Compound which acts as MYT1 inhibitor

Abstract

Disclosed are a class of compounds which act as MYT1 inhibitors. Particularly, the present invention relates to a compound represented by general formula (1) and a preparation method therefor, as well as a use of the compound represented by general formula (1), and an isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof as an MYT1 inhibitor. The compounds of the present invention as well as the isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof can be used for preparing a medicament for treating or preventing diseases related to MYT1 protein.

Description

Compounds as MYT1 inhibitors

[0001] This application claims priority to Chinese patent application CN2023114307283, filed on October 31, 2023. This application incorporates the entire text of the aforementioned Chinese patent application. Technical Field

[0002] The present invention belongs to the field of medicinal chemistry, and more specifically, relates to a class of compounds with MYT1 protein inhibitory effects, as well as a preparation method thereof and the use of such compounds in preparing drugs for treating or preventing MYT1-mediated diseases. Background Art

[0003] The cell cycle includes two checkpoints, G1 and G2, which enable cells to effectively repair DNA damage and maintain genomic stability. Both Wee1 and MYT1, members of the Wee kinase family, are involved in regulating this cell cycle. MYT1 is primarily located in the cell nucleus and specifically phosphorylates its substrate, CDK1 (cyclin-dependent kinase 1), at Threonine 14. This MYT1-mediated phosphorylation inhibits the activity of the CDK1 / cyclin B complex, thereby preventing cells from entering mitosis. Because many tumor cells carry p53 mutations that result in defects in G1 checkpoint repair, these cells are highly dependent on the G2 checkpoint for DNA damage repair. Therefore, inhibiting MYT1 activity to disrupt the G2 checkpoint, thereby selectively damaging G2-dependent tumor cells while minimizing damage to normal cells, is a promising targeted strategy. Therefore, there is an urgent need to research and discover compounds with potent MYT1-targeting activity.

[0004] Summary of the Invention

[0005] The present invention provides a compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:

[0006] In the general formula (1):

[0007] Ring A is: + indicates connection with carbonyl group, * indicates connection with connected;

[0008] R 1is -H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, (5-10 membered) heteroaryl, -N(R 3 )2、-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 )2, -SO2R 3a or -QR 3b wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl or (3-9 membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, and (5-10 membered)heteroaryl;

[0009] Ring B is (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl or (5-10 membered)heteroaryl;

[0010] Each R 2 Each is independently -H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, (5-10 membered) heteroaryl, -N(R 3 )2、-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 )2, -SO2R 3a or -QR 3b wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl or (3-9 membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5)2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, and (5-10 membered)heteroaryl; or two R on the same carbon atom 2 The carbon atom to which it is attached may form a (C4-C9)cycloalkyl, (C4-C9)cycloalkenyl, (4-9-membered)heterocycloalkyl, phenyl or (5-10-membered)heteroaryl group, wherein said (C4-C9)cycloalkyl, (C4-C9)cycloalkenyl, (4-9-membered)heterocycloalkyl, phenyl or (5-10-membered)heteroaryl group may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl and (C3-C8) cycloalkyl; or two R on the same carbon atom 2 Can form with the carbon atom to which it is attached

[0011] R A 、R B and R C Each independently represents -H, -OH, -OR 3 , halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl; or R B 、R C The carbon atoms to which they are attached constitute (C4-C10)cycloalkyl, (4-10 membered)heterocycloalkyl, phenyl or (5-10 membered)heteroaryl, wherein said (C4-C10)cycloalkyl, (4-10 membered)heterocycloalkyl, phenyl or (5-10 membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 3 、-N(R 3 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C8)cycloalkyl;

[0012] Each R 3 are independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl, -SO2R 3awherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl or (3-9 membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy or halogen; or two R on the same nitrogen atom 3 Together with the nitrogen atom attached thereto, they can form a (3-9 membered) heterocycloalkyl group, wherein said (3-9 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C8)cycloalkyl;

[0013] Each R 3a is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl, or (5-10-membered)heteroaryl, wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl, or (5-10-membered)heteroaryl group may each independently be optionally substituted with 1, 2, 3, or 4 of the following groups: -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen;

[0014] Each R 3b are independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl, -N(R 3 )2、-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 )2 or -SO2R 3a wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl or (3-9 membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5)2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, and (5-10 membered)heteroaryl;

[0015] Q is (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene, (3-9-membered)heterocycloalkylene, (C6-C10)arylene, or (5-10-membered)heteroarylene, wherein said (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene, (C6-C10)arylene, (5-10-membered)heteroarylene, or (3-9-membered)heterocycloalkylene may each independently be optionally substituted with 1, 2, 3, or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, and (5-10 membered)heteroaryl;

[0016] Each R 4 R is independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl, or (5-10-membered)heteroaryl, wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl, or (5-10-membered)heteroaryl may each independently be optionally substituted with 1, 2, 3, or 4 of -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy, or halogen; or two R on the same nitrogen atom 4 Together with the nitrogen atom attached thereto, they can form a (3-9 membered) heterocycloalkyl group, wherein said (3-9 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C8)cycloalkyl;

[0017] Each R 5are independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl, -SO2R 3a wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl or (3-9 membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy or halogen; or two R on the same nitrogen atom 5 together with the nitrogen atom to which it is attached, may form a (3-9 membered) heterocycloalkyl group, wherein said (3-9 membered) heterocycloalkyl group may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -CN, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C8)cycloalkyl; and

[0018] n is an integer of 0, 1, 2, 3, 4 or 5.

[0019] In another preferred embodiment, wherein in the general formula (1), R 1 is -H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, (5-10 membered) heteroaryl, -N(R 3 )2、-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 )2, -SO2R 3a or -QR 3b wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl or (3-9 membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, aryl and (5-6 membered)heteroaryl.

[0020] In another preferred embodiment, wherein in the general formula (1), R 1 are: -H, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, -C(O)N(CH3)2, -C(O)NH(CH3), -C(O)NH2, -SO2N(CH3)2, -SO2NH(CH3), -SO2NH2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -CF3, -CH2CF3, -OCF3, -OCH2CH3, -OCH(CH3)2,

[0021] In another preferred embodiment, wherein in the general formula (1), ring B is (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl or (5-6 membered) heteroaryl; ring B is preferably (5-6 membered) heterocycloalkyl or (5-6 membered) heteroaryl containing 1, 2 or 3 atoms independently selected from N, O or S, and each of which can be independently optionally replaced by 1

[0022] In another preferred embodiment, wherein in the general formula (1), each R 2 Each is independently -H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, (5-10 membered) heteroaryl, -N(R 3 )2、-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 )2, -SO2R 3a or -QR 3b wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10 membered)heteroaryl or (3-9 membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, aryl and (5-6 membered)heteroaryl.

[0023] In another preferred embodiment, wherein in the general formula (1), each R 2 Each is independently: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, -C(O)N(CH3)2, -C(O)NH(CH3), -C(O)NH2, -SO2N(CH3)2, -SO2NH(CH3), -SO2NH2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -CF3, -CH2CF3, -OCF3, -OCH2CH3, -OCH(CH3)2,

[0024] In another preferred embodiment, wherein in the general formula (1), R A 、R B and R C Each independently represents -H, -OH, -OR 3 , halogen, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl; or R B 、R C and (C4-C6)cycloalkyl, (4-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl, wherein said (C4-C6)cycloalkyl, (4-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl and (C3-C6)cycloalkyl.

[0025] In another preferred embodiment, wherein in the general formula (1), R A 、R B and R C Each independently is -H, -F, -Cl or

[0026] In another preferred embodiment, wherein in the general formula (1), each R 3are independently -H, (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl, (5-6 membered)heteroaryl, -SO2R 3a wherein said (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl or (5-6 membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br or -I; or two R on the same nitrogen atom 3 Together with the nitrogen atom to which it is attached, it can form a (3-6 membered) heterocycloalkyl group, wherein said (3-6 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl and (C3-C6)cycloalkyl.

[0027] In another preferred embodiment, wherein in the general formula (1), each R 3 Independently: -H, -CF3, -CH2CF3, -SO2CH3, -SO2CH2CH3 or -SO2CH(CH3)2.

[0028] In another preferred embodiment, wherein in the general formula (1), each R 3a is independently (C1-C5)alkyl, (C1-C5)haloalkyl, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl, wherein said (C1-C5)alkyl, (C1-C5)haloalkyl, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br, or -I.

[0029] In another preferred embodiment, wherein in the general formula (1), each R 3a Independently: -CF3, -CH2CF3,

[0030] In another preferred embodiment, wherein in the general formula (1), each R 3b are independently (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl, (5-6 membered)heteroaryl, -N(R 3 )2、-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 )2 or -SO2R 3a wherein said (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, phenyl, (5-6 membered)heteroaryl or (3-6 membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl and (5-6 membered)heteroaryl.

[0031] In another preferred embodiment, wherein in the general formula (1), each R 3b are independently: -H, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -C(O)N(CH3)2, -C(O)NH(CH3), -C(O)NH2, -SO2N(CH3)2, -SO2NH(CH3), -SO2NH2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -CF3, -CH2CF3, -OCH2CH3, -OCH(CH3)2,

[0032] In another preferred embodiment, wherein in the general formula (1), Q is (C1-C3) alkylene, (C2-C4) alkenylene, (C2-C4) alkynylene, (C3-C6) cycloalkylene, (3-6 membered) heterocycloalkylene, phenylene or (5-6 membered) heteroarylene, wherein the (C1-C3) alkylene, (C2-C4) alkenylene, (C2-C4) alkynylene, (C3-C6) cycloalkylene, phenylene, (5-6 membered) heteroarylene or (3-6 membered) The (3-6 membered)heterocycloalkylene radicals may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl and (5-6 membered)heteroaryl.

[0033] In another preferred embodiment, in the general formula (1), each Q is independently: * represents the end and R 3b connect.

[0034] In another preferred embodiment, wherein in the general formula (1), each R 4 is independently -H, (C1-C5)alkyl, (C1-C5)haloalkyl, (C1-C5)alkoxy, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl, wherein said (C1-C5)alkyl, (C1-C5)haloalkyl, (C1-C5)alkoxy, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br or -I; or two R on the same nitrogen atom 4 Together with the nitrogen atom to which it is attached, it can form a (3-6 membered) heterocycloalkyl group, wherein said (3-6 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl and (C3-C6)cycloalkyl.

[0035] In another preferred embodiment, wherein in the general formula (1), each R 4 are independently: -H, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3, -CH2CF3,

[0036] In another preferred embodiment, wherein in the general formula (1), each R 5 are independently -H, (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl, (5-6 membered)heteroaryl, or -SO2R 3a wherein said (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, phenyl, (5-6 membered)heteroaryl or (3-6 membered)heterocycloalkyl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br or -I; or two R on the same nitrogen atom 5 Together with the nitrogen atom to which it is attached, it can form a (3-6 membered) heterocycloalkyl group, wherein said (3-6 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CN, (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl and (C3-C6) cycloalkyl.

[0037] In another preferred embodiment, wherein in the general formula (1), each R 5 Independently: -H, -CF3, -CH2CF3, -SO2CH3, -SO2CH2CH3 or -SO2CH(CH3)2.

[0038] In another specific embodiment of the present invention, the compound of formula (1) has one of the following structures:

[0039] Another object of the present invention is to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent and / or excipient, and a compound of the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

[0040] Another object of the present invention is to provide the use of the compound represented by general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates, or solvates, or the pharmaceutical composition thereof, for preparing a medicament for treating, regulating, or preventing a disease associated with the MYT1 protein. The disease is preferably cancer, and the cancer is a hematological cancer or a solid tumor.

[0041] Another object of the present invention is to provide a method for treating, regulating or preventing diseases related to the MYT1 protein, comprising administering to a subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition.

[0042] It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.

[0043] Synthesis of compounds

[0044] The following specifically describes the preparation methods of the compound of general formula (1) of the present invention, but these specific methods do not constitute any limitation to the present invention.

[0045] The compounds of formula (1) described above can be synthesized using standard synthetic techniques or known techniques in combination with the methods described herein. In addition, the solvents, temperatures and other reaction conditions mentioned herein may vary. The starting materials used in the synthesis of the compounds can be synthesized or obtained from commercial sources. The compounds described herein and other related compounds having different substituents can be synthesized using known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols.A and B (Plenum 2000, 2001), Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rd Ed., (Wiley 1999). The general methods for the preparation of compounds can be modified by using appropriate reagents and conditions to introduce various groups into the formulae provided herein.

[0046] In one aspect, the compounds described herein are prepared according to methods known in the art. However, the conditions of the methods, such as reactants, solvents, bases, amounts of the compounds used, reaction temperatures, reaction times, etc., are not limited to the following explanations. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such combinations can be easily performed by those skilled in the art. In one aspect, the present invention also provides a method for preparing the compound of formula (1), wherein the compound of formula (1) can be prepared using the following general reaction scheme 1:

[0047] General reaction scheme 1

[0048] An embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein R 1 、R 2 、R A 、R B 、R C and Ring B are as defined above, X represents iodine or bromine, N represents nitrogen, O represents oxygen, and Br represents bromine. As shown in General Reaction Scheme 2, Compound 2-1 and Compound 2-2 undergo a coupling reaction in the presence of Pd2(dba)3 to produce Compound 2-3. Compound 2-3 and Compound 2-4 undergo a coupling reaction in the presence of Pd(dppf)Cl2 to produce Compound 2-5. The cyano group of Compound 2-5 undergoes hydrolysis under acidic conditions to produce the amide Compound 2-6. Compound 2-6 is deprotected to produce Compound 2-7. Compound 2-7 is subjected to chiral resolution to yield atropisomers 2-7-A and 2-7-B.

[0049] Further forms of compounds

[0050] "Pharmaceutically acceptable" as used herein refers to a substance, such as a carrier or diluent, that does not abrogate the biological activity or properties of the compound and is relatively non-toxic, i.e., a substance that does not cause undesirable biological effects or interact in a deleterious manner with any of its components when administered to a subject.

[0051] The term "pharmaceutically acceptable salt" refers to a form of a compound that does not cause significant irritation to the organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain specific aspects, pharmaceutically acceptable salts are obtained by reacting a compound of the formula with an acid or base, wherein the acid or base includes, but is not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use 1. st Acids and Bases in Ed., (Wiley, 2002).

[0052] It should be understood that references to pharmaceutically acceptable salts include solvent-added forms or crystallized forms, particularly solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvent and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of formula (1) are conveniently prepared or formed according to the methods described herein. For example, hydrates of compounds of formula (1) are conveniently prepared by recrystallization from a mixed solvent of water / organic solvent, using organic solvents including, but not limited to, tetrahydrofuran, acetone, ethanol or methanol. In addition, the compounds mentioned herein can exist in unsolvated and solvated forms. In general, for the purposes of the compounds and methods provided herein, the solvated forms are considered to be equivalent to the unsolvated forms.

[0053] In other embodiments, the compound of formula (1) is prepared in different forms, including but not limited to, amorphous, crushed and nano-particle forms. In addition, the compound of formula (1) includes crystalline forms and can also be polymorphic. Polymorphs include different lattice arrangements of the same elemental composition of the compound. Polymorphs generally have different X-ray diffraction spectra, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystalline form to dominate.

[0054] In another aspect, compounds of formula (1) may have chiral centers and / or axial chirality and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers, and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially purified compounds are included within the scope of the present invention. The present invention is intended to include all such isomeric forms of these compounds.

[0055] The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I) and C-14( 14 C). For example, deuterated compounds can be formed by replacing hydrogen atoms with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs generally have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug half-life in vivo. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0056] Unless otherwise specified, any reference to an atom in the compounds of the present invention refers to its stable atomic isotope. Unless otherwise specified, when a position in a molecular structure is designated as "H" or "hydrogen," such position should be understood to have the natural abundance of the hydrogen isotope. Similarly, when a position is designated as "D" or "deuterium," such position should be understood to have a deuterium isotope abundance at least 3000 times its natural abundance (the natural abundance of the deuterium isotope is 0.015%).

[0057] More preferably, the deuterium atom abundance at each deuterated site of the deuterated compound of the present invention is at least 3500 times its natural abundance (52.2% deuterium atom enrichment). More preferably, it is at least 4500 times (67.5% deuterium atom enrichment). More preferably, it is at least 5000 times (75% deuterium atom enrichment). More preferably, it is at least 6000 times (90% deuterium atom enrichment). More preferably, it is at least 6333 times (95% deuterium atom enrichment). More preferably, it is at least 6466.7 times (97% deuterium atom enrichment). More preferably, it is at least 6600 times (99% deuterium atom enrichment). More preferably, it is at least 6633.3 times (99.5% deuterium atom enrichment).

[0058] the term

[0059] Unless otherwise indicated, the terms used in this application, including the specification and claims, are defined as follows. It should be noted that, throughout the specification and the appended claims, the singular forms "a," "an," and "an" include plural referents unless the context clearly indicates otherwise. Conventional methods, such as mass spectrometry, nuclear magnetic resonance, HPLC, protein chemistry, biochemistry, recombinant DNA technology, and pharmacology, are employed unless otherwise indicated. Throughout this application, the use of "or" or "and" means "and / or," unless otherwise indicated.

[0060] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. Preferred are lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, and tert-butyl. More preferred are lower alkyl groups containing 1 to 3 carbon atoms, such as methyl, ethyl, propyl, and 2-propyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t Bu.

[0061] Unless otherwise specified, "alkylene" refers to a divalent alkyl group as defined above. Examples of alkylene groups include, but are not limited to, methylene and ethylene.

[0062] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched groups of 1 to 14 carbon atoms. Preferred are lower alkenyl groups containing 1 to 4 carbon atoms, such as ethenyl, 1-propenyl, 1-butenyl, or 2-methylpropenyl. More preferred are lower alkenyl groups containing 1 to 2 carbon atoms.

[0063] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl group as defined above.

[0064] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight-chain and branched groups having 1 to 14 carbon atoms. Preferred are lower alkynyl groups having 1 to 4 carbon atoms, such as ethynyl, 1-propynyl, or 1-butynyl. More preferred are lower alkynyl groups having 1 to 2 carbon atoms.

[0065] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl group as defined above.

[0066] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), preferably containing 3 to 14 ring carbon atoms (C 3-14 In some embodiments, the cycloalkyl group has 3-10 ring carbon atoms (C 3-10 In some embodiments, a cycloalkyl group has 3-8 ring carbon atoms (C 3-8 In some embodiments, the cycloalkyl group has 3-7 ring carbon atoms (C 3-7 In some embodiments, the cycloalkyl group has 3-6 ring carbon atoms (C 3-6 In some embodiments, the cycloalkyl group has 4-6 ring carbon atoms (C 4-6 In some embodiments, the cycloalkyl group has 5-6 ring carbon atoms (C 5-6 In some embodiments, a cycloalkyl group has 5-10 ring carbon atoms (C 5-10Cycloalkyl). If the carbocyclic ring contains at least one double bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl group," or if the carbocyclic ring contains at least one triple bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl group." Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is tricyclic. The ring-forming carbon atoms 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 groups). In some embodiments, the cycloalkyl group may be fused with an aryl group, a heteroaryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, the cycloalkyl group may be fused with an aryl group, a cycloalkyl group, and a heterocycloalkyl group. In some embodiments, cycloalkyl groups can be fused with aryl groups and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl groups and cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcaryl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.

[0067] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

[0068] Unless otherwise specified, "alkoxy" refers to an alkyl group bonded to the rest of the molecule through an ether oxygen atom. Representative alkoxy groups are those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy. As used herein, "alkoxy" includes unsubstituted and substituted alkoxy groups, especially those substituted with one or more halogens. Preferred alkoxy groups are selected from OCH3, OCF3, CHF2O, CF3CH2O, i- PrO, n- PrO, i- BuO, n- BuO or t- BuO.

[0069] Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group. Aryl is monocyclic or polycyclic, for example, a monocyclic aryl ring fused to one or more carbocyclic aromatic groups. Examples of aryl include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.

[0070] Unless otherwise specified, "aryloxy" refers to an aryl group bonded to the rest of the molecule through an ethereal oxygen atom. Examples of aryloxy groups include, but are not limited to, phenoxy and naphthoxy.

[0071] Unless otherwise specified, "arylene" refers to a divalent aromatic radical as defined above. Examples of arylene groups include, but are not limited to, 1,4-phenylene, 1,3-phenylene, 1,2-phenylene, naphthylene, and phenanthrenylene.

[0072] Unless otherwise specified, "heteroaryl" refers to a substituted or unsubstituted aromatic group containing one or more heteroatoms, the heteroatoms being independently selected from O, N or S, preferably 1, 2, 3 or 4 heteroatoms, preferably a 5-14 membered aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, more preferably a 5-9 membered aromatic group containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen, more preferably a 5-6 membered aromatic group containing 1-3 heteroatoms selected from oxygen, sulfur or nitrogen. The heteroaryl group is monocyclic or polycyclic. The monocyclic heteroaryl group is preferably a 5-6 membered aromatic group containing 1-3 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6 membered aromatic group containing 1-2 heteroatoms selected from oxygen, nitrogen or sulfur. More preferably, it is a 5-6 membered aromatic group containing 1 heteroatom selected from oxygen, nitrogen or sulfur. In some embodiments, the monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,

[0073] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0074] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system that may optionally contain one or more alkenylene groups as part of the ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and selenium, preferably a saturated or partially unsaturated ring containing 1-4 heteroatoms selected from oxygen, sulfur or nitrogen, more preferably a saturated or partially unsaturated ring containing 1-3 heteroatoms selected from oxygen, sulfur or nitrogen. More preferably, it is a saturated or partially unsaturated ring containing 1-2 heteroatoms selected from oxygen, sulfur or nitrogen. In some embodiments, heterocycloalkyl is a 5-8 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-8 membered heterocycloalkyl). Heterocycloalkyl is a 5-6 membered non-aromatic ring containing ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen or sulfur (5-6 membered heterocycloalkyl). In some embodiments, 5-6 membered heterocycloalkyl groups contain 1-3 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocycloalkyl groups contain 1-2 ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, 5-6 membered heterocycloalkyl groups contain 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. If the heterocycloalkyl group contains at least one double bond, the partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl group", or if the heterocycloalkyl group contains at least one triple bond, the partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkynyl group". The heterocycloalkyl group may include a monocyclic, bicyclic, spirocyclic or polycyclic (e.g., having two fused or bridged rings) ring system. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. The ring-forming carbon atoms and heteroatoms of heterocycloalkyl can be optionally oxidized to form oxo or thioxo or other oxidized bonds (e.g., C(O), S(O), C(S) or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. Heterocycloalkyl can be connected via ring-forming carbon atoms or ring-forming heteroatoms. In certain embodiments, heterocycloalkyl contains 0 to 3 double bonds. In certain embodiments, heterocycloalkyl contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are parts (also referred to as partially unsaturated heterocycles) of aromatic rings having one or more fused to the heterocycloalkyl ring (i.e., sharing a key therewith), such as benzo derivatives of piperidine, morpholine, azacycloheptatriene or thienyl. Heterocycloalkyl containing fused aromatic rings can be connected via any ring-forming atoms, including ring-forming atoms of fused aromatic rings.Examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa-9-azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanediyl, 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-1H-imidazole , 4-nitro-2-nitro-1-pyridine, 4 ...1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine, 4-nitro-1-pyridine,

[0075] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

[0076] Unless otherwise specified, "oxo" refers to =0; for example, a carbonyl group substituted with an oxo group is a "carbonyl group." "; the group formed by sulfur being replaced by an oxo group is called "sulfinyl" ", the group formed by sulfur being substituted by two oxo groups is called "sulfonyl" ”.

[0077] Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substituted") appearing before the name of a group indicates that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably substituted by F or Cl.

[0078] Unless otherwise specified, the term "substituted" refers to a substituent group other than one or more hydrogen atoms on a specified atom or group that is substituted by one or more hydrogen atoms, without exceeding the normal valence of the specified atom. For example, one or more hydrogen atoms of an alkyl, alkylene, alkenyl, alkynyl, hydroxyl or amido group can be substituted by one or more substituent groups. Wherein the substituent group includes but is not limited to alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxylate, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic radical, hydroxyl, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, mercaptan, thioketone or its combination. The definition of "substituted" does not include similar indefinite structures obtained by defining a substituent group having a further substituent group attached to infinity (for example, a substituted aryl group itself substituted by a substituted aryl group with a substituted alkyl group, which is further substituted by a substituted heteroalkyl group, etc.). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, a substituted aryl group is continuously substituted by two other substituted aryls to an aryl group substituted by ((substituted aryl) substituted aryl). Similarly, the above definition does not include substitution patterns that are not allowed (for example, a methyl group substituted by 5 fluorines or a heteroaryl group with two adjacent oxygen ring atoms). This substitution pattern that is not allowed is well known to those skilled in the art. Whenever used to modify a chemical group, "substituted" can describe other chemical groups defined herein. For example, the term "substituted aryl" includes but is not limited to "alkyl aryl". Unless otherwise specified, if a group is described as optionally substituted, any substituent of the group itself is unsubstituted.

[0079] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0080] Unless otherwise specified, it will be understood that the word "comprise", or variations such as "comprises" or "comprising", imply the inclusion of a stated element or integer, or group of elements or integers, but not the exclusion of any other element or integer, or group of elements or integers.

[0081] The substituent "-O-CH2-O-" refers to the substituent in which two oxygen atoms are connected to two adjacent carbon atoms of a heterocycloalkyl, aryl or heteroaryl group, for example:

[0082] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0083] When one of the variables is selected from a chemical bond, it means that the two groups it connects are directly connected. For example, when L in XLY represents a chemical bond, it means that the structure is actually XY.

[0084] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of skeletal atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thiopyranyl are six-membered rings, and cyclopentyl, pyrrolyl, furanyl, and thienyl are five-membered rings. "AB-membered" refers to any number of ring systems from A to B, for example, "3-10-membered" refers to a 3-, 4-, 5-, 6-, 7-, 8-, 9-, and / or 10-membered ring system, and "5-6-membered" refers to a 5- and / or 6-membered ring.

[0085] The term "fragment" refers to a specific part or functional group of a molecule. A chemical fragment is generally considered to be a chemical entity contained in or attached to a molecule.

[0086] The term "isomer" means any tautomer, stereoisomer, atropisomer, isotopomer, enantiomer or diastereomer of any compound of the present invention. The compounds of the present invention may have one or more chiral centers or double bonds and therefore exist in stereoisomeric form, for example, as double bond isomers (i.e., E / Z geometric isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (-)) or cis / trans isomers). Therefore, the compounds of the present invention encompass all corresponding stereoisomers, i.e., stereoisomerically pure (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) forms as well as enantiomers and stereoisomer mixtures, such as racemates. Enantiomeric and stereoisomeric mixtures of the compounds of the present invention can be separated into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high performance liquid chromatography, and crystallization of the compounds as chiral salt complexes or crystallization of the compounds in chiral solvents. Enantiomers and stereoisomers can also be obtained from stereoisomerically pure or enantiomerically pure intermediates, reagents and catalysts by well-known asymmetric synthetic methods.

[0087] The term "isotopomers" refers to molecules that differ in structure only in their isotopes but are otherwise identical in structure.

[0088] The term "atropisomer" refers to a conformational stereoisomer produced when rotation about a single bond within a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule and the substituents at either end of the single bond are asymmetric, i.e., atropisomers do not require a stereocenter. When the barrier to rotation about the single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation of the individual isomers is permitted (LaPlante et al., J. Med. Chem. 2011, 54, 20, 7005), preferably by chiral resolution.

[0089] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key or dotted wedge key Or use a wavy line Indicates a straight solid bond or straight dashed key

[0090] Unless otherwise stated, Indicates a single bond or a double bond.

[0091] Specific pharmaceutical and medical terms

[0092] The term "acceptable," as used herein, means that a prescribed ingredient or active ingredient has no undue adverse effect on health and well-being for the general purpose of treatment.

[0093] The terms "treat," "treatment," or "therapy" as used herein include alleviating, inhibiting, or ameliorating the symptoms of a disease or condition; inhibiting the development of complications; ameliorating or preventing underlying metabolic syndrome; inhibiting the development of a disease or symptom, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing a regression of a disease or symptom; alleviating complications caused by a disease or symptom, or preventing or treating signs caused by a disease or symptom. As used herein, a compound or pharmaceutical composition, upon administration, can improve a disease, symptom, or condition, particularly by improving its severity, delaying its onset, slowing its progression, or reducing its duration. Whether the administration is fixed or temporary, continuous or intermittent, the circumstances attributable to or related to the administration can be explained.

[0094] "Active ingredient" refers to the compound of formula (1), as well as pharmaceutically acceptable inorganic or organic salts of the compound of formula (1). The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and therefore appear in the form of racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. The asymmetric centers that may exist depend on the properties of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the present invention. The present invention is meant to include all such isomeric forms of these compounds.

[0095] The terms "compound," "composition," "agent," or "medicine or medicament" are used interchangeably herein and refer to a compound or composition that, when administered to a subject (human or animal), induces a desired pharmaceutical and / or physiological response through local and / or systemic action.

[0096] The term "administered," "administering," or "administration" as used herein refers to the direct administration of the compound or composition, or the administration of a prodrug, derivative, or analog of the active compound.

[0097] Although the numerical ranges and parameters used to define the broader scope of the present invention are approximate, the numerical values ​​of the specific examples are presented herein as precisely as possible. However, any numerical value inherently and inevitably contains standard deviations resulting from individual testing methods. As used herein, "about" generally refers to the actual value being within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as determined by one skilled in the art. Except in the experimental examples, or unless otherwise expressly indicated, all ranges, amounts, values, and percentages used herein (e.g., to describe material amounts, time periods, temperatures, operating conditions, quantitative ratios, and the like) are to be understood as modified by the word "about." Therefore, unless otherwise indicated, the numerical parameters disclosed in this specification and the appended claims are approximate and may be modified as needed. At a minimum, these numerical parameters should be understood to include the number of significant digits indicated and to include normal rounding.

[0098] Unless otherwise defined in this specification, the scientific and technical terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, unless otherwise defined in this specification, singular terms used in this specification include the plural form of the term, and plural terms also include the singular form of the term, unless otherwise defined in the context.

[0099] Therapeutic uses

[0100] The compounds of formula (1) or pharmaceutical compositions of the present invention are generally useful for inhibiting MYT1 protein, and thus can be used to treat one or more conditions associated with MYT1 protein activity. Therefore, in certain embodiments, the present invention provides a method for treating a condition mediated by MYT1 protein, comprising administering a compound of formula (1) or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0101] In some embodiments, a method for treating cancer is provided, comprising administering to a subject in need thereof an effective amount of any of the aforementioned pharmaceutical compositions comprising a compound of formula (1). In some embodiments, the cancer includes, but is not limited to, hematological malignancies (leukemia, lymphoma, myeloma including multiple myeloma, myelodysplastic syndrome and myeloproliferative syndrome) and solid tumors (cancers such as prostate, breast, lung, colon, pancreas, kidney, ovary and soft tissue cancer and osteosarcoma, as well as stromal tumors), preferably breast cancer, uterine cancer, endometrial cancer, ovarian cancer, uterine carcinosarcoma, ovarian carcinosarcoma, pancreatic ductal adenocarcinoma, lung cancer, intestinal cancer, gastric cancer, colorectal cancer, esophageal cancer, glioblastoma, neuroblastoma and cancer metastasis thereof.

[0102] Route of administration

[0103] The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into various formulations containing a safe and effective amount of the compounds of the present invention or their pharmaceutically acceptable salts and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. The safe and effective amount of the compound will be determined based on the patient's age, condition, and duration of treatment, among other factors.

[0104] "Pharmaceutically acceptable excipients or carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmacologically acceptable excipients or carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0105] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0106] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0107] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0108] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0109] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0110] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0111] 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.

[0112] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0113] The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compounds of the present invention is applied to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health status, all of which are within the skill of a skilled physician.

[0114] The features described above, or in the embodiments, may be combined in any combination. All features disclosed in this specification may be used in any combination, and each feature disclosed in this specification may be replaced by any alternative feature that serves the same, equivalent, or similar purpose. Therefore, unless otherwise specified, the features disclosed are merely general examples of equivalent or similar features. DETAILED DESCRIPTION

[0115] The following description will elaborate on various specific aspects, characteristics, and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions so that the present invention will be readily apparent. It should be understood that the following detailed description and examples describe specific embodiments and are provided for reference only. After reading the present description, those skilled in the art may make various changes or modifications to the present invention, and such equivalents are within the scope of the present invention.

[0116] In all embodiments, 1 H-NMR was recorded on a Vian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were by volume.

[0117] The present invention uses the following abbreviations: (Boc)2O represents di-tert-butyl dicarbonate; CDCl3 represents deuterated chloroform; Cs2CO3 represents cesium carbonate; CuI represents cuprous iodide; EtOAc represents ethyl acetate; Hexane represents n-hexane; HPLC represents high performance liquid chromatography; MeCN represents acetonitrile; DCM represents dichloromethane; DDQ represents 2,3-dichloro-5,6-dicyano-p-benzoquinone; DIPEA represents diisopropylethylamine; Dioxane represents 1,4-dioxane; DME represents ethylene glycol dimethyl ether; DMEDA represents N,N-dimethylethylenediamine; DMF represents N,N-dimethylformamide; DMAP represents 4-(dimethylamino)pyridine; DMSO represents dimethyl sulfoxide; EtOH represents ethanol; EtOAc represents ethyl acetate; EA represents ethyl acetate; hr represents hour; IPA represents isopropyl alcohol; =Biotage Isolera Prime rapid preparative liquid chromatograph; min = minute; K2CO3 = potassium carbonate; KOAc = potassium acetate; KOH = potassium hydroxide; K3PO4 = potassium phosphate; LiBH4 = lithium borohydride; min = minute; m-CPBA = meta-chloroperbenzoic acid; MeOH = methanol; MeONa = sodium methoxide; MS = mass spectrometry; NaBH(OAc)3 = sodium triacetoxyborohydride; NaH = sodium hydrogen; NMR = nuclear magnetic resonance; NBS = bromosuccinimide; NIS = iodosuccinimide; Pd / C = palladium on carbon; Pd(PPh3)4 = tetrakistriphenylphosphine palladium; Pd(OAc)2 = palladium acetate; Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PE = petroleum ether; Petroleum Ether represents petroleum ether; PMBNH2 represents 4-methoxybenzylamine; PPh3 represents triphenylphosphine; TEA represents triethylamine; TFA represents trifluoroacetic acid; TFAA represents trifluoroacetic anhydride; THF represents tetrahydrofuran; TsOH represents p-toluenesulfonic acid; TsCl represents p-toluenesulfonyl chloride; TfOH represents trifluoromethanesulfonic acid; TLC represents thin-layer chromatography; SFC represents supercritical fluid chromatography; XantPhos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos represents 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; and XantPhos Pd G3 represents [(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate.

[0118] Example 1 Synthesis of Compound 1

[0119] Step 1: Synthesis of compound int_1-3:

[0120] Int_1-1 (3.00 g, 9.47 mmol), int_1-2 (16.6 g, 66.3 mmol, 18.5 mL, 50% purity), Pd(dppf)Cl2 (693 mg, 947 umol), and K2CO3 (5.23 g, 37.9 mmol) were dissolved in a mixture of 1,4-dioxane (60 mL) and water (12 mL). The atmosphere was replaced with nitrogen three times, and the mixture was heated to 80°C and stirred for 2 hours. TLC monitoring indicated the reaction was complete. Water (100 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, PE / DCM = 19 / 1) to obtain a white solid (1.2 g, yield: 67.7%).

[0121] 1 H NMR: (400MHz, CHLOROFORM-d) δ6.94 (t, J = 9.0Hz, 1H), 2.24-2.13 (m, 6H).

[0122] Step 2: Synthesis of compound int_1-4:

[0123] Int_1-3 (1.00 g, 5.34 mmol) was dissolved in methanol (10 mL). MeONa (1.06 g, 5.88 mmol, 30% purity) was added at 0°C, and the reaction mixture was allowed to react at 80°C for 2 hours. Additional MeONa (3.85 g, 21.37 mmol, 30% purity) was added, and the reaction mixture was allowed to react at 80°C for 8 hours. Additional MeONa (4.81 g, 26.7 mmol, 30% purity) was added, and the reaction mixture was allowed to react at 80°C for 10 hours. TLC monitoring indicated the reaction was complete. Water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (200 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (880 mg, crude product), which was used directly in the next reaction.

[0124] 1 H NMR: (400MHz, CHLOROFORM-d) δ6.69 (d, J=11.0Hz, 1H), 3.86 (s, 3H), 2.13 (dd, J=1.3, 14.5Hz, 6H).

[0125] Step 3: Synthesis of compound int_1-5:

[0126] Int_1-4 (880 mg, 4.42 mmol) was dissolved in ethanol (3 mL) and water (2 mL). NH4Cl (2.36 g, 44.2 mmol) and acetic acid (133 mg, 2.21 mmol, 126 uL) were added. The mixture was heated to 50°C and iron powder (1.23 g, 22.1 mmol) was slowly added. After the addition, the mixture was heated to 80°C and stirred for 0.5 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered while hot, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1 to 5 / 1) to obtain a solid (760 mg, yield: 97.7%).

[0127] 1 H NMR: (400MHz, CHLOROFORM-d) δ6.15 (d, J = 11.7Hz, 1H), 3.83 (br s, 2H), 3.78 (s, 3H), 2.06 (d, J = 1.5Hz, 3H), 2.04 (s, 3H).

[0128] ESI-MS m / z:170[M+H] +

[0129] Step 4: Synthesis of compound int_1-7:

[0130] Int_1-5 (700 mg, 4.14 mmol) and int_1-6 (1.20 g, 4.14 mmol) were dissolved in DME (10 mL). Cs2CO3 (3.24 g, 9.93 mmol), Xantphos (239 mg, 414 μmol), and Pd2(dba)3 (379 mg, 414 μmol) were added. The reaction mixture was nitrogen-purged three times and heated to 90°C for 16 hours. LC-MS monitoring indicated the reaction was complete. After cooling the reaction mixture to room temperature, water (50 mL) was added. The aqueous phase was extracted with ethyl acetate (50 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 10 / 1) to obtain a solid (1.1 g, yield: 70.7%).

[0131] ESI-MS m / z:379[M+H] + .

[0132] Step 5: Synthesis of compound int_1-9:

[0133] Int_1-8 (118 mg, 1.78 mmol, 112 uL) and Cs2CO3 (609 mg, 1.87 mmol) were dissolved in DMF (4 mL). The reaction mixture was heated to 40°C for 0.5 hours. To this mixture were added int_1-7 (337 mg, 890 μmol), CuI (80.9 mg, 425 μmol), and DMEDA (60.4 mg, 425 μmol). The reaction mixture was purged with nitrogen three times and heated to 90°C for 16 hours. The reaction was monitored by LC-MS. After cooling to room temperature, water (50 mL) was added. The aqueous phase was extracted with ethyl acetate (50 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 4 / 1) to yield a solid (216 mg, yield: 66.9%).

[0134] ESI-MS m / z:365[M+H] + .

[0135] Step 6: Synthesis of compound int_1-10:

[0136] Sulfuric acid (4 mL) was slowly added to int_1-9 (291 mg, 800 μmol) at 0°C. The reaction mixture was allowed to react at 0°C for 3 hours, monitored by LC-MS. Ice water (30 mL) was slowly added to the reaction mixture, and the pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (30 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, which was then purified by column chromatography (SiO2, PE / EtOAc = 1 / 0 to 3 / 1) to yield a solid (225 mg, yield: 73.7%).

[0137] MS(ESI):383[M+H] + .

[0138] Step 7: Synthesis of Compound 1:

[0139] Under nitrogen, int_1-10 (191 mg, 500 μmol) was dissolved in dichloromethane (2 mL). BBr (1.25 g, 5 mmol) was added to the reaction mixture at 0°C. The reaction mixture was incubated at 0°C for 1 hour under nitrogen and monitored by LC-MS. Ice water (20 mL) and NaH2PO4 (3 g) were slowly added to the reaction mixture. The pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (30 mL x 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 purified by column chromatography to yield compound 1 (150 mg, yield: 81.5%).

[0140] MS(ESI):369[M+H] + .

[0141] 1 H NMR(400MHz,DMSO-d6)δ10.02(s,1H),8.14(s,1H),7.99(d,J=2.3Hz,1H),7.16–6 .97(m,2H),6.89(s,2H),6.80(d,J=11.1Hz,1H),2.50(s,3H),1.68–1.53(m,6H).

[0142] Example 2 Synthesis of Compound 1-1 and Compound 1-2

[0143] Compound 1 (100 mg, 0.27 mmol) was subjected to SFC chiral separation to obtain compound 1-2 (35 mg) and compound 1-1 (25 mg).

[0144] Compound 1-1: MS (ESI): 369 [M+H] + .

[0145] Compound 1-2: MS (ESI): 369 [M+H] + .

[0146] Using the above synthesis method and different raw materials, the target compounds in Table 1 can be obtained.

[0147] Table 1

[0148] Biological Example 1 In vitro inhibition test of MYT1 kinase activity by the compounds of the present invention

[0149] After pre-incubation of recombinant MYT1 protein and compound at room temperature for 15 minutes, 10 μM ATP was added to initiate the reaction. After incubation at room temperature for 60 minutes, Promega's ADP-GLO reagent was added. After incubation in the dark for 40 minutes, the detection solution was added and incubated for another 45-60 minutes. Chemiluminescence was measured using ENVISION. Inhibition rate and IC were calculated compared with the DMSO group. 50 The results are shown in Table 2 below.

[0150] Table 2. Inhibitory activity of the compounds of the present invention against recombinant protein MYT1 (IC 50, nM) +++ indicates IC 50 Less than or equal to 200nM++ indicates IC 50 200nM to 500nM + indicates IC 50 Greater than 500nM

[0151] Biological Example 2 In vitro antiproliferative activity of the compounds of the present invention on MIA PaCa-2 cells

[0152] 3000 MIAPaCa-2 cells / well were plated in 384-well plates and allowed to adhere overnight. DMSO or compound was added at a maximum concentration of 10 μM in a 1:5 dilution series. Cell survival was assessed 72 hours after drug addition by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was calculated. 50 The results are shown in Table 3 below.

[0153] Table 3 Antiproliferative activity of the compounds of the present invention on MIA PaCa-2 cells

[0154] Reference compound RP-6306 is compound 182 in WO2021195781A1.

[0155] From the data in Table 3, it can be seen that the compounds of the present invention alone have no strong anti-proliferative activity against MIA PaCa-2 cells.

[0156] Biological Example 3 In vitro antiproliferative activity of the compound of the present invention combined with WEE1 inhibitor (MK1775) on MIA PaCa-2 cells

[0157] 3000 MIA PaCa-2 cells / well were plated in a 384-well plate and treated with 80 nM MK1775. After overnight attachment, DMSO or a 1:5 serial dilution of the compound with a maximum concentration of 1000 nM was added. 72 hours after drug addition, cell survival was assessed by measuring intracellular ATP levels. The percentage of cell survival inhibition by the compound was calculated compared to the DMSO group, and the IC was then calculated. 50 The results are shown in Table 4 below.

[0158] Table 4 In vitro antiproliferative activity of the compounds of the present invention combined with MK1775 on MIAPaCa-2 cells

[0159] From the data in Table 4, it can be seen that the compound of the present invention combined with MK1775 has a strong in vitro anti-proliferative activity against MIA PaCa-2 cells, and the anti-proliferative activity of the compound 1 of the present invention combined with MK1775 is stronger than that of RP-6306.

[0160] Biological Example 4 In vivo pharmacokinetic study of the compounds of the present invention

[0161] Female CD-1 mice aged 7 to 10 weeks were selected and administered intravenously and orally at doses of 2 mg / kg and 10 mg / kg, respectively. Mice were fasted for at least 12 hours before administration and resumed feeding 4 hours after administration. Water was freely available throughout the experiment. On the day of the experiment, animals in the intravenous group received a single injection of the corresponding compound via the tail vein at a volume of 10 mL / kg. Animals in the oral group received a single injection of the corresponding compound via gavage at a volume of 10 mL / kg. Animals were weighed before administration, and the administration volume was calculated based on body weight. Samples were collected at 0.083 (injection group), 0.167, 0.5, 1, 2, 4, 8, and 24 hours. Approximately 200 μL of whole blood was collected from the submandibular venous plexus at each time point for plasma preparation for concentration determination by high-performance liquid chromatography-tandem mass spectrometry (LC-MS / MS). All animals were euthanized by CO2 anesthesia after the collection of the PK sample at the last time point. Phoenix WinNonlin was used. TM Plasma concentrations were processed using a non-compartmental model using the pharmacokinetic software version 8.3 (Certara), and pharmacokinetic parameters were calculated using the linear-log trapezoidal method. The in vivo pharmacokinetic results are shown in Table 5 below.

[0162] Table 5 In vivo pharmacokinetic evaluation results of the compounds of the present invention

[0163] Note: Compound 1 injection dose: 1 mg / kg, oral dose: 5 mg / kg.

[0164] As shown in Table 5, in mouse pharmacokinetic studies, Compound 1 exhibited a significantly higher Vdss than RP-6306, indicating that Compound 1 is less distributed in plasma and more distributed in other tissues, offering significant advantages for the treatment of solid tumors. Furthermore, Compound 1 exhibited superior oral bioavailability compared to RP-6306, demonstrating significant improvements in pharmacokinetic properties.

[0165] Biological Example 5 In vitro permeability test of the compounds of the present invention

[0166] In vitro passive permeability or the ability to serve as a P-glycoprotein (P-gp) transport substrate was tested using MDCK cells (MDCK wild type) or MDCK cells stably transduced with MDR1 (MDCK-MDR1). Permeability experiments were performed in duplicate in a transwell system at a single concentration (5 μM) and incubated for 90 minutes. The apical to basolateral (A to B, AB) and basolateral to apical (B to A, BA) transport of the corresponding compounds were measured, and the permeation rate (apparent permeability) of the test compound was calculated (P app x 10 -6 cm / sec) and efflux ratio (P app (BA) / P app (AB)). Digoxin, Metoprolol, and Atenolol served as controls.

[0167] Biological Example 6 In vitro solubility and stability test of the compound of the present invention

[0168] Preparation of standard curve: Weigh 10.01 mg of sample into a volumetric flask, dilute to 10 mL with acetonitrile / water (v / v, 9 / 1) to prepare a 1.001 mg / mL standard solution, then dilute successively to 0.5005, 0.1001, 0.05005, 0.01001 and 0.001001 mg / mL to make a standard curve, with the peak area of ​​the sample as the vertical axis and the concentration as the horizontal axis, and fit to a linear equation.

[0169] Solubility and stability testing: 15 mg of sample was added to 3 mL of solvent (FaSSIF, FeSSIF, SGF, or water) to prepare a suspension with a target concentration of 5 mg / mL. The suspension was agitated on a shaker (800 rpm) at 37°C for 0.5 hours. The suspension was then filtered and the filtrate diluted with diluent to a desired peak height not exceeding that of the standard curve. Solubility and purity were determined by HPLC.

[0170] Biological Example 7 In vivo efficacy study - mouse HCC1569 subcutaneous transplant tumor model

[0171] HCC1569 is a breast cancer cell line. Each nude mouse was subcutaneously inoculated with 10×10 6 HCC1569 cells were treated with the compound once daily orally, alone or in combination with weekly intraperitoneal injections of Gemcitabine, until tumors reached 100-200 mm³. Tumor volume was measured twice weekly at the end of dosing. Tumor growth inhibition (TGI) was calculated as 1-(tumor volume of the drug group on day 28 - tumor volume of the drug group on day 1) / (tumor volume of the vehicle control group on day 28 - tumor volume of the drug group on day 1).

[0172] Biological Example 8 In Vivo Efficacy Study - Mouse OVCAR-3 Subcutaneous Transplant Tumor Model

[0173] OVCAR-3 is an ovarian cancer cell line. Each nude mouse was subcutaneously inoculated with 10×10 6 OVCAR-3 cells were administered orally once daily, either alone or in combination with weekly intraperitoneal injections of Gemcitabine, until tumors reached 100-200 mm³. Tumor volume was measured twice weekly at the end of dosing. Tumor growth inhibition (TGI) was calculated as 1-(tumor volume of the dosing group on day 28 - tumor volume of the dosing group on day 1) / (tumor volume of the vehicle control group on day 28 - tumor volume of the dosing group on day 1).

[0174] In vitro CYP enzyme inhibitory activity of compounds in Biological Example 9

[0175] Prepare working solutions of the test compound and positive control compound. Add 20 μL of substrate solution (diclofenac as a CYP2C9 substrate, dextromethorphan as a CYP2D6 substrate, midazolam or testosterone as a CYP2D6 substrate) to the corresponding wells of a 96-well plate. Then, add 2 μL of the test compound and positive control compound to the corresponding wells. Remove human liver microsomes from a –80°C freezer and place on ice. Prepare the human liver microsome working solution and add 158 μL of the human liver microsome solution to all wells. Preheat the 96-well plate at 37°C for 10 minutes. Prepare NADPH working solution, add 20 μL NADPH solution to all wells, mix and incubate the 96-well plate at 37°C (CYP2D6 incubation for 20 minutes, CYP3A4 incubation for 3 minutes, CYP2C9 incubation for 10 minutes), and then add 400 μL stop solution (200 ng / mL Tolbutamide and 200 ng / mL Labetalol acetonitrile solution as internal standard) to terminate the reaction. The sample was centrifuged at 4000 rpm for 20 minutes to precipitate the protein. Take 200 μL of supernatant and dilute it with 100 μL buffer, shake for 10 minutes, and then send it to LC / MS / MS for detection. Data analysis: XL fit was used to plot the relationship between the percentage of the control group and the concentration of the test compound, and for nonlinear regression analysis of the data. IC 50 The values ​​are determined using a 3- or 4-parameter logistic equation:

[0176] 3-parameter logistic equation: 4-parameter logistic equation:

[0177] The test results show that the compound of the present invention has good safety.

[0178] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A compound represented by the general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates: In the general formula (1): Ring A is: + indicates connection with carbonyl group, * indicates connection with Connected; R 1 is -H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, (5-10 membered) heteroaryl, -N(R 3 )2.-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 2. -SO2R 3a or -QR 3b wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl or (3-9-membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, and (5-10 membered)heteroaryl; Ring B is (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl or (5-10 membered)heteroaryl; Each R 2 each independently represents -H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, (5-10 membered) heteroaryl, -N(R 3 )2.-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 2. -SO2R 3a or -QR 3b wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl or (3-9-membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, and (5-10 membered) heteroaryl; or two R on the same carbon atom 2 The carbon atom to which it is attached may form a (C4-C9) cycloalkyl, (C4-C9) cycloalkenyl, (4-9-membered) heterocycloalkyl, phenyl or (5-10-membered) heteroaryl group, wherein the (C4-C9) cycloalkyl, (C4-C9) cycloalkenyl, (4-9-membered) heterocycloalkyl, phenyl or (5-10-membered) heteroaryl group may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl and (C3-C8) cycloalkyl; or two R on the same carbon atom 2 Can form with the carbon atom to which it is attached R A , R B and R C are independently -H, -OH, -OR 3 , halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl; or R B , R C The carbon atoms to which they are attached constitute (C4-C10)cycloalkyl, (4-10-membered)heterocycloalkyl, phenyl or (5-10-membered)heteroaryl, wherein said (C4-C10)cycloalkyl, (4-10-membered)heterocycloalkyl, phenyl or (5-10-membered)heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 3 、-N(R 3 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C8)cycloalkyl; Each R 3 are independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl, -SO2R 3a wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl or (3-9-membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy or halogen; or two R on the same nitrogen atom 3 Together with the nitrogen atom attached thereto, they can form a (3-9 membered) heterocycloalkyl group, wherein the (3-9 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C8)cycloalkyl; Each R 3a is independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl or (5-10-membered)heteroaryl, wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl or (5-10-membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy or halogen; Each R 3b are independently (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl, -N(R 3 )2.-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 )2 or -SO2R 3a wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl or (3-9-membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, and (5-10 membered)heteroaryl; Q is (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene, (3-9-membered)heterocycloalkylene, (C6-C10)arylene, or (5-10-membered)heteroarylene, wherein said (C1-C6)alkylene, (C2-C6)alkenylene, (C2-C6)alkynylene, (C3-C8)cycloalkylene, (C6-C10)arylene, (5-10-membered)heteroarylene, or (3-9-membered)heterocycloalkylene may each independently be optionally substituted with 1, 2, 3, or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (3-9 membered)heterocycloalkyl, (C6-C10)aryl, and (5-10 membered)heteroaryl; Each R 4 is independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl or (5-10-membered)heteroaryl, wherein said (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C3-C8)cycloalkyl, (3-9-membered)heterocycloalkyl, (C6-C10)aryl or (5-10-membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy or halogen; or two R on the same nitrogen atom 4 Together with the nitrogen atom attached thereto, they can form a (3-9 membered) heterocycloalkyl group, wherein the (3-9 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -OR 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C8)cycloalkyl; Each R 5 are independently -H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkane alkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, (5-10 membered) heteroaryl, -SO2R 3a wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl or (3-9-membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C6)alkyl, (C1-C6)alkoxy or halogen; or two R on the same nitrogen atom 5 together with the nitrogen atom to which it is attached, may form a (3-9 membered) heterocycloalkyl group, wherein said (3-9 membered) heterocycloalkyl group may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, halogen, -OH, -CN, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl and (C3-C8) cycloalkyl; and n is an integer of 0, 1, 2, 3, 4 or 5.

2. The compound according to claim 1 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 1 is -H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, (5-10 membered) heteroaryl, -N(R 3 )2.-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 2. -SO2R 3a or -QR 3b wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl or (3-9-membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, aryl and (5-6-membered)heteroaryl.

3. The compound according to claim 2 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 1 For: -H, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, -C(O)N(CH3)2, -C(O)NH(CH3), -C(O)NH2, -SO2N(CH3)2, -SO2NH(CH3), -SO2NH2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -CF3, -CH2CF3, -OCF3, -OCH2CH3, -OCH(CH3)2, 4. The compound according to any one of claims 1 to 3 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), ring B is a (C3-C6) cycloalkyl, a (3-6 membered) heterocycloalkyl, a phenyl or a (5-6 membered) heteroaryl; and ring B is preferably a (5-6 membered) heterocycloalkyl or a (5-6 membered) heteroaryl containing 1, 2 or 3 atoms independently selected from N, O or S.

5. The compound according to any one of claims 1 to 4 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 2 each independently represents -H, halogen, -CN, (C1-C6) alkyl, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C8) cycloalkyl, (3-9 membered) heterocycloalkyl, (C6-C10) aryl, (5-10 membered) heteroaryl, -N(R 3 )2.-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 2. -SO2R 3a or -QR 3b wherein the (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C8)cycloalkyl, (C6-C10)aryl, (5-10-membered)heteroaryl or (3-9-membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, aryl and (5-6-membered)heteroaryl.

6. The compound according to claim 5 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 2 Each independently represents: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, -C(O)N(CH3)2, -C(O)NH(CH3), -C(O)NH2, -SO2N(CH3)2, -SO2NH(CH3), -SO2NH2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -CF3, -CH2CF3, -OCF3, -OCH2CH3, -OCH(CH3)2, 7. The compound according to any one of claims 1 to 6 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R A , R B and R C are independently -H, -OH, -OR 3 , halogen, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl; or R B , R C The carbon atoms to which they are attached constitute a (C4-C6)cycloalkyl, (4-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl, wherein the (C4-C6)cycloalkyl, (4-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl and (C3-C6)cycloalkyl.

8. The compound according to claim 7 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R A , R B and R C Each independently is -H, -F, -Cl or 9. The compound according to any one of claims 1 to 8 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 3 are independently -H, (C1-C5) alkyl, (C1-C5) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl, (5-6 membered) heteroaryl, -SO2R 3a wherein the (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br or -I; or two R on the same nitrogen atom 3 Together with the nitrogen atom to which it is attached, it can form a (3-6 membered) heterocycloalkyl group, wherein the (3-6 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl and (C3-C6)cycloalkyl.

10. The compound according to claim 9 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 3 Independently: -H, -CF3, -CH2CF3, -SO2CH3, -SO2CH2CH3 or -SO2CH(CH3)2.

11. The compound according to any one of claims 1 to 10 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 3a It is independently (C1-C5)alkyl, (C1-C5)haloalkyl, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl, wherein the (C1-C5)alkyl, (C1-C5)haloalkyl, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, phenyl or (5-6-membered)heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br, or -I.

12. The compound according to claim 11 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 3a Independently for: -CF3, -CH2CF3, 13. The compound according to any one of claims 1 to 12 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 3b are independently (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl, (5-6 membered)heteroaryl, -N(R 3 )2.-OR 3 、-C(O)N(R 4 )2、-SO2N(R 4 )2 or -SO2R 3a wherein the (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, phenyl, (5-6-membered)heteroaryl or (3-6-membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6-membered)heterocycloalkyl, phenyl and (5-6-membered)heteroaryl.

14. The compound according to claim 13 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 3b are independently: -H, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -C(O)N(CH3)2, -C(O)NH(CH3), -C(O)NH2, -SO2N(CH3)2, -SO2NH(CH3), -SO2NH2, -SO2CH3, -SO2CH2CH3, -SO2CH(CH3)2, -CF3, -CH2CF3, -OCH2CH3, -OCH(CH3)2, 15. The compound according to any one of claims 1 to 14, or each isomer, each crystalline form, pharmaceutically acceptable salt, hydrate or solvate thereof, wherein in the general formula (1), Q is (C1-C3) alkylene, (C2-C4) alkenylene, (C2-C4) alkynylene, (C3-C6) cycloalkylene, (3-6 membered) heterocycloalkylene, phenylene or (5-6 membered) heteroarylene, wherein the (C1-C3) alkylene, (C2-C4) alkenylene, (C2-C4) alkynylene, (C3-C6) cycloalkylene, phenylene, (5-6 membered) heteroarylene or (3-6 membered) heterocycloalkylene may each be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3) alkyl, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, (3-6 membered) heterocycloalkyl, phenyl and (5-6 membered) heteroaryl.

16. The compound according to claim 15 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each Q is independently: * represents the end and R 3b connect.

17. The compound according to any one of claims 1 to 16 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 4 is independently -H, (C1-C5) alkyl, (C1-C5) haloalkyl, (C1-C5) alkoxy, (C3-C6) cycloalkyl, (3-6-membered) heterocycloalkyl, phenyl or (5-6-membered) heteroaryl, wherein said (C1-C5) alkyl, (C1-C5) haloalkyl, (C1-C5) alkoxy, (C3-C6) cycloalkyl, (3-6-membered) heterocycloalkyl, phenyl or (5-6-membered) heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C3) alkyl, (C1-C3) alkoxy, -F, -Cl, -Br or -I; or two R on the same nitrogen atom 4 Together with the nitrogen atom to which it is attached, it can form a (3-6 membered) heterocycloalkyl group, wherein the (3-6 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -NH(CH3), -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl and (C3-C6)cycloalkyl.

18. The compound according to claim 17 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 4 are independently: -H, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3, -CH2CF3, 19. The compound according to any one of claims 1 to 18 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 5 are independently -H, (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, (3-6 membered)heterocycloalkyl, phenyl, (5-6 membered)heteroaryl, or -SO2R 3a wherein the (C1-C5)alkyl, (C1-C5)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl, phenyl, (5-6-membered)heteroaryl or (3-6-membered)heterocycloalkyl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, (C1-C3)alkyl, (C1-C3)alkoxy, -F, -Cl, -Br or -I; or two R on the same nitrogen atom 5 Together with the nitrogen atom to which it is attached, it can form a (3-6 membered) heterocycloalkyl group, wherein the (3-6 membered) heterocycloalkyl group can be independently optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -Cl, -Br, -I, -OH, -CN, (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl and (C3-C6) cycloalkyl.

20. The compound according to claim 19 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), each R 5 Independently: -H, -CF3, -CH2CF3, -SO2CH3, -SO2CH2CH3 or -SO2CH(CH3)2.

21. The compound according to any one of claims 1 to 20 or any of its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), the compound has one of the following structures:

22. A pharmaceutical composition, characterized in that It contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1 to 21, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates as active ingredients.

23. Use of the compound according to any one of claims 1 to 21, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the pharmaceutical composition according to claim 22 in the preparation of a medicament for treating or preventing MYT1-mediated diseases.

24. The use according to claim 23, wherein the disease is cancer, and the cancer is blood cancer and solid tumor.

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