95 3 2 5 95

[0590] Table 1

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607] Table 2. NMR data and LC-MS retention times of some compounds in Table 1.

[0608]

[0609]

[0610]

[0611] Example 297: In vitro inhibition assay of recombinant protein Wee-1 enzyme activity by the compound of the present invention.

[0612] The inhibitory effect of the compound on the activity of recombinant protein Wee-1 was determined using the HTRF method. Details are as follows.

[0613] After incubating DMSO or serially diluted compounds (maximum 200 nM, 1:5 serial dilution) and recombinant proteins in kinase buffer at 37°C for 30 minutes, Fluorescein-PolyGAT and ATP were added, followed by the addition of substrate to initiate the reaction. After reacting at room temperature for 90 minutes, antibody and detection solution were added, and incubation continued at room temperature for another 60 minutes. Fluorescence values ​​were then 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, thereby calculating the compound inhibition percentage and IC50. 50The results are shown in Table 3 below.

[0614] Table 3. Inhibitory activity of the compounds of the present invention against recombinant protein Wee-1

[0615] compound <![CDATA[(IC 50 )]]> compound <![CDATA[(IC 50 )]]> compound <![CDATA[(IC 50 )]]> compound <![CDATA[(IC 50 )]]> 1 +++ 2 +++ 3 +++ 4 +++

[0616] 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 +++ 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 +++

[0617] 123 +++ 124 +++ 125 +++ 126 +++ 127 +++ 128 +++ 129 +++ 130 +++ 131 +++ 132 +++ 133 +++ 134 +++ 135 +++ 136 +++ 137 +++ 138 +++ 139 +++ 279 +++ 280 +++ 289 +++ 290 +++ 291 +++ 292 +++ 293 +++ 294 +++ 295 +++ 296 +++

[0618] +++ indicates IC 50 Less than or equal to 10 nM

[0619] ++ indicates IC 50 10 nM to 50 nM

[0620] + indicates IC 50 Greater than 50 nM.

[0621] As shown in Table 3, the compounds of this invention have good inhibitory activity against the enzyme activity of recombinant protein Wee-1.

[0622] Example 298: In vitro antiproliferative activity of the compounds of the present invention against MIA PaCa-2 cells.

[0623] 3000 MIA PaCa-2 cells / well were seeded into 384-well plates and allowed to adhere overnight. Then, DMSO or a compound at a maximum concentration of 5 μM, serially diluted 1:5, was added. Cell viability was evaluated by measuring intracellular ATP levels 72 hours after drug addition. The percentage of cell viability inhibition by the compound was calculated compared to the DMSO group, and the IC50 was calculated. 50 The values ​​are shown in Table 4 below.

[0624] Table 4. Antiproliferative activity of the compounds of the present invention against MIA PaCa-2 cells.

[0625] compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> 1 236 2 259 3 1090 4 968 5 1180 6 910 49 >5000 50 148 64 400 87 184 105 441 108 225 110 186 112 >5000 121 89 137 >5000 295 72 296 161

[0626] As can be seen from the data in Table 4, the compounds of the present invention have strong anti-proliferative activity against MIA PaCa-2 cells.

[0627] Example 299: In vitro antiproliferative activity of the compound of the present invention in combination with gemcitabine against MIA PaCa-2 cells.

[0628] 3000 MIA PaCa-2 cells / well were seeded into 384-well plates and 20 nM Gemcitabine was added. After overnight adhesion, DMSO or a compound serially diluted 1:5 at a maximum concentration of 100 nM was added. Cell viability was evaluated by measuring intracellular ATP levels 72 hours after drug addition. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC50 was then calculated. 50 The values ​​are shown in Table 5 below.

[0629] Table 5. In vitro antiproliferative activity of the compounds of this invention in combination with gemcitabine against MIA PaCa-2 cells.

[0630] compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> 1 1.9 2 0.245 3 6.4 4 2.4 5 2.1 6 5.3 49 >100 50 >100 64 3.5 87 1.6 105 2.1 108 11 110 1.1 112 29 121 1.4 137 26 295 1.5 296 3.1

[0631] As can be seen from the data in Table 5, the compounds of this invention, in combination with gemcitabine, exhibit strong in vitro antiproliferative activity against MIA PaCa-2 cells.

[0632] Example 300 In vivo efficacy study – Mouse HT29 subcutaneous xenograft model

[0633] HT29 is a colon cancer cell line. Each nude mouse was subcutaneously inoculated with 5 x 10⁵ cells. 6 HT29 cells were collected, and the tumor was allowed to grow to 100-200 mm. 3 During administration, the compound was administered orally once daily, either alone or in combination with 15 mg / kg Gemcitabine administered intraperitoneally once a week, twice a week, and tumor volume was measured at the dosing endpoint. The tumor growth inhibition rate (TGI) was calculated as follows: TGI = 1 - (tumor volume on day 18 of the treated group - tumor volume on day 1 of the treated group) / (tumor volume on day 18 of the solvent control group - tumor volume on day 1 of the treated group). The results are shown in Tables 6 and 7.

[0634] Table 6. Growth inhibition rate of HT29 subcutaneous xenograft tumors in mice – single drug

[0635]

[0636] Table 7. Growth inhibition rate of HT29 subcutaneous xenografts in mice – in combination with 15 mg / kg Gemcitabine

[0637]

[0638] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and various changes or modifications can 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 of general formula (1) or an optical isomer thereof or a pharmaceutically acceptable salt thereof: ， In general formula (1): X is N; Y represents -F, -Cl, -Br, -I, -CN, -S(O)2CH3, -P(O)(CH3)2, -C(O)NH2, -CH3, -CF3, , ,or ; Z represents a chemical bond or -NH-; Ring A is , , , , , , , , , , , , , , , , , , , , , , , , or ; R 1 for or ; R 4a and R 5a Each is independently a (C1-C6) alkyl group, wherein the (C1-C6) alkyl group is optionally substituted with 1, 2, 3 or 4 of the following groups: -D; or R 4a and R 5a The S atoms attached thereto can together form a (4-7) heterocyclic alkyl group, wherein the heterocyclic alkyl group has a heteroatom selected from sulfur; R 4b and R 5b Each is independently a (C1-C6) alkyl group, wherein the (C1-C6) alkyl group is optionally substituted with 1, 2, 3 or 4 of the following groups: -D; or R 4b and R 5b The P atoms attached thereto can collectively form a (4-7) heterocyclic alkyl group, wherein the heterocyclic alkyl group has a heteroatom selected from phosphorus; Each R 3 Independently -H, -D, halogen, -OR 8 -CN, (C1-C6)alkyl, (C1-C6)haloalkyl or (C2-C6)alkenyl; The B ring is a (C5-C11) partially unsaturated cycloalkyl or a (5-11) partially unsaturated heterocycloalkyl, wherein the heterocycloalkyl has a heteroatom selected from nitrogen, sulfur and oxygen; X 1 for , or ; X 2 For chemical bonds, , or ; X 3 For CH, N or CR c ; X 4 For CH, N or CR d ; X 5 For NR a or CH-R b ; Each R 2 Independently -H, -D, halogen, -OR 8 -NR 8 R 9 -CN, (C1-C6)alkyl or (C1-C6)haloalkyl; or two adjacent R 2 The atoms they are attached to can together form (C3-C9) cycloalkyl groups; or two R atoms on the same carbon atom of the B ring. 2 The carbon atoms they are attached to can together form (C3-C6) cycloalkyl groups; or R 2 and an adjacent R e The atoms they are attached to can together form (C3-C9) cycloalkyl groups; R a For -H, -(CH2) m OR 8 -(CH2) m NR 8 R 9 (C1-C6)alkyl, (C1-C6)haloalkyl, or (C3-C14)cycloalkyl, wherein the (C1-C6)alkyl is optionally substituted with 1, 2, 3, or 4 of the following groups: -D and R 8 ; R b For -H, -(CH2) n OR 8 -NR 11 R 12 -(CH2) n NR 8 R 9 (C1-C6)alkyl, (C1-C6)haloalkyl, or (C3-C14)cycloalkyl, wherein the (C1-C6)alkyl is optionally substituted with 1, 2, 3, or 4 of the following groups: -D and R 8 ; R c and R d Each independently constitutes a halogen, -OR 8 -CN, (C1-C6)alkyl, (C1-C6)haloalkyl or (C3-C9)cycloalkyl; R e It is -H, -D, (C1-C6)alkyl, or (C1-C6) haloalkyl; R f1 R f2 R g1 and R g2 Each is independently -H, -D, (C1-C6)alkyl or (C1-C6) haloalkyl; or R f2 and an adjacent R e The atoms they are attached to can together form (C3-C9) cycloalkyl groups; R 6 It is an (C1-C3) alkyl group; R 7 It is an (C1-C3) alkyl group; R 8 and R 9 Each is independently -H, (C1-C6)alkyl, or (C3-C14)cycloalkyl; R 11 and R 12 Each is independently -H or (C1-C3) alkyl; and 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 1, 2 or 3, and m is an integer of 1, 2 or 3.

2. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when R 1 for When, R 4a and R 5a Each is independently a (C1-C3) alkyl group, wherein the (C1-C3) alkyl group is optionally substituted with 1, 2, 3 or 4 of the following groups: -D; or R 4a and R 5a The S atoms attached to it can together form a (4-6) heterocyclic alkyl group.

3. The compound of claim 2 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when R 1 for At that time, structural unit for: , , , , , , , or .

4. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when R 1 for When, R 4b and R 5b Each is independently a (C1-C3) alkyl group, wherein the (C1-C3) alkyl group is optionally substituted with 1, 2, 3 or 4 of the following groups: -D; or R 4b and R 5b The P atoms attached to it can together form a (4-6) heterocyclic alkyl group.

5. The compound of claim 4 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when R 1 for At that time, structural unit for: , , , , , , , , or .

6. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), each R 3 Independently -H, -D, -F, -Cl, -Br, -I, -OH, -OR 11 -CN, (C1-C3)alkyl, (C1-C3)haloalkyl or (C2-C4)alkenyl, R 11 Each is independently (C1-C3)alkyl or (C3-C6)cycloalkyl.

7. The compound of claim 6 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), each R 3 Independently: -H, -D, -F, -Cl, -Br, -I, -OH, -OCH3, -CN , , , , , , , or .

8. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), the structural unit for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

9. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), ring B is a (C5-C8) partially unsaturated cycloalkyl or a (5-8) partially unsaturated heterocycloalkyl; and R e It can be: -H, -D, -CH3 or -CH2CH3.

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

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

12. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), X 2 For: chemical bonds, , , , , , , , , , ,or .

13. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when X 5 For NR a When, R a -H, -(CH2)2OR 11 -(CH2)2NR 11 R 12 (C1-C3)alkyl, (C1-C3)haloalkyl, or (C3-C6)cycloalkyl, wherein the (C1-C3)alkyl is optionally substituted with 1, 2, 3, or 4 of the following groups: -D, -CH3, and .

14. The compound of claim 13 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when X 5 For NR a When, R a For: -H, -(CH2)2OCH3, -(CH2)2OH, -(CH2)2N(CH3)2, , , , , , , , , , , or .

15. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when X 5 CH-R b When, R b -H, -(CH2)2OR 11 -NR 11 R 12 -(CH2)2NR 11 R 12 (C1-C3)alkyl, (C1-C3)haloalkyl, or (C3-C6)cycloalkyl, wherein the (C1-C3)alkyl is optionally substituted with 1, 2, 3, or 4 of the following groups: -D, -CH3, and .

16. The compound of claim 15 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), when X 5 CH-R b When, R b The following are possible values: -H, -N(CH3)2, -(CH2)2OCH3, -(CH2)2OH, -(CH2)2N(CH3)2. , , , , , , , , , or .

17. The compound of claim 1 or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), X 3 For: CH, N or CR c , wherein R c For: -F, -Cl, -Br, -I, -OH, -CH3, , -OCH3, -OCH2CH3, or -OCH(CH3)2.

18. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), X 4 For: CH, N or CR d , wherein R d For: -F, -Cl, -Br, -I, -OH, -CH3, , -OCH3, -OCH2CH3, or -OCH(CH3)2.

19. The compound of claim 18 or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), each R 2 Independently -H, -D, -F, -Cl, -Br, -I, -OR 11 -NR 11 R 12 -CN, (C1-C3)alkyl, or (C1-C3)haloalkyl; or two adjacent R 2 The atoms they are attached to can together form (C3-C6) cycloalkyl groups; or two R atoms on the same carbon atom of the B ring. 2 The carbon atoms they are attached to can together form (C3-C6) cycloalkyl groups; or R 2 and an adjacent R e The atoms they are attached to can form (C3-C6) cycloalkyl groups.

20. The compound of claim 19 or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), each R 2 Independently: -H, -D, -F, -Cl, -Br, -I, -OH, -OCH3, -N(CH3)2, -CN, , , , , , ,or .

21. The compound of any one of claims 1-20, or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), the structural unit for: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , or .

22. A compound or its optical isomer or pharmaceutically acceptable salt, wherein said compound has one of the following structures: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 23. A pharmaceutical composition, characterized in that, It contains a pharmaceutically acceptable excipient or carrier, and a compound, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, as the active ingredient, as described in any one of claims 1-22.

24. The use of a compound as described in any one of claims 1-22, or an optical isomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 23, in the preparation of a Wee-1 inhibitor.

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