Pyrimidine compounds as Wee-1 inhibitors

Abstract

The invention discloses pyrimidine compounds of general formula (1) as Wee-1 inhibitors and their preparation methods, as well as the use of compounds of general formula (1) and their 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 filed on February 19, 2021 (2021 / 12 / 19), Chinese patent application 2021108156003 filed on July 19, 2021 (2021 / 17 / 19), and Chinese patent application 2022101294609 filed on February 11, 2022 (2022 / 11). 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 a class of pyrimidine compounds with Wee-1 kinase inhibitory activity, their preparation methods, and their application 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 Tyr15 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 G2 checkpoint, thereby regulating the transition of cells from G2 to M phase [CellCycle,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 functions closely related to tumorigenesis and development, such as DNA synthesis, DNA homology repair, and post-translational modifications of chromosomal histones [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 [PLoSOne, 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. 5 -P(O)(R 6 )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 and R 2 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 1 and R 2 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;

[0015] 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 -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 -OR8 -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 ;

[0016] The B ring is (C6-C14) aryl or (5-11) heteroaryl;

[0017] Each R 4 Independently -H, halogen, R 8 -OH, -(CH2) n OR 8 -OR 8 -(CH2) n NR 8 R 9 -NR 8 R 9 -CN, -O(CH2) m NR 8 R 9 -N(R) 9 (CH2) mNR 8 R 9 -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, (C1-C6)alkoxy, -CH2-(3-15)heterocyclic alkyl, (3-15)heterocyclic alkyl, (5-9)heteroaryl, or (C6-C10)aryl, wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)ynyl, (C3-C9)cycloalkyl, (C1-C6)alkoxy, -CH2-(3-15)heterocyclic alkyl, (3-15)heterocyclic alkyl, (5-9)heteroaryl, or (C6-C10)aryl may optionally be substituted with 1, 2, 3, or 4 of the following groups: -H, halogen, R 8 -OH, -(CH2) n OR 8 -OR 8 -(CH2) n NR 8 R 9 -NR 8 R 9 -CN, -O(CH2) m NR 8 R 9 -N(R) 9 (CH2) m NR 8 R 9 (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C9)cycloalkyl, (C1-C6)alkoxy, -CH2-(3-15)heterocyclic alkyl, (3-15)heterocyclic alkyl, (5-9)heteroaryl, (C6-C10)aryl and -R 7 ; or two adjacent R 4 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 -OR 8 -(CH2) n NR 8 R 9 -NR 8 R 9 -CN, -O(CH2) m NR 8 R 9 -N(R) 9 (CH2) m NR 8 R 9 -C(O)R 8 -C(O)NR 8 R 9 -NR 9 C(O)R 8 -NR 9 S(O)2R 8 -S(O) p R 8 -S(O)2NR 8 R 9 , (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C9)cycloalkyl, (C1-C6)alkoxy, -CH2-(4-9-membered)heterocyclic alkyl, (4-9-membered)heterocyclic alkyl, (5-9-membered)heteroaryl and (C6-C10)aryl;

[0018] R 5 It is (C1-C3)alkyl or (C3-C6)cycloalkyl;

[0019] R 6 It is (C1-C3)alkyl or (C3-C6)cycloalkyl;

[0020] R 7 It is a (3-11-membered) heterocyclic alkyl group, wherein the heterocyclic alkyl group may optionally be substituted with 1, 2, 3 or 4 of the following groups: -H, R 8 -OR 8 and -NR 8 R 9 ;

[0021] 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 9The 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 ;

[0022] R 10 It is -H, (C1-C3)alkyl or (C3-C6)cycloalkyl;

[0023] R 11 and R 12 Each is independently -H, (C1-C3)alkyl 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

[0024] p is an integer of 0, 1, or 2; q is an integer of 1, 2, 3, or 4; r is an integer of 1, 2, or 3; s is an integer of 1, 2, 3, or 4; n is an integer of 0, 1, 2, or 3; and m is an integer of 1, 2, or 3.

[0025] 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, -C(O)NH(CH3), -C(O)N(CH3)2, (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl, (C2-C3)alkynyl or (5-6-membered)heteroaryl, wherein the (C1-C3)alkyl, (C1-C3)haloalkyl, (C3-C5)cycloalkyl, (C2-C3)alkynyl 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.

[0026] 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, -C(O)NH(CH3), -C(O)N(CH3)2, -CH3, -CF3, Y is preferably -H, -F, -Br, -I, -CN, -S(O)2CH3, -P(O)(CH3)2, -C(O)NH2, -C(O)NH(CH3), -C(O)N(CH3)2, -CF3, Y is more preferably -CN.

[0027] In another preferred embodiment, wherein in the general formula (1), ring A is (C6-C10) aryl, (5-10) heteroaryl, or (5-10) heterocyclic alkyl.

[0028] In another preferred embodiment, in the general formula (1), ring A is:

[0029] Ring A is preferred Ring A is preferred Ring A is preferred Ring A is preferred Ring A is preferred

[0030] In another preferred embodiment, wherein in the general formula (1), R 1 and R 2 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 1 and R 2 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.

[0031] In another preferred embodiment, in the general formula (1), the structural unit for: Preferred More preferably More preferably

[0032] In another preferred embodiment, wherein in the general formula (1), each R 3 Independently -H, -D, -F, -Cl, -Br, -I, -OH, -CH2OR 11 -CH2NR11 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.

[0033] 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, -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, -S(O)2NH2, -S(O)2NH(CH3), -S(O)2N(CH3)2, R 3 Preferred values ​​are -H, -D, -F, -Cl, -OCH3, -CN. R 3 More preferably -H, -F, OCH3,

[0034] In another preferred embodiment, in the general formula (1), the structural unit for:

[0035] Preferred More preferably More preferably

[0036] In another preferred embodiment, in the general formula (1), the B ring is (C6-C10) aryl or (5-10) heteroaryl.

[0037] In another preferred embodiment, in the general formula (1), ring B is:

[0038]

[0039]

[0040] In another preferred embodiment, wherein in the general formula (1), each R 4 Independently -H, -F, -Cl, -Br, -I, -OH, -CH2OR 11 -(CH2)2OR 11 -(CH2)3OR 11 -OR 11 -CH2NR 11 R 12 -(CH2)2NR 11 R 12 -(CH2)3NR 11 R 12 -NR 11 R 12 -CN, -O(CH2)2NR 11 R 12 -N(R) 12 (CH2)2NR 11 R 12 -C(O)NR 11 R 12 -NR12 C(O)R 11 -NR 12 S(O)2R 11 -S(O)2R 11 -SR 11 -S(O)2NR 11 R 12 (C1-C4)alkyl, (C1-C4)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, (C1-C4)alkoxy, -CH2-(4-11)heterocyclic alkyl, (4-11)heterocyclic alkyl, (5-9)heteroaryl, or (C6-C10)aryl, wherein the (C1-C4)alkyl, (C1-C4)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, (C1-C4)alkoxy, -CH2-(4-11)heterocyclic alkyl, (4-11)... Heterocyclic alkyl, (5-9 membered) heteroaryl, or (C6-C10) aryl groups may optionally be substituted with 1, 2, 3, or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -(CH2)2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2, -CN, -O(CH2)2N(CH3)2, -NH-(CH2)2N(CH3)2, -N(CH3)-(CH2)2N(CH3)2. Or two adjacent Rs on ring B 4 The atoms bonded to each other can collectively form a (5-7 member) heterocyclic alkyl group or a (C5-C7) cycloalkyl group, wherein the heterocyclic alkyl group and the cycloalkyl group may optionally be substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2N(CH3) 2. -(CH2)2N(CH3)2, -N(CH3)2, -CN, -O(CH2)2N(CH3)2, -NH-(CH2)2N(CH3)2, -N(CH3)-(CH2)2 N(CH3)2, -C(O)CH3, -C(O)NH2, -C(O)N(CH3)2, -S(O)2CH3, -SCH3, -S(O)2NH2, -S(O)2N(CH3)2,

[0041] In another preferred embodiment, wherein in the general formula (1), each R 4 Independently, -H, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH2NH2, -(CH2)2NH2, -(CH2)3NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCF2H, -C H2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2, -CN, -O(CH2)2N(CH3)2, -NH-(CH2)2N(CH3)2, -N(CH3 )-(CH2)2N(CH3)2, -C(O)NH2, -C(O)N(CH3)2, -S(O)2CH3, -SCH3, -S(O)2NH2, -S(O)2N(CH3)2,

[0042] In another preferred embodiment, wherein in the general formula (1), each R 4 Independently

[0043] In another preferred embodiment, in the general formula (1), R 4 Preferably, the following are used: -H, -F, -Cl, -Br, -I, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH2NH2, -(CH2)2NH2, -(CH2)3NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCF2H, -CH2N(CH3)2, -N(CH3)2.

[0044] R 4 More preferably, -H, -F, -Cl, -Br, -I, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH2NH2, -(CH2)2NH2, -(CH2)3NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2N(CH3)2, -N(CH3)2, -CN,

[0045] In another preferred embodiment, in the general formula (1), two adjacent R on ring B 4The atoms they are attached to can collectively form a (5-7 member) heterocyclic alkyl group, wherein the heterocyclic alkyl group is: Or two adjacent Rs on ring B 4 The atoms they are attached to can collectively form a (C5-C7) cycloalkyl group, wherein the (C5-C7) cycloalkyl group is: The (5-7 membered) heterocyclic alkyl and (C5-C7) cycloalkyl groups may optionally be substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2, -CN, -O(CH2)2N(CH3)2, -NH -(CH2)2N(CH3)2, -N(CH3)-(CH2)2N(CH3)2, -C(O)CH3, -C(O)NH2, -C(O)N(CH3)2, -S(O)2CH3, -SCH3, -S(O)2NH2, -S(O)2N(CH3)2,

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

[0047]

[0048] In another preferred embodiment, in the general formula (1), the structural unit for:

[0049] In another preferred embodiment, in the general formula (1), the structural unit for:

[0050] In another preferred embodiment, in the general formula (1), the structural unit Preferred options are:

[0051] More preferably:

[0052] 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:

[0053]

[0054] Among them, A, B, Y, Z, R 1 R 2 R 3 R 4 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0055] 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:

[0056]

[0057] Among them, A, B, Y, R 1 R 2 R 3 R 4 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0058] In some embodiments of the present invention, the present invention provides compounds of general formula (4) or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0059]

[0060] Among them, A, Y, Z, R 1 R 2 R 3 R 4 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0061] In some embodiments of the present invention, the present invention provides compounds as described in general formula (5a) or general formula (5b), or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0062]

[0063] Among them, A, Y, R 1 R 2 R 3 R 4 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0064] In some embodiments of the present invention, the present invention provides compounds of general formula (6) or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0065]

[0066] Among them, B, Y, Z, R 1 R 2 R 3 R 4 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0067] 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), general formula (7f) or general formula (7g), or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0068]

[0069]

[0070] Among them, B, Y, and R 1 R 2 R 3 R 4 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0071] In some embodiments of the present invention, the present invention provides compounds of general formula (8a), general formula (8b), general formula (8c), general formula (8d), general formula (8e), general formula (8f) or general formula (8g), or various isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof:

[0072]

[0073] Among them, Y and R 1 R 2 R 3 R 4 The definitions of q and s are as described above, and examples are given in specific embodiments.

[0074] In various embodiments of the present invention, the compound of general formula (1) has one of the following structures:

[0075]

[0076]

[0077]

[0078]

[0079]

[0080] 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.

[0081] 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 kinase.

[0082] Another object of the present invention is to provide a method for treating, modulating or preventing diseases mediated by Wee-1 protein kinase, comprising administering to a subject a therapeutically effective amount of a compound of general formula (1) of the present invention, or any isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate of the present invention, or a pharmaceutical composition thereof.

[0083] Through the synthesis and careful study of various new compounds involving the inhibition of Wee-1 protein kinase, the inventors discovered that the compound of general formula (1) unexpectedly possesses strong Wee-1 protein kinase inhibitory activity.

[0084] 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.

[0085] Compound Synthesis

[0086] 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.

[0087] 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. thEd., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd The method described in Ed. (Wiley 1999) can be used to prepare compounds by altering the conditions by using appropriate reagents and introducing different groups into the molecular formulas provided herein.

[0088] 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:

[0089] General reaction process 1

[0090]

[0091] Compounds of general formula (1) can be prepared according to general reaction procedure 1, wherein R 1 R 2 R 3 R 4 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, 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.

[0092] General reaction process 2

[0093]

[0094] Compounds of general formula (1) can be prepared according to general reaction procedure 2, wherein R 1 R 2 R 3 R 4X, 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.

[0095] General reaction process 3

[0096]

[0097] Compounds of general formula (1) can be prepared according to general reaction procedure 3, wherein R 1 R 2 R 3 R 4 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.

[0098] General reaction process 4

[0099]

[0100] Compounds of general formula (1) can be prepared according to general reaction procedure 4, wherein R 1 R 2 R 3 R 4 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... 2 This 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.

[0101] Further forms of the compound

[0102] "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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] the term

[0109] 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".

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] Unless otherwise specified, "aryloxy group" refers to an aryl group bonded to the rest of the molecule via an ether oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy groups.

[0117] Unless otherwise specified, "arylene" refers to a divalent aryl group as defined above. Examples of arylene groups include, but are not limited to, phenylene, naphthylene, and phenanthrene.

[0118] 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,

[0119] Unless otherwise specified, “hybrid aryl” refers to a divalent heteroaryl group as defined above.

[0120] 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,

[0121] Unless otherwise specified, “heterocyclic alkylene” means a divalent heterocyclic alkylene as defined above.

[0122] 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.

[0123] "Optional" or "optionally" means that the event or condition described below may, but is not required, occur, and the description includes both the scenario in which the event or condition occurs and the scenario in which the event or condition does not occur.

[0124] 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:

[0125] When the number of a linking group is 0, such as -(CH2)0-, it indicates that the linking group is a single bond.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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

[0130] Unless otherwise stated, use Indicates a single bond or a double bond.

[0131] Specific pharmaceutical and medical terminology

[0132] 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.

[0133] 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.

[0134] "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.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] Therapeutic uses

[0140] 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.

[0141] 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).

[0142] route of administration

[0143] 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.

[0144] "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.), and emulsifiers (such as Tween). Wetting agents (such as sodium dodecyl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0145] When applying the compounds of this invention, they can be administered orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), or topically.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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.

[0153] 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.

[0154] 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

[0155] 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.

[0156] In all embodiments, 1 H-NMR was recorded using a Vian 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.

[0157] The following abbreviations are used in this invention: (Boc)₂O represents di-tert-butyl dicarbonate; CDCl₃ represents deuterated chloroform; CSA represents camphor-10-sulfonic acid (β); EtOAc represents ethyl acetate; Hexane represents n-hexane; HPLC represents high performance liquid chromatography; MeCN represents acetonitrile; DCE represents 1,2-dichloroethane; DCM represents dichloromethane; DIPEA represents diisopropylethylamine; 1,4-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; NIS represents iodosuccinimide; Pd / C represents palladium on carbon; Pd(PPh3)4 represents tetrakis(triphenylphosphine)palladium; Pd2(dba)3 represents tris(dibenzylacetone)dipalladium(0); PE represents petroleum ether; RuPhos Pd G3 represents (2-dicyclohexylphosphino-2′6′-diisopropoxy-11′-biphenyl)[2-(2′-amino-11′-biphenyl)]palladium(II) methanesulfonate; SEMCl represents 2-(trimethylsilyl)ethoxymethyl chloride; TBAB represents tetrabutylammonium bromide; TBAB represents tetrabutylammonium fluoride; TFA represents trifluoroacetic acid; TfOH represents trifluoromethanesulfonic acid; T3P represents 1-propylphosphonic anhydride; XantPhos represents 4,5-bis(diphenylphosphino-9,9-dimethyloxanthracene; TLC represents thin-layer chromatography; XPhos represents 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; LC-MS represents liquid chromatography-mass spectrometry; RT represents retention time.

[0158] Example 1: Synthesis of Compound 1

[0159]

[0160] Step 1: Synthesis of compound int_1-2:

[0161]

[0162] 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.

[0163] ESI-MS m / z: 273 [M+H] + .

[0164] Step 2: Synthesis of compound int_1-4:

[0165]

[0166] 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). The mixture was reacted overnight at 85 °C under nitrogen protection. 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%).

[0167] ESI-MS m / z: 286 [M+H] +

[0168] Step 3: Synthesis of compounds int_1-5:

[0169]

[0170] 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.

[0171] ESI-MS m / z: 186 [M+H] +

[0172] Step 4: Synthesis of compounds int_1-7:

[0173]

[0174] 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%).

[0175] 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)

[0176] ESI-MS m / z: 335 [M+H] +

[0177] Step 5: Synthesis of compounds int_1-8:

[0178]

[0179] 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.

[0180] ESI-MS m / z: 351 [M+H] +

[0181] Step 6: Synthesis of compounds int_1-10:

[0182]

[0183] Int_1-8 (335 mg, 0.95 mmol) was dissolved in DMF (20 mL), and int_1-9 (298 mg, 1.2 mmol) and trifluoroacetic acid (115 mg, 1 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 column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a white solid (160 mg, yield: 31%).

[0184] ESI-MS m / z: 535 [M+H] +

[0185] Step 7: Synthesis of compound int_1-11:

[0186]

[0187] Int_1-10 (800 mg, 1.5 mmol) was dissolved in dichloromethane (80 mL), and trifluoroacetic acid (4.2 g, 37.4 mmol) was added. The reaction was carried out at room temperature for 1 hour, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a yellow solid (800 mg, crude product). The crude product can be used directly in the next reaction.

[0188] ESI-MS m / z: 435 [M+H] +

[0189] Step 8: Synthesis of Compound 1:

[0190]

[0191] Int_1-11 (800 mg, 1.84 mmol) and DIPEA (4.8 g, 37.4 mmol) were dissolved in dichloromethane (10 mL) and methanol (10 mL). Formaldehyde aqueous solution (37-40%, 1 mL) and sodium borohydride acetate (3.2 g, 15 mmol) were added, and the reaction was carried out at room temperature for 1 hour. The reaction was monitored by LC-MS until completion. Water (100 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 20:1) to give a pale yellow solid product (500 mg, yield: 60%).

[0192] 1H NMR (400MHz, Chloroform-d) δ8.33 (s, 1H), 7.65 (d, J = 9.3Hz, 2H), 7.45 (s, 2H), 7.25 (d,J=2.2Hz,1H),7.20-7.13(m,1H),7.06(d,J=8.2Hz,1H),6.54(d,J=7.9Hz,1H),3 .51(s,2H),3.33(s,6H),2.89(t,J=6.0Hz,2H),2.67(t,J=5.9Hz,2H),2.42(s,3H).

[0193] ESI-MS m / z: 449 [M+H] +

[0194] Example 2 Synthesis of Compound 3

[0195]

[0196] Step 1: Synthesis of compound int_3-2:

[0197]

[0198] Int_3-1 (2 g, 8.35 mmol) and int_1-5 (1.55 g, 8.35 mmol) were dissolved in isopropanol (5 mL), and DIPEA (4.32 g, 33.4 mmol, 5.83 mL) was added. The reaction mixture was heated to 80 °C and reacted overnight. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature, evaporated to dryness, and purified by column chromatography to give a pale yellow solid (1.5 g, yield: 46.3%). ESI-MS m / z: 388 [M+H] +

[0199] Step 2: Synthesis of compound int_3-3:

[0200]

[0201] Int_3-2 (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%).

[0202] ESI-MS m / z: 350 [M+H] +

[0203] Step 3: Synthesis of compound int_3-4:

[0204]

[0205] Int_3-3 (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.

[0206] ESI-MS m / z: 366 [M+H] +

[0207] Step 4: Synthesis of Compound 3:

[0208]

[0209] Int_3-4 (100 mg, 0.273 mmol) was dissolved in DMF (5 mL), and int_3-5 (45 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 (80 mg, yield: 63%).

[0210] 1 H NMR(400MHz,Chloroform-d)δ7.92(s,1H),7.87(d,J=8.0Hz,1H),7.64(s,1H),7.49(t,J=7 .9Hz,1H),7.33(d,J=2.2Hz,1H),7.20(dd,J=8.1,2.3Hz,1H),7.02(d,J=8.2Hz,1H),6.89( s,1H),6.51(d,J=7.8Hz,1H),3.54(s,2H),3.34(s,6H),2.87(t,J=5.9Hz,2H),2.68(t,J=5 .9Hz,2H),2.43(s,3H),1.57(td,J=7.9,4.0Hz,1H),1.04-0.91(m,2H),0.64-0.54(m,2H).

[0211] ESI-MS m / z: 464 [M+H] +

[0212] Example 3 Synthesis of Compound 6

[0213]

[0214] Step 1: Synthesis of compound int_6-3:

[0215]

[0216] Int_6-1 (1.6 g, 6.4 mmol), int_6-2 (1.37 g, 6.4 mmol), cesium carbonate (4.17 g, 12.8 mmol), Pd2(dba)3 (586 mg, 0.64 mmol), and Xantphos (741 mg, 1.28 mmol) were dissolved in 1,4-dioxane (100 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 (1.2 g, yield: 49%).

[0217] ESI-MS m / z: 382 [M+H] +

[0218] Step 2: Synthesis of compound int_6-4:

[0219]

[0220] 1.2 g (3.15 mmol) of int_6-4 was dissolved in 80 mL of dichloromethane. Then, m-CPBA (85%, 893.3 mg, 4.4 mmol) was added at room temperature, and the mixture was stirred for 30 minutes. LC-MS monitoring showed the reaction was complete. The reaction solution was washed with sodium bicarbonate aqueous solution (100 mL x 2), the aqueous phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product (1.1 g, crude product). The crude product can be used directly in the next reaction step.

[0221] ESI-MS m / z: 398 [M+H] +

[0222] Step 3: Synthesis of compound int_6-5:

[0223]

[0224] Int_6-4 (1.3 g, 3.15 mmol) was dissolved in DMF (50 mL), and int_3-5 (767.4 mg, 4.73 mmol) and trifluoroacetic acid (718 mg, 6.3 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 column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a white solid (1.1 g, yield: 70%).

[0225] LC-MS: 496 [M+H] +

[0226] Step 4: Synthesis of compound int_6-6:

[0227]

[0228] Int_6-5 (580 mg, 1.07 mmol) was dissolved in methanol (50 mL), and lithium hydroxide (675 mg, 16.06 mmol) was added. The reaction was carried out at room temperature for 5 hours, and LC-MS monitoring showed that the reaction was complete. The pH was adjusted to 5-6 with dilute hydrochloric acid, and the solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography to obtain a yellow powder (500 mg, yield: 91%).

[0229] ESI-MS m / z: 468 [M+H] +

[0230] Step 5: Synthesis of Compound 6:

[0231]

[0232] Int_6-6 (93 mg, 0.2 mmol) was dissolved in DMF (10 mL), and ammonium chloride (22 mg, 0.4 mmol), TEA (0.2 mL), and HATU (152 mg, 0.4 mmol) were added. The mixture was stirred overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to give an off-white solid (40 mg, yield: 43%).

[0233] 1H NMR (400MHz, DMSO-d6) δ11.71(s,1H),9.57(s,1H),8.67(s,1H),7.88(d,J=72.4Hz,2H),7.41(dd,J=8.7,5.1Hz,2H),7.30(s,2H),6.9 9(d,J=8.3Hz,1H),6.29(d,J=7.9Hz,1H),3.40(s,2H),3.34(s,6H),2.73(t,J=5.9Hz,2H),2.56(t,J=5.9Hz,2H),2.29(s,3H).ESI-MS m / z:467[M+H] +

[0234] Example 4 Synthesis of Compound 7

[0235]

[0236] Step 1: Synthesis of Compound 7:

[0237]

[0238] Int_6-6 (80 mg, 0.17 mmol) was dissolved in DMF (10 mL), and methylamine hydrochloride (12 mg, 0.17 mmol), TEA (34 mg, 0.34 mmol), and HATU (129 mg, 0.34 mmol) were added. The mixture was stirred overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to give an off-white solid (8 mg, yield: 7%).

[0239] 1 H NMR(400MHz,Chloroform-d)δ11.06(s,1H),8.27(s,1H),7.70(d,J=8.0Hz,1H),7 .41(t,J=8.0Hz,1H),7.30(d,J=2.2Hz,1H),7.20(d,J=8.2Hz,1H),7.09-7.01(m, 2H),6.47(dd,J=7.9,0.8Hz,1H),6.21(d,J=5.2Hz,1H),3.52(s,2H),3.39(s,6H) ,2.98(d,J=4.8Hz,3H),2.88(t,J=6.0Hz,2H),2.68(t,J=6.0Hz,2H),2.43(s,3H).

[0240] ESI-MS m / z: 481 [M+H] +

[0241] Example 5 Synthesis of Compound 8

[0242]

[0243] Step 1: Synthesis of Compound 8:

[0244]

[0245] Int_6-6 (80 mg, 0.17 mmol) was dissolved in DMF (10 mL), and dimethylamine in tetrahydrofuran solution (2.0 M, 0.09 mL, 0.17 mmol), TEA (34 mg, 0.34 mmol), and HATU (129 mg, 0.34 mmol) were added. The mixture was stirred overnight at room temperature, and LC-MS monitoring showed that the reaction was complete. The solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to give an off-white solid (61 mg, yield: 56%).

[0246] 1 H NMR(400MHz,Chloroform-d)δ9.44(s,1H),8.12(s,1H),7.70(d,J=8.0Hz,1H),7.44(t,J=7.9Hz,1H),7.32(d,J=2.3Hz,1H),7.23-7.17(m,2H), 7.05(d,J=8.2Hz,1H),6.47(d,J=7.8Hz,1H),3.52(s,2H),3.35(s,6H), 3.10(s,6H),2.88(t,J=5.9Hz,2H),2.67(t,J=5.9Hz,2H),2.42(s,3H).

[0247] ESI-MS m / z: 495 [M+H] +

[0248] Example 6 Synthesis of Compound 9

[0249]

[0250] Step 1: Synthesis of compound int_9-2:

[0251]

[0252] Int_9-1 (1.48 g, 5.4 mmol), int_1-5 (1.0 g, 4 mmol), and DIPEA (2.82 mL, 16.2 mmol) were dissolved in isopropanol (15 mL), and the mixture was heated to 60 °C and stirred overnight. LC-MS monitoring showed that the reaction was complete. The reaction solution was evaporated to dryness, and the crude product was purified by reverse-phase preparative HPLC to obtain a pale yellow solid (300 mg, yield: 13%).

[0253] ESI-MS m / z: 424 [M+H] +

[0254] Step 2: Synthesis of compound int_9-3:

[0255]

[0256] Int_9-2 (84 mg, 0.2 mmol), 2-(furan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (46 mg, 0.24 mmol), potassium carbonate (56 mg, 0.4 mmol), and Pd(dppf)Cl2 (14 mg, 0.02 mmol) were dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was heated to 80 °C and stirred for 16 hours under argon protection. LC-MS monitoring showed that the reaction was complete. The reaction solution was evaporated to dryness, and the crude product was purified by reverse-phase preparative HPLC to obtain an orange-yellow solid (40 mg, yield: 55%).

[0257] ESI-MS m / z: 364 [M+H] +

[0258] Step 3: Synthesis of Compound 9:

[0259]

[0260] Int_9-2 (40 mg, 0.11 mmol) was dissolved in DMF (50 mL), and int_3-5 (18 mg, 0.11 mmol) and CSA (51 mg, 0.22 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 16 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 (50 mg, yield: 93%).

[0261] 1H NMR (400MHz, Chloroform-d) δ8.32(d,J=21.4Hz,2H),7.79(d,J=8.0Hz,1H),7.49(dd,J=16.8,8.9Hz,2H),7.36(s,1H),7.05(d,J=9. 3Hz,2H),6.51(s,3H),3.57(d,J=9.5Hz,2H),3.34(d,J=6.9Hz,6H),2.91(t,J=5.9Hz,2H),2.73(t,J=5.8Hz,3H),2.47(s,4H).ESI-MS m / z:490[M+H] +

[0262] Example 7 Synthesis of Compound 11

[0263]

[0264] Step 1: Synthesis of compound int_11-2:

[0265]

[0266] Int_11-1 (1.45 g, 6.4 mmol), int_1-5 (1.3 g, 7 mmol), and DIPEA (2.82 mL, 16.2 mmol) were dissolved in isopropanol (30 mL), and the mixture was heated to 80 °C and stirred overnight. LC-MS monitoring showed that the reaction was complete. The reaction solution was evaporated to dryness, and the crude product was purified by reverse-phase preparative HPLC to obtain a pale yellow solid (1.7 g, yield: 71%).

[0267] ESI-MS m / z: 376 [M+H] +

[0268] Step 2: Synthesis of Compound 11:

[0269]

[0270] Int_11-2 (600 mg, 1.59 mmol) was dissolved in DMF (30 mL), and int_3-5 (258 mg, 1.59 mmol) and CSA (743 mg, 3.2 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 16 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 (510 mg, yield: 64%).

[0271] 1H NMR(400MHz,Chloroform-d)δ8.15(s,1H),7.74(d,J=8.0Hz,1H),7.55(s,1H),7.48(t,J=8.0Hz,1H),7.28(d,J=2.3Hz,1H),7.19(dd,J=8.1,2.3Hz, 1H),7.04(d,J=8.2Hz,1H),6.93(s,1H),6.53(d,J=7.8Hz,1H),3.53(s,2H ),3.35(s,6H),2.88(t,J=5.9Hz,2H),2.68(t,J=5.9Hz,2H),2.43(s,3H).

[0272] ESI-MS m / z: 502 [M+H] +

[0273] Example 8 Synthesis of Compound 12

[0274]

[0275] Step 1: Synthesis of compound int_12-1-2:

[0276]

[0277] Int12-1-1 hydrochloride (10.0 g, 46.10 mmol) was dissolved in TfOH (50.0 mL), and NIS (15.7 g, 69.88 mmol) was added under nitrogen protection at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature, poured into ice water, and the pH was adjusted to 8-9 with dilute NaOH solution. Filtering yielded a black solid int12-1-2 (14 g, 46.0 mmol, crude product), which could be used directly in the next reaction.

[0278] ESI-MS m / z: 305 [M+H] +

[0279] Step 2: Synthesis of compound int_12-1-3:

[0280]

[0281] Int_12-1-2 (14.0 g, 46.0 mmol) and (Boc)2O (25.1 g, 115 mmol, 26.4 mL) were dissolved in DCM (200 mL), and TEA (14.0 g, 138 mmol, 19.2 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 16 hours. LC-MS monitoring showed that the reaction was complete. Water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (150 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (1.1 mg, crude product). The crude product was purified by column chromatography (SiO2, EtOAc / PE = 0 / 1-1 / 9) to give a white solid (10 g, yield: 53.7%).

[0282] ESI-MS m / z: 349 [M+H] +

[0283] Step 3: Synthesis of compound int_12-1-4:

[0284]

[0285] Int_12-1-3 (6.00 g, 14.8 mmol), methylboric acid (8.90 g, 148.4 mmol), cesium carbonate aqueous solution (2 M, 14.8 mL), and Pd(dppf)Cl2.CH2Cl2 (1.2 g, 1.5 mmol) were dissolved in a mixed solvent of 1,4-dioxane (100 mL). The mixture was heated to 100 °C and stirred for 5 hours under argon protection. LC-MS monitoring showed that the reaction was complete. The reaction solution was evaporated to dryness, and the crude product was purified by column chromatography (SiO2, EtOAc / PE = 0 / 1-1 / 9) to give a white solid (2.5 g, yield: 57.6%).

[0286] 1H NMR: (400MHz, DMSO-d6) δ7.92(br d,J=8.5Hz,2H),4.61(br s,2H),3.61(t,J=5.9Hz,2H),2.75(t,J=5.9Hz,2H),2.32(s,3H),1.48-1.37(m,9H)

[0287] ESI-MS m / z: 237 [M+H] +

[0288] Step 4: Synthesis of compound int_12-1:

[0289]

[0290] INT12-1-4 (2.30 g, 7.80 mmol) was dissolved in methanol (40.0 mL), and 10% Pd / C (230 mg) was added. The reaction mixture was reacted at room temperature for 16 hours under a hydrogen atmosphere (15.0 Psi.). LC-MS monitoring showed that the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to give a yellow gel (2.00 g, yield: 96.9%).

[0291] 1 H NMR (400MHz, DMSO-d6) δ = 6.28 (d, J = 1.6Hz, 1H), 6.14 (s, 1H), 5.75 (s, 1H), 4.77 (s, 2H), 4.31 (br s,2H),3.51(t,J=6.0Hz,2H),2.48-2.44(m,2H),2.04(s,3H),1.41(s,9H)

[0292] ESI-MS m / z: 207 [M+H] +

[0293] Step 5: Synthesis of compound int_12-2:

[0294]

[0295] Int_1-8 (1.05 g, 3 mmol) was dissolved in DMF (100 mL), and int_12-1 (787 mg, 3 mmol) and trifluoroacetic acid (342 mg, 3 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 column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a yellow solid (1.2 g, yield: 87%).

[0296] ESI-MS m / z: 549 [M+H] +

[0297] Step 6: Synthesis of compound int_12-3:

[0298]

[0299] Int_12-2 (1.2 g, 2.19 mmol) was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (6.24 g, 54.7 mmol) was added. The reaction was carried out at room temperature for 1 hour, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a yellow solid (1 g, crude product). The crude product can be used directly in the next reaction.

[0300] ESI-MS m / z: 449 [M+H] +

[0301] Step 7: Synthesis of Compound 12:

[0302]

[0303] Int_12-3 (1 g, 2.23 mmol) and DIPEA (6.5 g, 50 mmol) were dissolved in dichloromethane (20 mL) and methanol (20 mL). Formaldehyde aqueous solution (37-40%, 2 mL) and sodium borohydride acetate (3.4 g, 16 mmol) were added. The reaction was carried out at room temperature for 1 hour, monitored by LC-MS, until the reaction was complete. Water (100 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 20:1) to give a pale yellow solid product (700 mg, yield: 92%).

[0304] 1 H NMR (400MHz, DMSO-d6) δ9.96(brs,1H),9.27(brs,1H),8.54(s,1H),7.54(t,J=7.9Hz,1H),7.36(d,J=2.2Hz, 1H),7.28-7.15(m,2H),6.42(d,J=8.0Hz,1H),4.13(s,2H),3.35(s,9H),2.83(d,J=4.8Hz,4H),2.11(s,3H).

[0305] ESI-MS m / z: 463 [M+H] +

[0306] Example 9 Synthesis of Compound 13

[0307]

[0308] Step 1: Synthesis of compound int_13-1-2:

[0309]

[0310] Int_12-1-3 (3.00 g, 7.42 mmol), int_13-1-1 (4.97 g, 37.1 mmol), cesium carbonate aqueous solution (2.00 M, 7.42 mL), and Pd(dppf)Cl2.CH2Cl2 (606 mg, 742 μmol) were dissolved in 1,4-dioxane (40 mL). The mixture was heated to 100 °C and stirred for 5 hours under argon protection. LC-MS monitoring showed that the reaction was complete. The reaction solution was evaporated to dryness, and the crude product was purified by column chromatography (SiO2, EtOAc / PE = 0 / 1-1 / 9) to give a white solid (1.2 g, yield: 53.1%).

[0311] ESI-MS m / z: 249 [M+H] +

[0312] Step 2: Synthesis of compound int_13-1:

[0313]

[0314] 1.00 g (3.29 mmol) of int_13-1-2 was dissolved in methanol (40.0 mL), and 10% Pd / C (100 mg) was added. The reaction mixture was reacted at room temperature for 16 hours under a hydrogen atmosphere (15.0 Psi.). LC-MS monitoring showed that the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to give a yellow gel (600 mg, yield: 61%).

[0315] 1 H NMR (400MHz, DMSO-d6) δ6.30 (d, J=2.0Hz, 1H), 6.15 (br s, 1H), 4.81 (s, 2H), 4.31 (br s, 2H), 3.49 (br t,J=5.9Hz,2H),2.41(q,J=7.5Hz,2H),1.41(s,9H),1.07(t,J=7.5Hz,3H)ESI-MS m / z:221[M+H] +

[0316] Step 3: Synthesis of compound int_13-2:

[0317]

[0318] Int_1-8 (100 mg, 0.281 mmol) was dissolved in DMF (5 mL), and int_13-1 (79 mg, 0.281 mmol) and trifluoroacetic acid (63.9 mg, 0.56 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 column chromatography (SiO2, DCM: MeOH = 100:1 to 30:1) to give a yellow solid (34 mg, yield: 21.5%).

[0319] ESI-MS m / z: 563 [M+H] +

[0320] Step 4: Synthesis of compound int_13-3:

[0321]

[0322] Int_13-2 (34 mg, 0.06 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 2 hours, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a yellow solid (31 mg, crude product). The crude product can be used directly in the next reaction.

[0323] ESI-MS m / z: 463 [M+H] +

[0324] Step 5: Synthesis of Compound 13:

[0325]

[0326] Int_13-3 (500 mg, 1.08 mmol) and DIPEA (3.2 g, 25 mmol) were dissolved in dichloromethane (10 mL) and methanol (10 mL). Formaldehyde aqueous solution (37-40%, 1 mL) and sodium borohydride acetate (1.7 g, 8 mmol) were added. The reaction was carried out at room temperature for 1 hour, monitored by LC-MS, until the reaction was complete. Water (100 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 20:1) to give a white solid product (129 mg, yield: 25%).

[0327] 1H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.76-7.59(m,2H),7.43(d,J=27.0Hz,2H),7.18(s,1H),7.07(s,1H),6.56(d,J=7.9Hz,1H),3 .55(s,2H),3.36(s,6H),2.83(d,J=6.1Hz,2H),2.73(t,J=5.8Hz,2H),2.58(q,J=7.6Hz,2H),2.45(s,3H),1.18(t,J=7.6Hz,3H).ESI-MS m / z:477[M+H] +

[0328] Example 10 Synthesis of Compound 16

[0329]

[0330] Step 1: Synthesis of compound int_16-1-2:

[0331]

[0332] Int_12-1-3 (3.00 g, 7.42 mmol), int_16-1-1 (3.19 g, 37.1 mmol), cesium carbonate (4.84 g, 14.8 mmol), and Pd(dppf)Cl2.CH2Cl2 (606 mg, 742 μmol) were dissolved in 1,4-dioxane (40 mL) and water (4 mL). The mixture was heated to 100 °C and stirred for 5 hours under argon protection. LC-MS monitoring showed that the reaction was complete. The reaction solution was evaporated to dryness, and the crude product was purified by column chromatography (SiO2, EtOAc / PE = 0 / 1-1 / 9) to give a white solid (1.4 g, yield: 59.3%).

[0333] 1 H NMR (400MHz, DMSO-d6) δ7.95(d,J=2.0Hz,1H),7.62(d,J=2.3Hz,1H),4.62(brs,2H),3.63(br t,J=5.9Hz,2H),2.98(t,J=5.9Hz,2H),2.04-1.94(m,1H),1.47-1.35(m,9H),1.05-0.93(m,2H),0.74-0.62(m,2H)

[0334] Step 2: Synthesis of compound int_16-1:

[0335]

[0336] 1.20 g (3.77 mmol) of int_16-1-2 was dissolved in 20.0 mL of methanol and 20.0 mL of water. 2.02 g (37.7 mmol) of NH4Cl and 2.10 g (37.7 mmol) of Fe powder were added. The reaction mixture was heated to 80 °C and reacted for 5 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was then concentrated under reduced pressure to give a white solid (470 mg, yield: 43.2%).

[0337] 1 H NMR (400MHz, DMSO-d6) δ6.18-6.08(m,2H),4.79(s,2H),4.32(br s,2H),3.53(br t,J=5.8Hz,2H),2.69(br t,J=6.0Hz,2H),1.79-1.71(m,1H),1.42(s,10H),0.86-0.77(m,2H),0.49-0.43(m,2H)

[0338] ESI-MS m / z: 233 [M+H] +

[0339] Step 3: Synthesis of compound int_16-2:

[0340]

[0341] Int_1-8 (100 mg, 0.28 mmol) was dissolved in DMF (5 mL), and int_16-1 (81 mg, 0.28 mmol) and trifluoroacetic acid (63.9 mg, 0.56 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 column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a yellow solid (60 mg, yield: 37%).

[0342] ESI-MS m / z: 575 [M+H] +

[0343] Step 4: Synthesis of compound int_16-3:

[0344]

[0345] Int_16-2 (60 mg, 0.10 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction was carried out at room temperature for 2 hours, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a yellow solid (55 mg, crude product). The crude product can be used directly in the next reaction.

[0346] ESI-MS m / z: 475 [M+H] +

[0347] Step 5: Synthesis of Compound 16:

[0348]

[0349] Int_16-3 (55 mg, 0.116 mmol) and DIPEA (298 mg, 2.3 mmol) were dissolved in dichloromethane (2 mL) and methanol (2 mL). Formaldehyde aqueous solution (37-40%, 1 mL) and sodium borohydride acetate (600 mg, 2.83 mmol) were added. The reaction was carried out at room temperature for 1 hour, monitored by LC-MS, until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using HPLC to obtain a white solid product (40 mg, yield: 70%).

[0350] 1 H NMR(400MHz,Chloroform-d)δ8.35(s,1H),7.69(d,J=8.0Hz,1H),7.51(d,J=35.5Hz,3H),7.16(s,1H),6.88(s,1H),6.56(d,J=7.9Hz,1H),3.53(s ,2H),3.36(d,J=1.7Hz,6H),2.98(d,J=6.1Hz,2H),2.75(t,J=6.2Hz,2H) ,2.46(s,3H),1.82(s,1H),0.88(d,J=8.0Hz,2H),0.56(d,J=5.4Hz,2H).

[0351] ESI-MS m / z: 489 [M+H] +

[0352] Example 11 Synthesis of Compound 19

[0353]

[0354]

[0355] Step 1: Synthesis of compound int_19-1-2:

[0356]

[0357] Int_12-1-3 (5.00 g, 12.4 mmol), int_19-1-1 (2.64 g, 37.1 mmol), cesium carbonate (8.06 g, 24.7 mmol), and RuPhos Pd G3 (606 mg, 742 μmol) were dissolved in 1,4-dioxane (50 mL). The mixture was heated to 100 °C and stirred for 5 hours under argon protection. LC-MS monitoring showed that the reaction was complete. The reaction solution was evaporated to dryness, and the crude product was purified by column chromatography (SiO2, EtOAc / PE = 0 / 1-1 / 9) to give a white solid (1.7 g, yield: 39.6%).

[0358] ESI-MS m / z: 348 [M+H] +

[0359] Step 2: Synthesis of compound int_19-1:

[0360]

[0361] 0.70 g (2.01 mmol) of int_19-1-2 was dissolved in methanol (40.0 mL), and 10% Pd / C (100 mg) was added. The reaction mixture was reacted at room temperature under a hydrogen atmosphere (15.0 Psi.) for 16 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to give a white solid (410 mg, yield: 63.5%).

[0362] 1 H NMR (400MHz, DMSO-d6) δ6.08(d,J=2.0Hz,1H),5.93(s,1H),4.76(s,2H),4.30(br s,2H),3.44-3.37(m,2H),2.99(br t,J=6.2Hz,4H),2.42(br s,1H),1.89-1.79(m,4H),1.65(br s,1H),1.43(s,9H)

[0363] ESI-MS m / z: 318 [M+H] +

[0364] Step 3: Synthesis of compound int_19-2:

[0365]

[0366] Int_1-8 (56 mg, 0.158 mmol) was dissolved in DMF (5 mL), and int_19-1 (50 mg, 0.158 mmol) and trifluoroacetic acid (64 mg, 0.631 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 column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to obtain an orange-yellow solid (50 mg, yield: 52.6%).

[0367] ESI-MS m / z: 604 [M+H] +

[0368] Step 4: Synthesis of compound int_19-3:

[0369]

[0370] Int_19-2 (50 mg, 0.083 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 2 hours, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to obtain a yellow solid (50 mg, crude product). The crude product can be used directly in the next reaction.

[0371] ESI-MS m / z: 504 [M+H] +

[0372] Step 5: Synthesis of Compound 19:

[0373]

[0374] Int_19-3 (30 mg, 0.060 mmol) and DIPEA (298 mg, 2.3 mmol) were dissolved in dichloromethane (2 mL) and methanol (2 mL). Formaldehyde aqueous solution (37-40%, 1 mL) and sodium borohydride acetate (200 mg, 0.95 mmol) were added. The reaction was carried out at room temperature for 1 hour, monitored by LC-MS, until the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography using HPLC to obtain a white solid product (5 mg, yield: 16.2%).

[0375] 1H NMR(400MHz,Chloroform-d)δ8.30(s,2H),7.56(d,J=18.1Hz,2H),7.46(d,J=9.7Hz,1H),6.92(d,J=2.0Hz,1H),6.75(s,1H),6.51( d,J=7.8Hz,1H),3.93(s,2H),3.30(s,6H),3.06(d,J=12.4Hz,6H),2.94(d,J=6.0Hz,2H),2.68(s,3H),1.83(d,J=6.3Hz,4H).ESI-MS m / z:518[M+H] +

[0376] Example 12 Synthesis of Compound 22

[0377]

[0378] Step 1: Synthesis of compound int_22-1-1:

[0379]

[0380] Int_12-1-3 (500 mg, 1.24 mmol), methanol (39.6 mg, 1.24 mmol), CuI (236 mg, 1.24 mmol), Cs₂CO₃ (806 mg, 2.47 mmol), and (1R,2R)-N₁,N₂-dimethylcyclohexane-1,2-diamine (175.96 mg, 1.24 mmol) were dissolved in methanol (8 mL). The mixture was heated to 110 °C and stirred for 1 hour under nitrogen protection. LC-MS monitoring showed the reaction was complete. The reaction solution was evaporated to dryness, and the crude product was purified by column chromatography (SiO₂, EtOAc / PE = 1 / 10) to give a white solid (420 mg, yield: 27.5%).

[0381] 1 H NMR(400MHz,Chloroform-d)δ7.67(s,1H),7.55(d,J=1.9Hz,1H),4.64(s,2H),3.94(s,3H),3.68(t,J=5.9Hz,2H),2.82(br t,J=5.8Hz,2H),1.51(s,9H)

[0382] Step 2: Synthesis of compound int_22-1:

[0383]

[0384] Int_22-1-1 (420 mg 1.36 mmol) was dissolved in methanol (10.0 mL), and 10% Pd / C (100 mg) was added. The reaction mixture was reacted at room temperature for 16 hours under a hydrogen atmosphere (15.0 Psi.). LC-MS monitoring showed that the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to give a white gel (370 mg, yield: 97.5%).

[0385] 1 H NMR(400MHz,Chloroform-d)δ6.10(br d,J=13.1Hz,2H),4.47(s,2H),3.79(s,3H),3.61(br s,4H),2.65(br t,J=5.6Hz,2H),1.50(s,9H)

[0386] ESI-MS m / z: 223 [M+H] +

[0387] Step 3: Synthesis of compound int_22-2:

[0388]

[0389] Int_1-8 (179 mg, 0.51 mmol) was dissolved in DMF (10 mL), and int_22-1 (212 mg, 0.76 mmol) and trifluoroacetic acid (114 mg, 1 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 column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to obtain a pale yellow solid (250 mg, yield: 87%).

[0390] ESI-MS m / z: 565 [M+H] +

[0391] Step 4: Synthesis of compound int_22-3:

[0392]

[0393] Int_22-2 (100 mg, 0.18 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 2 hours, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to obtain a yellow solid (100 mg, crude product). The crude product can be used directly in the next reaction.

[0394] ESI-MS m / z: 465 [M+H] +

[0395] Step 5: Synthesis of Compound 22:

[0396]

[0397] Int_22-3 (84 mg, 0.18 mmol) and DIPEA (298 mg, 2.3 mmol) were dissolved in dichloromethane (2 mL) and methanol (2 mL). Formaldehyde aqueous solution (37-40%, 0.5 mL) and sodium borohydride acetate (500 mg, 2.36 mmol) were added, and the reaction was carried out at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain a white solid product (45 mg, yield: 52%).

[0398] 1 H NMR(400MHz,Chloroform-d)δ8.31(s,1H),7.61(d,J=18.0Hz,2H),7.39(s,2H),6.75(s,2H),6.4 9(d,J=7.7Hz,1H),3.67(s,3H),3.44(s,2H),3.30(s,6H),2.71(s,2H),2.63(s,2H),2.38(s,3H).

[0399] ESI-MS m / z: 479 [M+H] +

[0400] Example 13 Synthesis of Compound 29

[0401]

[0402] Step 1: Synthesis of compound int_29-2:

[0403]

[0404] Int_1-8 (105 mg, 0.3 mmol) was dissolved in DMF (5 mL), and int_29-1 (81 mg, 0.3 mmol) and trifluoroacetic acid (34 mg, 0.3 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 column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a pale yellow solid (56 mg, yield: 33.5%).

[0405] ESI-MS m / z: 557 [M+H] +

[0406] Step 2: Synthesis of compound int_29-3:

[0407]

[0408] Int_29-2 (190 mg, 0.341 mmol) was dissolved in a mixture of methanol and THF (v / v = 1:1, 15 mL), and potassium carbonate (48 mg, 0.341 mmol) was added. The reaction was carried out at room temperature for 2 hours, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a yellow solid (190 mg, crude product). The crude product can be used directly in the next reaction.

[0409] ESI-MS m / z: 461 [M+H] +

[0410] Step 3: Synthesis of Compound 29:

[0411]

[0412] Int_29-3 (190 mg, 0.412 mmol) was dissolved in dichloromethane (5 mL) and methanol (5 mL), and formaldehyde aqueous solution (37-40%, 1 mL) and sodium borohydride acetate (212 mg, 1 mmol) were added. The reaction was carried out at room temperature for 1 hour, and LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a yellow solid product (106 mg, yield: 55%).

[0413] 1 H NMR(400MHz,Chloroform-d)δ8.32(s,1H),7.79-7.55(m,3H),7.44(s,1H),7.24(d,J=5.8Hz,1H),7.17(s,1H),6.63( d,J=8.4Hz,1H),6.54(d,J=7.9Hz,1H),3.64(s,2H),3.34(s,6H),2.52(s,2H),2.42(s,3H),0.99(s,2H),0.91(s,2H).

[0414] ESI-MS m / z: 475 [M+H] +

[0415] Example 14 Synthesis of Compound 42

[0416]

[0417] Step 1: Synthesis of compound int_42-1-1:

[0418]

[0419] 5.50 g (18.1 mmol) of int_13-1-2 was dissolved in 50 mL of 1,4-dioxane, and 55.0 mL of HCl / dioxane solution (4 M) was added. The reaction mixture was stirred at room temperature for 2 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 (4 g, yield: 91.9%). The crude product can be used directly in the next reaction step.

[0420] ESI-MS m / z: 205 [M+H] +

[0421] Step 2: Synthesis of compound int_42-1-2:

[0422]

[0423] Dissolve int_42-1-1 (3.80 g, 18.6 mmol) in methanol (40 mL), then add NaOAc (3.05 g, 37.2 mmol), NaBH3CN (1.75 g, 27.9 mmol) and (HCHO). n (838 mg), the reaction solution was heated to 50 °C and reacted for 4 hours. LC-MS monitoring showed that the reaction was complete. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then subjected to column chromatography (…). 40g Sepa Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient@60mL / min) yielded a white solid (3.2g, yield: 78.8%).

[0424] 1 H NMR(400MHz,Chloroform-d)δ8.09(d,J=2.0Hz,1H),7.75(d,J=1.6Hz,1H),6.79(dd,J=17.3,11.0Hz,1H),5.7 2(d,J=17.3Hz,1H),5.41(d,J=11.0Hz,1H),3.60(s,2H),2.86-2.91(m,2H),2.69-2.73(m,2H),2.43ppm(s,3H)

[0425] Step 3: Synthesis of compound int_42-1:

[0426]

[0427] Int_42-1-2 (3.00 g, 13.7 mmol) was dissolved in ethanol (30.0 mL) and water (30.0 mL). Under nitrogen protection, NH4Cl (4.41 g, 82.5 mmol) and Fe powder (4.61 g, 82.4 mmol) were added. The reaction mixture was heated to 70 °C and reacted for 6 hours. LC-MS monitoring showed the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was then concentrated to obtain the crude product. The crude product was subjected to column chromatography (…). 40g Sepa Silica Flash Column, Eluent of 0-60% Ethyl acetate / Petroleum ether gradient@60mL / min) yielded a yellow solid (2.43g, yield: 93.9%).

[0428] 1 H NMR (400MHz, DMSO-d6) δ6.82 (dd, J=17.3, 10.9Hz, 1H), 6.72 (d, J=1.6Hz, 1H), 6.27 (s, 1H),5.57(dd,J=17.3,1.3Hz,1H),5.28(dd,J=10.9,1.3Hz,1H),4.13(s,2H),3.34(br s,2H),2.90(br t,J=5.9Hz,2H),2.80ppm(s,3H)

[0429] ESI-MS m / z: 189 [M+H] +

[0430] Step 4: Synthesis of Compound 42:

[0431]

[0432] Int_1-8 (100 mg, 0.281 mmol) was dissolved in DMF (30 mL), and int_42-1 (54 mg, 0.281 mmol) and trifluoroacetic acid (113 mg, 1.1 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 16 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 (3 mg, yield: 2.3%).

[0433] ESI-MS m / z: 475 [M+H] +

[0434] Example 15 Synthesis of Compound 43

[0435]

[0436] Step 1: Synthesis of compound int_43-1-2:

[0437]

[0438] Int_12-1-3 (5.00 g, 12.4 mmol), int_43-1-1 (1.64 g, 16.7 mmol, 2.31 mL), CuI (141 mg, 742 μmol), TEA (5.01 g, 49.5 mmol, 6.89 mL), and Pd(PPh3)2Cl2 (434 mg, 618 μmol) were dissolved in 1,4-dioxane (40 mL). The mixture was heated to 70 °C and stirred for 1 hour under argon protection. LC-MS monitoring showed that the reaction was complete. Water (30 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then subjected to column chromatography (SiO2, EtOAc / PE = 0 / 1-1 / 9) to give a yellow solid (3.5 g, yield: 75.6%).

[0439] ESI-MS m / z: 319 [M+H] +

[0440] Step 2: Synthesis of compound int_43-1-3:

[0441]

[0442] Int_43-1-2 (3.50 g, 9.35 mmol) was dissolved in methanol (50.0 mL), and K2CO3 (645 mg, 4.67 mmol) was added at 10 °C. The reaction mixture was allowed to react at room temperature for 5 hours. LC-MS monitoring showed that the reaction was complete. Water (30 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (50 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then subjected to column chromatography (SiO2, EtOAc / PE = 0 / 1-1 / 9) to give a white solid (2.6 g, yield: 92%). 1 HNMR(400MHz,Chloroform-d)δ8.14(d,J=2.0Hz,1H),7.90(d,J=1.5Hz,1H),4.59(s,2H),3.64(t,J=5.9Hz,2H),3.37(s,1H),2.98(br t,J=5.8Hz,2H),1.43(s,9H)

[0443] ESI-MS m / z: 247 [M+H] +

[0444] Step 3: Synthesis of compound int_43-1:

[0445]

[0446] Int_43-1-3 (2.10 g, 6.95 mmol) was dissolved in ethanol (30.0 mL) and water (30.0 mL), and NH4Cl (3.72 g, 69.46 mmol) and Fe powder (3.88 g, 69.5 mmol) were added. The reaction solution was heated to 70 °C and reacted for 2 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered to obtain a filtrate, which was concentrated. The aqueous phase was extracted with ethyl acetate (50 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was subjected to column chromatography (SiO2, EtOAc / PE = 0 / 1-1 / 9) to give a white solid (1 g, yield: 52.9%).

[0447] 1H NMR (400MHz, DMSO-d6) δ6.58(d,J=2.2Hz,1H),6.38(s,1H),5.07(s,2H),4.33(s,2H),4.22(s,1H),3.51(br t,J=5.8Hz,2H),2.66(t,J=5.9Hz,2H),1.42(s,9H)

[0448] ESI-MS m / z: 217 [M+H] +

[0449] Step 4: Synthesis of compound int_43-2:

[0450]

[0451] Int_1-8 (105 mg, 0.3 mmol) was dissolved in DMF (5 mL), and int_43-1 (82 mg, 0.299 mmol) and trifluoroacetic acid (34 mg, 0.3 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 column chromatography (SiO2, DCM:MeOH = 100:1 to 30:1) to give a yellow solid (65 mg, yield: 62%).

[0452] ESI-MS m / z: 559 [M+H] +

[0453] Step 5: Synthesis of compound int_43-3:

[0454]

[0455] Int_43-2 (65 mg, 0.116 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1 mL) was added. The reaction was carried out at room temperature for 2 hours, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to give a yellow solid (60 mg, crude product). The crude product can be used directly in the next reaction.

[0456] ESI-MS m / z: 459 [M+H] +

[0457] Step 6: Synthesis of Compound 43:

[0458]

[0459] Int_43-3 (53 mg, 0.116 mmol) and DIPEA (298 mg, 2.3 mmol) were dissolved in dichloromethane (2 mL) and methanol (2 mL). Formaldehyde aqueous solution (37-40%, 0.5 mL) and sodium borohydride acetate (50 mg, 0.24 mmol) were added, and the reaction was carried out at room temperature for 1 hour. LC-MS monitoring showed the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain a yellow solid product (32 mg, yield: 58.6%).

[0460] 1 H NMR(400MHz,Chloroform-d)δ8.31(s,1H),7.61(d,J=8.0Hz,1H),7.57–7.44(m,3H),7.25(s,1H),7.12(s,1H),6.51(d d,J=7.9,0.8Hz,1H),3.45(s,2H),3.30(s,6H),3.22(s,1H),2.94(t,J=6.0Hz,2H),2.66(t,J=6.0Hz,2H),2.39(s,3H).

[0461] ESI-MS m / z: 473 [M+H] +

[0462] Example 16 Synthesis of Compound 52

[0463]

[0464] Step 1: Synthesis of compound int_52-1-3:

[0465]

[0466] Int_52-1-1 (50 g, 189 mmol, 25.5 mL) and int_52-1-2 (49.5 g, 284 mmol, 40.9 mL) were dissolved in dichloromethane (400 mL), and TBAB (36.6 g, 113 mmol) and NaHCO3 (1 M, 1000 mL) were added. The reaction mixture was heated to 40 °C and reacted for 16 hours. LC-MS monitoring showed that the reaction was complete. Water (300 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (500 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (52 g, yield: 99%) as a brown oily substance. The crude product can be used directly in the next reaction.

[0467] 1 H NMR(400MHz,Chloroform-d)δ7.28-7.26(m,3H),7.24(s,4H),4.13(q,J=7.3Hz,2H),3.94(dd,J=3.4,8.9Hz,2H), 3.87-3.84(m,1H),3.82-3.79(m,4H),3.77-3.75(m,3H),3.73-3.67(m,9H),3.29-3.21(m,3H),3.20-3.10(m,4H)

[0468] Step 2: Synthesis of compound int_52-1-4:

[0469]

[0470] INT_52-1-3 (52 g, 188 mmol) was dissolved in acetonitrile (50 mL), and H₂SO₄ (3 M, 240.00 mL) was added. The reaction mixture was heated to 100 °C and reacted for 16 hours. LC-MS monitoring showed that the reaction was complete. Water (50 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (300 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then subjected to column chromatography (…). 220g Sepa Silica Flash Column, Eluent of 0-30% Ethylacetate / Petroleum ether gradient @ 80 mL / min) was purified to give a white solid (25 g, yield: 82.9%).

[0471] 1H NMR(400MHz,Chloroform-d)δ7.20-7.09(m,4H),2.89-2.77(m,4H),2.63-2.45(m,4H)

[0472] Step 3: Synthesis of compound int_52-1-5:

[0473]

[0474] 13 g (81.1 mmol) of int_52-1-4 was dissolved in 100 mL of H₂SO₄. KNO₃ (9.02 g, 89.3 mmol) was added at -10 °C. The reaction mixture was incubated at -10 °C for 5 minutes, and LC-MS monitoring showed the reaction was complete. The reaction mixture was then poured into 500 mL of ice water. The aqueous phase was extracted with ethyl acetate (3 x 500 mL), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then subjected to column chromatography (…). 120g Sepa Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient@60mL / min) was purified to give a yellow solid (9g, yield: 54.1%).

[0475] 1 H NMR(400MHz,Chloroform-d)δ8.19-8.03(m,2H),7.42(d,J=8.3Hz,1H),3.10-3.00(m,4H),2.72-2.63(m,4H)

[0476] Step 4: Synthesis of compound int_52-1-6:

[0477]

[0478] Int_52-1-5 (5g, 24.4mmol) and dimethylamine (2M, 36.5mL) were dissolved in DCE (50mL). HOAc (146mg, 2.44mmol, 139.4µL) and NaBH(OAc)3 (15.5g, 73.1mmol) were added at room temperature. The reaction mixture was allowed to react for 16 hours at room temperature, and LC-MS monitoring showed the reaction was complete. A saturated NaHCO3 solution (150mL) was added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (300mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then subjected to column chromatography (…). 80g Sepa Silica Flash Column, Eluent of 0-10% MeOH (10% NH3·H2O) / DCM gradient@60mL / min) was purified to give a white solid (3.7g, yield: 64.8%). 1 H NMR (400MHz, DMSO-d6) δ8.03(d,J=2.4Hz,1H),7.97(dd,J=2.5,8.3Hz,1H),7.42(d,J=8.3Hz,1H),3.00(dt, J=7.7,13.4Hz,2H),2.81-2.68(m,2H),2.65-2.55(m,1H),2.17(s,6H),2.04-1.87(m,2H),1.40-1.21(m,2H)

[0479] Step 5: Synthesis of compound int_52-1:

[0480]

[0481] 3.60 g (15.4 mmol) of int_52-1-6 was dissolved in methanol (20.0 mL), and 10% Pd / C (3 g, 15.4 mmol) was added. The reaction mixture was reacted at room temperature under a hydrogen atmosphere (15.0 Psi.) for 16 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to give a white solid (2.5 g, yield: 79.6%).

[0482] 1 H NMR (400MHz, DMSO-d6) δ6.74(d,J=8.0Hz,1H),6.34(d,J=2.3Hz,1H),6.26(dd,J=2.4,7.9Hz,1H),4.74(br s,2H),2.63-2.52(m,3H),2.48-2.41(m,2H),2.20-2.06(m,6H),2.01-1.77(m,2H),1.33-1.07(m,2H)

[0483] ESI-MS m / z: 205 [M+H] +

[0484] Step 6: Synthesis of Compound 52:

[0485]

[0486] Int_1-8 (200 mg, 0.562 mmol) was dissolved in DMF (10 mL), and int_52-1 (115 mg, 0.562 mmol) and trifluoroacetic acid (226 mg, 2.2 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 16 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 (71 mg, yield: 15%).

[0487] 1 H NMR(400MHz,Chloroform-d)δ8.34(s,1H),7.69(d,J=8.0Hz,1H),7.60(s,1H),7.44(s,1H),7.35(s,1H),7.18(s,1H),7.08(d,J= 8.0Hz,1H),6.54(d,J=7.9Hz,1H),3.34(s,6H),2.90-2.55(m,5H),2.26(s,6H),2.12-2.01(m,2H),1.36(dd,J=12.4,7.1Hz,2H).

[0488] ESI-MS m / z: 491 [M+H] +

[0489] Example 17 Synthesis of Compound 55

[0490]

[0491] Step 1: Synthesis of compound int_55-1-2:

[0492]

[0493] 40.0 g (205 mmol) of int_55-1-1 was dissolved in 160 mL of H₂SO₄. HNO₃ (20.9 g, 216 mmol, 14.9 mL, 65% purity) was added at 0 °C. The reaction mixture was maintained at 0 °C for 4 hours, and LC-MS monitoring showed the reaction was complete. The reaction mixture was then poured into 300 mL of ice water. The aqueous phase was extracted with ethyl acetate (500 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (32 g, yield: 65%) as a yellow solid. The crude product can be used directly in the next reaction step.

[0494] 1H NMR (400MHz, DMSO-d6) δ12.65(br s,2H),8.18(d,J=2.5Hz,1H),8.10(dd,J=8.3,2.5Hz,1H),7.55(d,J=8.5Hz,1H),3.80(s,2H),3.77ppm(s,2H)

[0495] Step 2: Synthesis of compound int_55-1-3:

[0496]

[0497] Dissolve int_55-1-2 (32.0 g, 133 mmol) in THF (500 mL), and add BH at 0 °C. 3· THF solution (1M, 267 mL) was used, and the reaction was maintained at 0℃ for 4 hours. LC-MS monitoring showed the reaction was complete. Water (600 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (500 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then subjected to column chromatography (…). 220g Sepa Silica Flash Column, Eluent of 0-10% MeOH / DCM gradient@80mL / min) was purified to give a yellow solid (17g, yield: 60.1%). 1 H NMR (400MHz, DMSO-d6) δ8.07(d,J=2.5Hz,1H),7.99(dd,J=8.5,2.5Hz,1H),7.47(d,J=8.5Hz,1H),4.82(br s,2H),3.59-3.68(m,4H),2.89ppm(t,J=6.8Hz,4H)

[0498] Step 3: Synthesis of compound int_55-1-4:

[0499]

[0500] Int_55-1-3 (15 g, 71.0 mmol) and TEA (35.9 g, 355 mmol, 49.4 mL) were dissolved in DCM (400 mL). MsCl (23.6 g, 206 mmol, 16 mL) was added at 0 °C, and the reaction mixture was maintained at 0 °C for 3 hours. TLC monitoring showed that the reaction was complete. Ice water (200 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (300 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product (20 g, yield: 76.7%). The crude product can be used directly in the next reaction step.

[0501] 1 H NMR(400MHz,Chloroform-d)δ8.18-8.10(m,2H),7.47(d,J=8.3Hz,1H),4.49(q,J=6.7Hz,4H),3.25(t,J=6.8Hz,4H),3.01(d,J=5.5Hz,6H)

[0502] Step 4: Synthesis of compound int_55-1-5:

[0503]

[0504] Int_55-1-4 (1 g, 2.72 mmol), methylamine (338 mg, 3.27 mmol, 30% purity), and DIPEA (879 mg, 6.80 mmol, 1.19 mL) were dissolved in ethanol (15 mL). The reaction solution was heated to 50 °C and reacted for 16 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, DCM / MeOH = 10 / 1) to give a red oily substance (20 g, yield: 76.7%).

[0505] 1 H NMR(400MHz,Chloroform-d)δ8.04-7.98(m,2H),7.28(s,1H),7.26(s,1H),3.13(br s,4H),2.73(br s,4H),2.48(s,3H)

[0506] Step 5: Synthesis of compound int_55-1:

[0507]

[0508] Int_55-1-5 (1 g, 4.85 mmol) was dissolved in methanol (20.0 mL), and 10% Pd / C (500 mg, 4.85 mmol) was added. The reaction mixture was reacted at room temperature for 16 hours under a hydrogen atmosphere (15.0 Psi.). LC-MS monitoring showed that the reaction was complete. The reaction mixture was filtered to give a white solid (800 mg, yield: 93.6%).

[0509] 1 H NMR (400MHz, Methanol-d4) δ6.86 (d, J=7.8Hz, 1H), 6.58-6.49 (m, 2H), 2.82 (br s, 4H), 2.57 (br s, 4H), 2.36 (s, 3H)

[0510] ESI-MS m / z: 177 [M+H] +

[0511] Step 6: Synthesis of Compound 55:

[0512]

[0513] Int_1-8 (200 mg, 0.57 mmol) was dissolved in DMF (10 mL), and int_55-1 (99 mg, 0.562 mmol) and trifluoroacetic acid (226 mg, 2.2 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 16 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 (42 mg, yield: 16.2%).

[0514] 1 H NMR(400MHz,Chloroform-d)δ8.34(s,1H),7.62(s,2H),7.23(s,1H),7.23(s,2H ),7.06(s,2H),6.55(s,1H),3.34(s,6H),3.13(s,4H),2.91(s,4H),2.60(s,3H).

[0515] ESI-MS m / z: 463 [M+H] +

[0516] Example 18 Synthesis of Compound 60

[0517]

[0518] Step 1: Synthesis of compound int_60-1-2:

[0519]

[0520] 1.9 g (10.7 mmol) of int_60-1-1 was dissolved in acetonitrile (8 mL), followed by the addition of a tetrahydrofuran solution of dimethylamine (2.0 M, 5.9 mL) and triethylamine (3.25 g, 32.1 mmol). After reacting for 10 minutes, sodium borohydride acetate (6.8 g, 32.1 mmol) was added, and the reaction was stirred for 16 hours. LC-MS monitoring showed that the reaction was complete. Water (100 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was then subjected to column chromatography (SiO2, DCM:MeOH = 100:1 to 20:1) to give a white solid (1.2 g, yield: 55%).

[0521] ESI-MS m / z: 207 [M+H] +

[0522] Step 2: Synthesis of compound int_60-1:

[0523]

[0524] Int_60-1-2 (900 mg 4.36 mmol) was dissolved in methanol (20.0 mL), and 10% Pd / C (150 mg) was added. The reaction mixture was reacted at room temperature for 16 hours under a hydrogen atmosphere (15.0 Psi.). LC-MS monitoring showed that the reaction was complete. The reaction mixture was filtered to give a white solid (700 mg, yield: 91%).

[0525] ESI-MS m / z: 177 [M+H] +

[0526] Step 3: Synthesis of Compound 60:

[0527]

[0528] Int_1-8 (600 mg, 1.59 mmol) was dissolved in DMF (30 mL), and int_60-1 (258 mg, 1.46 mmol) and trifluoroacetic acid (365 mg, 3.2 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 16 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 (530 mg, yield: 72%).

[0529] 1 H NMR(400MHz,Chloroform-d)δ8.35(s,1H),7.68-7.59(m,2H),7.45(s,2H),7.33(s,1H),7.22(d,J=8.5Hz,1H),7. 15(d,J=8.1Hz,1H),6.56(dd,J=7.9,0.7Hz,1H),3.35(s,6H),3.35-3.25(m,1H),3.15-2.98(m,4H),2.43(s,6H).

[0530] ESI-MS m / z: 463 [M+H] +

[0531] Example 19 Synthesis of Compound 61

[0532]

[0533] Step 1: Synthesis of Compound 61:

[0534]

[0535] Int_1-8 (67 mg, 0.2 mmol) was dissolved in DMF (5 mL), and int_61-1 (57 mg, 0.3 mmol) and trifluoroacetic acid (92 mg, 0.8 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 16 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 (38 mg, yield: 39%).

[0536] 1 H NMR(400MHz,Chloroform-d)δ8.32(s,1H),7.62(s,2H),7.36(d,J=8.6Hz,4H),6.91(d,J=9.0Hz ,2H),6.53(d,J=7.9Hz,1H),3.33(s,6H),3.24-3.16(m,4H),2.58(t,J=5.0Hz,4H),2.35(s,3H).

[0537] ESI-MS m / z: 478 [M+H] +

[0538] Example 20 Synthesis of Compound 62

[0539]

[0540] Step 1: Synthesis of Compound 62:

[0541]

[0542] Int_1-8 (67 mg, 0.2 mmol) was dissolved in DMF (5 mL), and int_62-1 (55 mg, 0.2 mmol) and trifluoroacetic acid (115 mg, 1 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 16 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 (40 mg, yield: 35%).

[0543] 1H NMR(400MHz,Chloroform-d)δ8.31(s,1H),7.66(s,2H),7.33(d,J=8.5Hz,4H),6.90(d,J=9.0Hz,2H),6.53(d,J=7.9Hz,1H),3.70(d,J=12.1Hz,2H ),3.33(s,6H),2.75-2.66(m,2H),2.63(s,4H),2.45(s,4H),2.40-2.32( m,1H),2.28(s,3H),1.94(d,J=12.6Hz,2H),1.66(qd,J=12.1,4.0Hz,2H).

[0544] ESI-MS m / z: 561 [M+H] +

[0545] Example 21 Synthesis of Compound 63

[0546]

[0547] Step 1: Synthesis of Compound 63:

[0548]

[0549] Int_1-8 (67 mg, 0.2 mmol) was dissolved in DMF (5 mL), and int_63-1 (39 mg, 0.2 mmol) and trifluoroacetic acid (92 mg, 0.8 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 16 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 (10 mg, yield: 17%).

[0550] 1 H NMR(400MHz,Chloroform-d)δ8.36(s,1H),7.68(d,J=8.0Hz,1H),7.62(s,1H),7.46(t,J=8.2Hz,1H),7.41(s,1H),7.21(d,J=8.1Hz,1H),7.13( s,1H),6.97(d,J=8.1Hz,1H),6.70(dd,J=8.4,2.4Hz,1H),6.54(d,J=7.9Hz,1H),3.34(s,6H),3.27(t,J=5.0Hz,4H),2.70(s,4H),2.44(s,3H).

[0551] ESI-MS m / z: 478 [M+H] +

[0552] Example 22 Synthesis of Compound 64

[0553]

[0554]

[0555] Step 1: Synthesis of compound int_64-3:

[0556]

[0557] Int_64-1 (298 mg, 1.2 mmol), int_64-2 (200 mg, 1.2 mmol), cesium carbonate (782 mg, 2.4 mmol), Pd2(dba)3 (110 mg, 0.12 mmol), and Xantphos (138 mg, 0.24 mmol) were dissolved in 1,4-dioxane (20 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 an orange-yellow solid product (130 mg, yield: 33%).

[0558] ESI-MS m / z: 334 [M+H] +

[0559] Step 2: Synthesis of compound int_64-4:

[0560]

[0561] Int_64-3 (130 mg, 0.39 mmol) was dissolved in dichloromethane (15 mL), and m-CPBA (85%, 92 mg, 0.45 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 washed with sodium bicarbonate aqueous solution (50 mL * 2), the aqueous phase was extracted with ethyl acetate (50 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product (120 mg, crude product). The crude product can be used directly in the next reaction step.

[0562] ESI-MS m / z: 350 [M+H] +

[0563] Step 3: Synthesis of Compound 64:

[0564]

[0565] Int_64-4 (120 mg, 0.34 mmol) was dissolved in DMF (10 mL), and int_3-5 (95 mg, 0.59 mmol) and trifluoroacetic acid (158 mg, 1.56 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 an orange-yellow solid (1.1 g, yield: 70%).

[0566] 1 H NMR(400MHz,Chloroform-d)δ8.27(s,1H),7.49(s,1H),7.23(s,2H),7.07(s,2H),6.98(s,1H ),6.94-6.76(m,1H),3.63-3.31(m,2H),3.10(s,5H),2.83(s,2H),2.63(s,2H),2.40(s,3H).

[0567] LC-MS: 448 [M+H] +

[0568] Example 23 Synthesis of Compound 77

[0569]

[0570] Step 1: Synthesis of compound int_77-2:

[0571]

[0572] Int_77-1 (350 mg, 1.174 mmol), int_1-3 (110 mg, 1.174 mmol), cesium carbonate (574 mg, 1.761 mmol), Pd2(dba)3 (54 mg, 0.059 mmol), and Xantphos (68 mg, 0.117 mmol) were dissolved in 1,4-dioxane (15 mL), and the reaction mixture was reacted overnight at 80 °C. LC-MS monitoring showed that the reaction was complete. The reaction mixture was filtered and distilled under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to give a pale yellow solid product (374 mg, yield: 89%). ESI-MS m / z: 311 [M+H] +

[0573] Step 3: Synthesis of compound int_77-3:

[0574]

[0575] Int_77-2 (374 mg, 1.174 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (8 mL) was added. The reaction was carried out at room temperature for 1 hour, 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 (252 mg, crude product). The crude product can be used directly in the next reaction.

[0576] ESI-MS m / z: 211 [M+H] +

[0577] Step 4: Synthesis of compound int_77-5:

[0578]

[0579] Int_77-3 (252 mg, 1.2 mmol) and int_77-4 (209 mg, 1.2 mmol) were dissolved in DMF (12 mL), and DIPEA (3.1 g, 24 mmol) 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 filtered and distilled under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain the final product (133 mg, yield: 31.9%).

[0580] ESI-MS m / z: 348 [M+H] +

[0581] Step 5: Synthesis of Compound 77:

[0582]

[0583] Int_77-5 (330 mg, 0.95 mmol) was dissolved in DMF (20 mL), and int_3-5 (162 mg, 1 mmol) and trifluoroacetic acid (342 mg, 3 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 (150 mg, yield: 33%).

[0584] 1H NMR(400MHz,Chloroform-d)δ8.37(s,1H),7.67(d,J=8.0Hz,1H),7.28(d,J=2.1Hz,1H),7.22-7.13(m,1H),7.06(d,J=8.2Hz,1H),6.97(t,J= 8.0Hz,1H),6.85(d,J=7.9Hz,1H),4.45(t,J=8.3Hz,2H),3.52(s,2H),3.16(m,8H),2.90(t,J=6.0Hz,2H),2.70(t,J=5.9Hz,2H),2.44(s,3H).

[0585] ESI-MS m / z: 474 [M+H] +

[0586] Example 24 Synthesis of Compound 78

[0587]

[0588] Step 1: Synthesis of compound int_78-2:

[0589]

[0590] Dissolve int_78-1 (2.7 g, 13.77 mmol) in DCE (60 mL). Under nitrogen protection, add methyl magnesium bromide in THF solution (3.0 M, 4.6 mL) at 0 °C. After the addition is complete, stir for 30 minutes. Then add int_1-6 (2.56 g, 13.77 mmol). The reaction mixture is brought to room temperature and stirred overnight. LC-MS monitoring shows that the reaction is complete. Pour the reaction mixture into ice water, and the solid precipitates. Filter to obtain the crude product (1.6 g, yield: 34%). The crude product can be used directly in the next reaction.

[0591] ESI-MS m / z: 345 [M+H] +

[0592] Step 2: Synthesis of compound int_78-3:

[0593]

[0594] Int_78-2 (1 g, 2.9 mmol) was dissolved in DMF (50 mL). Under nitrogen protection, NaH (60% inocyanate, 140 mg, 3.5 mmol) was added at 0 °C. After the addition was complete, the mixture was stirred for 30 minutes. Then, SEMCl (584 mg, 3.5 mmol) was added, and the reaction mixture was heated to room temperature and stirred overnight. LC-MS monitoring showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, DCM:MeOH = 100:1 to 20:1) to give a pale yellow solid (500 mg, yield: 36%). ESI-MS m / z: 475 [M+H] +

[0595] Step 3: Synthesis of compound int_78-4:

[0596]

[0597] Int_78-3 (500 mg, 1.05 mmol), int_1-3 (587 mg, 6.32 mmol), cesium carbonate (855 mg, 2.63 mmol), Pd2(dba)3 (96 mg, 0.105 mmol), and Xantphos (73 mg, 0.126 mmol) were dissolved in DMF (20 mL). The mixture was reacted overnight at 85 °C under nitrogen protection. 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 20:1) to give a pale yellow solid product (500 mg, yield: 97%).

[0598] ESI-MS m / z: 488 [M+H] +

[0599] Step 4: Synthesis of compound int_78-5:

[0600]

[0601] Int_78-3 (250 mg, 0.5 mmol) was dissolved in dichloromethane (20 mL), and m-CPBA (85%, 153 mg, 0.75 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. Water (100 mL) was added to the reaction solution, and the aqueous phase was extracted with dichloromethane (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product (200 mg, crude product). The crude product can be used directly in the next reaction step.

[0602] ESI-MS m / z: 504 [M+H] +

[0603] Step 5: Synthesis of compound int_78-6:

[0604]

[0605] Int_78-5 (252 mg, 0.5 mmol) was dissolved in DMF (10 mL), and int_3-5 (81 mg, 0.5 mmol) and trifluoroacetic acid (57 mg, 0.5 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 16 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 column chromatography (SiO2, DCM:MeOH = 100:1 to 20:1) to give a pale yellow solid (100 mg, yield: 33%).

[0606] ESI-MS m / z: 602 [M+H] +

[0607] Step 6: Synthesis of Compound 78:

[0608]

[0609] Int_78-6 (100 mg, 0.17 mmol) was dissolved in THF (5 mL), and TBAF (536 mg, 1.7 mmol) was added. The reaction mixture was heated to 80 °C and stirred for 16 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 pale yellow solid (2 mg, yield: 2.5%).

[0610] ESI-MS m / z: 472 [M+H] +

[0611] Example 25 Synthesis of Compound 79

[0612]

[0613] Step 1: Synthesis of compound int_79-1:

[0614]

[0615] Int_78-2 (220 mg, 0.637 mmol) was dissolved in DMF (10 mL). Under nitrogen protection, NaH (60% in oil, 40 mg, 1 mmol) was added at 0 °C. After the addition was complete, the mixture was stirred for 10 minutes, and then iodomethane (117 mg, 0.828 mmol) was added. The reaction mixture was brought to room temperature and stirred overnight. LC-MS monitoring showed that the reaction was complete. The reaction mixture was poured into ice water, and a solid precipitated. The solid was filtered to obtain the crude product (160 mg, yield: 70%). The crude product can be used directly in the next reaction step.

[0616] ESI-MS m / z: 359 [M+H] +

[0617] Step 2: Synthesis of compound int_79-2:

[0618]

[0619] Int_79-1 (160 mg, 0.445 mmol), int_1-3 (84 mg, 0.9 mmol), cesium carbonate (362 mg, 1.11 mmol), Pd2(dba)3 (4 mg, 0.0445 mmol), and Xantphos (3 mg, 0.0534 mmol) were dissolved in DMF (10 mL). The mixture was reacted overnight at 85 °C under nitrogen protection. LC-MS monitoring showed that the reaction was complete. The reaction solution was poured into ice water, and the solid precipitated. Filtration yielded the crude product (100 mg, yield: 60%). The crude product could be used directly in the next reaction step.

[0620] ESI-MS m / z: 372 [M+H] +

[0621] Step 3: Synthesis of compound int_79-3:

[0622]

[0623] 100 mg (0.27 mmol) of int_79-2 was dissolved in 10 mL of dichloromethane and 10 mL of DMF. Then, 70 mg (0.4 mmol) of m-CPBA was added at room temperature, and the mixture was stirred for 30 minutes at room temperature. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product can be used directly in the next reaction step.

[0624] ESI-MS m / z: 388 [M+H] +

[0625] Step 5: Synthesis of Compound 79:

[0626]

[0627] Int_79-3 (100 mg, 0.26 mmol) was dissolved in DMF (10 mL), and int_3-5 (65 mg, 0.4 mmol) and trifluoroacetic acid (62 mg, 0.54 mmol) were added. The reaction mixture was heated to 80 °C and stirred for 16 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 pale yellow solid (2 mg, yield: 15.8%).

[0628] ESI-MS m / z: 486 [M+H] +

[0629] Example 26 Synthesis of Compound 80

[0630]

[0631] Step 1: Synthesis of compound int_80-2:

[0632]

[0633] Int_80-1 (250 mg, 1.269 mmol) was dissolved in dichloromethane (20 mL), and DIPEA (655 mg, 5.075 mmol), DMAP (50 mg, 0.41 mmol), and (Boc)₂O (325 mg, 2.538 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 * 1). 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:EA = 10:1) to obtain the product (320 mg, yield: 85%).

[0634] ESI-MS m / z: 197 [M+H] + .

[0635] Step 2: Synthesis of compound int_80-3:

[0636]

[0637] Int_80-2 (1.03 g, 3.468 mmol), int_1-3 (323 mg, 3.468 mmol), cesium carbonate (1.677 g, 5.202 mmol), Pd2(dba)3 (160 mg, 0.173 mmol), and Xantphos (201.6 mg, 0.346 mmol) were dissolved in 1,4-dioxane (50 mL). The mixture was reacted overnight at 85 °C under nitrogen protection. 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 further processed by HPLC to obtain a solid product (640 mg, yield: 60%). ESI-MS m / z: 310 [M+H] +

[0638] Step 3: Synthesis of compound int_80-4:

[0639]

[0640] Int_80-3 (640 mg, 2.069 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature for 1 hour, and LC-MS monitoring showed that the reaction was complete. The reaction solution was directly concentrated under reduced pressure to obtain the crude product (600 mg, crude product). The crude product can be used directly in the next reaction step.

[0641] ESI-MS m / z: 210 [M+H] +

[0642] Step 4: Synthesis of compound int_80-5:

[0643]

[0644] Int_80-4 (600 mg, 2.87 mmol) and int_1-6 (630 mg, 3.4 mmol) were dissolved in DMF (10 mL), and DIPEA (661 mg, 5.8 mmol) 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 filtered and distilled under reduced pressure to obtain the crude product. The crude product was subjected to preparative HPLC to obtain a solid product (320 mg, yield: 53%).

[0645] ESI-MS m / z: 359 [M+H] +

[0646] Step 5: Synthesis of compound int_80-6:

[0647]

[0648] Int_80-5 (95 mg, 0.265 mmol) was dissolved in dichloromethane (20 mL), and m-CPBA (85%, 70 mg, 0.345 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 (90 mg, crude product). The crude product can be used directly in the next reaction step.

[0649] ESI-MS m / z: 375 [M+H] +

[0650] Step 6: Synthesis of Compound 80:

[0651]

[0652] Int_80-6 (90 mg, 0.161 mmol) was dissolved in dichloromethane (5 mL), and int_3-5 (298 mg, 1.2 mmol) and trifluoroacetic acid (91 mg, 0.8 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 (37 mg, yield: 48.7%).

[0653] 1 H NMR(400MHz,Chloroform-d)δ8.73(d,J=26.1Hz,2H),7.81(s,1H),7.61(s,1H),7.37(s,1H),7.14(dd,J=22.2,7. 0Hz, 4H), 3.50 (d, J = 17.6Hz, 2H), 3.31 (s, 6H), 2.92 (t, J = 6.0Hz, 2H), 2.70 (t, J = 6.0Hz, 2H), 2.45 (d, J = 5.1Hz, 3H).

[0654] ESI-MS m / z: 473 [M+H] +

[0655] Synthesis of compounds 2, 4, 5, 10, 14, 15, 17, 18, 20, 21, 23, 28, 30, 41, 44, 51, 53, 54, 56, 59, 65, 76, and 80-160 in Examples 27-160

[0656] Using the above synthetic method and different raw materials, the target compounds 2, 4-5, 10, 14-15, 17-18, 20-21, 23-28, 30-41, 44-51, 53-54, 56-59, 65-76, and 80-160 in Table 1 can be obtained.

[0657] The LC-MS analysis method is as follows:

[0658] Instrument: Agilent LC:1260 InfinityII + MS: G6125B

[0659] Chromatographic column: Welch: Core-shell 2.7um 4.3*50mm

[0660] Column temperature: 30℃

[0661] Wavelength: 254nm / 214nm

[0662] Mobile phase A: H2O (0.1% formic acid)

[0663] Mobile phase B: Acetonitrile (0.1% formic acid)

[0664] gradient:

[0665] 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

[0666] Table 1

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675] Table 2. NMR data of some compounds in Table 1

[0676]

[0677]

[0678]

[0679]

[0680]

[0681]

[0682] Example 161: In vitro inhibition assay of recombinant protein Wee-1 enzyme activity by the compounds of the present invention.

[0683] The inhibitory effect of the compound on the activity of recombinant protein Wee-1 was determined using the HTRF method. Details are as follows.

[0684] 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. 50 The results are shown in Table 3 below.

[0685] Table 3. Inhibitory activity of the compounds of the present invention against recombinant protein Wee-1

[0686] compound <![CDATA[(IC 50 )]]> compound <![CDATA[(IC 50 )]]> compound <![CDATA[(IC 50 )]]> compound <![CDATA[(IC 50 )]]> 1 +++ 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 + 11 +++ 12 +++

[0687] 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 +++ 123 +++ 124 +++ 125 +++ 126 +++ 127 +++ 128 +++ 129 +++ 130 +++

[0688] 131 +++ 132 +++ 133 +++ 134 +++ 135 +++ 136 +++ 137 +++ 138 +++ 139 +++ 140 +++ 141 +++ 142 +++ 143 +++ 144 +++ 145 + 146 +++ 147 +++ 148 +++ 149 +++ 150 ++ 151 +++ 152 +++ 153 +++ 154 +++ 155 +++ 156 +++ 157 +++ 158 +++ 159 +++ 160 +++

[0689] +++ indicates IC 50 Less than or equal to 10 nM

[0690] ++ indicates IC 50 10 nM to 50 nM

[0691] + indicates IC 50 Greater than 50 nM.

[0692] As shown in Table 3, the compounds of this invention have good inhibitory activity against the enzyme activity of recombinant protein Wee-1.

[0693] Example 162: In vitro antiproliferative activity of the compounds of the present invention against MIA PaCa-2 cells.

[0694] 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 Values, results are shown in Table 4 below. Table 4 Antiproliferative activity of the compounds of the present invention against MIA PaCa-2 cells

[0695] compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> compound <![CDATA[IC 50 (nM)]]> 1 735 2 398 3 879 4 >5000 5 >5000 6 3720 7 >5000 8 >5000 9 669 10 1620 11 205 12 222 13 400 14 47 15 198 16 501 17 266 18 116 19 227 20 913 22 296 25 413 28 422 29 285 41 >5000 42 368 43 460 52 153 55 185 60 247 61 243 62 203 63 256 64 1840 77 >5000 78 >5000 79 1040 80 >5000 85 >5000 87 184 97 137 101 213 105 135 106 >5000

[0696] 107 254 108 1542 111 230 112 1209 113 570 115 256 116 470 117 92 118 134 119 125 120 180 121 204 122 63 123 101 124 193 127 301 128 142 129 216 130 685 131 1038 133 14 137 1311 145 >5000 146 217 147 2210 148 292 150 460 152 186 153 110 154 123 155 112 156 209

[0697] 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.

[0698] Example 163: In vitro antiproliferative activity of the compound of the present invention in combination with gemcitabine against MIA PaCa-2 cells.

[0699] 3000 MIA PaCa-2 cells / well were seeded in 384-well plates and 20 nM or 200 nM Gemcitabine (GMC) 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.

[0700] Table 5. In vitro antiproliferative activity of the compounds of this invention in combination with gemcitabine against MIA PaCa-2 cells.

[0701]

[0702]

[0703] 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.

[0704] Example 164 In vivo efficacy study – Mouse HT29 subcutaneous xenograft model

[0705] HT29 is a colon cancer cell line. Each nude mouse was subcutaneously inoculated with 5 x 10⁵ cells. 6 HT29 cells were used. When the tumors reached 100-200 mm³, the compound was administered orally once daily, either alone or in combination with 15 mg / kg Gemcitabine 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 20 of the treated group - tumor volume on day 1 of the treated group) / (tumor volume on day 20 of the solvent control group - tumor volume on day 1 of the treated group). The results are shown in Tables 6 and 7.

[0706] Table 6. Growth inhibition rate of HT29 subcutaneous xenograft tumors in mice – single drug

[0707]

[0708] Table 7. Growth inhibition rate of HT29 subcutaneous xenografts in mice – in combination with 15 mg / kg Gemcitabine

[0709]

[0710] Example 165 In vivo efficacy study – Mouse HT29 subcutaneous xenograft model

[0711] HT29 is a colon cancer cell line. Each nude mouse was subcutaneously inoculated with 5 x 10⁵ cells. 6 HT29 cells were induced to develop tumors. When the tumors reached 100-200 mm³, the compound was administered orally once daily in combination with 30 mg / kg Gemcitabine intraperitoneally once 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 20 of the treated group - tumor volume on day 1 of the treated group) / (tumor volume on day 20 of the solvent control group - tumor volume on day 1 of the treated group). The results are shown in Table 8.

[0712] Table 8. Growth inhibition rate of HT29 subcutaneous xenografts in mice – and the effect of combination with 30 mg / kg Gemcitabine

[0713] compound dose Tumor volume on day 1 of drug administration Tumor volume on day 20 of drug administration TGI

[0714] <![CDATA[(mm 3 )]]> <![CDATA[(mm 3 )]]> Comparison not applicable 121 1457 not applicable Gemcitabine 30mg / kg 121 653 60％ Compound 14 30mg / kg 121 38 106％ Compound 18 30mg / kg 121 218 92％ Compound 87 30mg / kg 121 395 79％ Compound 97 30mg / kg 121 278 88％ Compound 101 30mg / kg 121 95 102％ Compound 117 30mg / kg 121 283 87％ Compound 128 30mg / kg 121 284 87％

[0715] As can be seen from Tables 6, 7 and 8, when the compounds of the present invention are used as single drugs, they can inhibit tumor growth in the HT29 mouse subcutaneous xenograft model. When the compounds of the present invention are used in combination with Gemcitabine, they show a more significant inhibitory effect on tumor growth.

[0716] 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 is a halogen, -CN, or (C2-C6) alkynyl group; Z is -NH-; Ring A is (C6-C10) aryl or (5-10-membered) heteroaryl, wherein the (5-10-membered) heteroaryl is an aromatic group containing one or more heteroatoms N, and the heteroaryl is monocyclic or polycyclic; R 1 and R 2 Each is independently (C1-C6) alkyl; or R 1 and R 2 The S atoms attached thereto can collectively form a (4-7) heterocyclic alkyl group, wherein the (4-7) heterocyclic alkyl group is a non-aromatic ring or ring system having at least one heteroatom ring member that is independently sulfur. Each R 3 Independently -H, -D, halogen, -(CH2) n OR 8 (C1-C6)alkyl or (C2-C6)alkenyl; or two adjacent R groups 3 The atoms to which they are attached can collectively form (5-9-membered) heterocyclic alkyl or (C5-C9) cycloalkyl, wherein the (5-9-membered) heterocyclic alkyl is a non-aromatic ring or cyclic system having at least one heteroatom ring member that is independently nitrogen. Ring B is (C6-C10) aryl or (5-10) heteroaryl, wherein the (5-10) heteroaryl is an aromatic group containing one or more heteroatoms N, and the heteroaryl is monocyclic or polycyclic; Each R 4 Independently -H, halogen, -(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, (C1-C6)alkoxy, -CH2-(3-15)heterocyclic alkyl, (3-15)heterocyclic alkyl, (5-9)heteroaryl or (C6-C10)aryl, wherein the -CH2-(3-15)heterocyclic alkyl or (3-15)heterocyclic alkyl is a non-aromatic ring or cyclic system, optionally Containing one or more alkenyl groups as part of a ring structure, having at least one heteroatom ring member independently selected from nitrogen and oxygen, wherein the (5-9-membered) heteroaryl group is an aromatic group containing one or more heteroatoms O or N, and the heteroaryl group is monocyclic or polycyclic, wherein the (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C9)cycloalkyl, (3-15-membered) heterocycloalkyl, or (5-9-membered) heteroaryl group is optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -(CH2). n OR 8 (C1-C6)alkyl, (C3-C9)cycloalkyl, (C1-C6)alkoxy, (3-15)heterocyclic alkyl and -R 7 The (3-15) heterocyclic alkyl group is a non-aromatic ring or cyclic system having at least one heteroatom ring member independently selected from nitrogen and oxygen; or two adjacent R 4 The atoms to which they are attached can collectively form a (5-9 membered) heterocyclic alkyl or (C5-C9) cycloalkyl group, wherein the (5-9 membered) heterocyclic alkyl group is a non-aromatic ring or ring system, optionally containing one or more alkenyl groups as part of the ring structure, having at least one heteroatom ring member independently selected from nitrogen, sulfur, and oxygen, and wherein the (5-9 membered) heterocyclic alkyl or (C5-C9) cycloalkyl group is optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -(CH2). n OR 8 -(CH2) n NR 8 R 9 , (C1-C6)alkyl, (C3-C9)cycloalkyl, (C1-C6)alkoxy and (4-9)heterocyclic alkyl, wherein the (4-9)heterocyclic alkyl is a non-aromatic ring or cyclic system having at least one heteroatom ring member that is independently nitrogen; R 7 (3-11 membered)heterocycloalkyl, wherein the (3-11 membered)heterocycloalkyl group is a non-aromatic ring or ring system having at least one heteroatom ring member that is independently nitrogen, the heterocycloalkyl group being optionally substituted with 1, 2, 3, or 4 of the following groups: -H and R 8 ; R 8 and R 9 each independently -H or (Ci-C6)alkyl; and, q is an integer of 1, 2, 3 or 4, r is an integer of 1, 2 or 3, s is an integer of 1, 2, 3 or 4, and n is an integer of 0, 1, 2 or 3.

2. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), Y is -F, -Cl, -Br, -I, -CN or (C2-C3) alkynyl.

3. The compound of claim 2 or an optical isomer or a pharmaceutically acceptable salt thereof, wherein Y in the general formula (1) is: -F, -CI, -Br, -I, -CN or .

4. The compound of any one of claims 1-3, or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), ring A is: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

5. The compound of claim 4, or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), ring A is: , , , , or .

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

7. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), R 1 and R 2 Each is independently (C1-C3) alkyl; or R 1 and R 2 The S atoms attached thereto can collectively form a (4-6) heterocyclic alkyl group, wherein the (4-6) heterocyclic alkyl group is a non-aromatic ring or ring system having at least one heteroatom ring member that is independently sulfur.

8. The compound of claim 7 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), each R 3 Independently -H, -D, -F, -Cl, -Br, -I, -CH2OR 11 -OR 11 (C1-C3)alkyl or (C2-C4)alkenyl; or two adjacent R groups 3 The atoms to which they are attached can collectively form (5-7 member) heterocyclic alkyl or (C5-C7) cycloalkyl; wherein the (5-7 member) heterocyclic alkyl is a non-aromatic ring or cyclic system having at least one independent nitrogen heteroatom ring member, R 11 It is -H or (C1-C3) alkyl.

10. The compound of claim 9 or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), each R 3 Independently: -H, -D, -F, -Cl, -Br, -I, -CH2OCH3, -OCH3 , , , , , or .

11. The compound of claim 10, or an optical isomer or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), each R 3 is independently: -H, -F, -OCH3, or .

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

13. The compound of claim 1 or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), ring B is: , , , , , , , , , , , , , , , or .

14. The compound of claim 1 or its optical isomer or pharmaceutically acceptable salt, wherein in the general formula (1), each R 4 Independently -H, -F, -Cl, -Br, -I, -CH2OR 11 -(CH2)2OR 11 -(CH2)3OR 11 -OR 11 -CH2NR 11 R 12 -(CH2)2NR 11 R 12 -(CH2)3NR 11 R 12 -NR 11 R 12 -CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C2-C4)alkenyl, (C2-C4)ynyl, (C3-C6)cycloalkyl, (C1-C4)alkoxy, -CH2-(4-11)heterocyclic alkyl, (4-11)heterocyclic alkyl, (5-9)heteroaryl or (5-9)aryl, wherein the -CH2-(4-11)heterocyclic alkyl or (4-11)heterocyclic alkyl is a non-aromatic ring or ring system, optionally containing one or more alkenyl groups as part of the ring structure, having a... The (5-9-membered) heteroaryl group is an aromatic group containing one or more heteroatoms O or N, and is monocyclic or polycyclic. The (C1-C4) alkyl, (C2-C4) alkenyl, (C3-C6) cycloalkyl, (4-11-membered) heterocycloalkyl, or (5-9-membered) heteroaryl group may be independently and optionally substituted with 1, 2, 3, or 4 of the following groups: -H, OH, -CH2OCH3, -(CH2)2OCH3, -OCH3, -OCH2CH3, -OCH(CH3)2. , , , , , , , , , , , , , , , and ; or two adjacent Rs on ring B 4 The atoms bonded to each other can collectively form a (5-7 member) heterocyclic alkyl or (C5-C7) cycloalkyl group, wherein the (5-7 member) heterocyclic alkyl group is a non-aromatic ring or ring system, optionally containing one or more alkenyl groups as part of the ring structure, and having at least one heteroatom ring member independently selected from nitrogen, sulfur, and oxygen. The (5-7 member) heterocyclic alkyl or (C5-C7) cycloalkyl group may be independently and optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2. , , , , , , , , , , , , , , , , , , , , , , and ;where R 11 and R 12 Each is independently -H or (C1-C3) alkyl.

15. The compound of claim 14 or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), each R 4 Independently, -H, -F, -Cl, -Br, -I, -CH2OCH3, -(CH2)2OCH3, -(CH2)3OCH3, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH2NH2, -(CH2)2NH2, -(CH2)3NH2, -OCH3, -OCH2CH3, -OCH(CH3)2, -OCF3, -OCF2H, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2, -CN, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

16. The compound of claim 14 or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), each R 4 Independently or .

17. The compound of claim 14, or an optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein in the general formula (1), two adjacent R on the B ring... 4 The atoms to which they are attached can collectively form a (5-7 member) heterocyclic alkyl group, wherein the (5-7 member) heterocyclic alkyl group is: , , , , , or ; or two adjacent Rs on ring B 4 The atoms they are attached to can collectively form a (C5-7) cycloalkyl group, wherein the (5-7) cycloalkyl group is: , or ; and wherein the heterocyclic alkyl and cycloalkyl groups are optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -CH2OCH3, -(CH2)2OCH3, -(CH2)2OH, -OCH3, -OCH2CH3, -OCH(CH3)2, -CH2N(CH3)2, -(CH2)2N(CH3)2, -N(CH3)2. , , , , , , , , , , , , , , , and .

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

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

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

21. A compound or its optical isomer or pharmaceutically acceptable salt, wherein said compound has one of the following structures: , , , , , , , , , , , , , , , , or .

22. A pharmaceutical composition comprising, It contains a pharmaceutically acceptable excipient or carrier, and a compound or its optical isomer or pharmaceutically acceptable salt as any one of claims 1-21 as the active ingredient.

23. The use of a compound as described in any one of claims 1-21, an optical isomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 22, in the preparation of a medicament for treating related diseases mediated by Wee-1 protein kinase.

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