Compounds as MYT1 inhibitors

Abstract

The invention discloses a compound used as an MYT1 inhibitor. Specifically, the invention relates to a compound as shown in a general formula (1) and a preparation method thereof, and application of the compound as shown in the general formula (1) and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thereof as MYT1 inhibitors. The compound and isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates of the compound can be used for preparing medicines for treating or preventing diseases related to MYT1 protein. # imgabs0 #

Description

Compounds as MYT1 inhibitors

[0001] This application claims priority to Chinese patent application No. 202210822834.5, filed on July 12, 2022, and Chinese patent application No. 202310048632.4, filed on January 31, 2023. This application incorporates the entirety 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] R A -C(O)NH(R 4 )、-C(O)(R 3a ) or -SO2R 3a ;

[0008] R Bis -H or -N(R 3 )2;

[0009] X 1 CR a1 or N;

[0010] X 2 CR a2 or N;

[0011] X 3 CR a3 or N;

[0012] R a1 、R a2 、R a3 and R 1 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 R a3 and R 1 Together with the carbon atoms to which they are attached, they 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 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 and (C3-C8)cycloalkyl;

[0013] When R a1 、R a2 、R a3 and R 1 When neither is -CN, R 2 for: where X 4 、X 5 、X 6 、X 7 、X 8 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, and X 4 、X 5 、X 6 、X 7 、X 8 4 of them are not -H at the same time; or X 4 and X 5 Yes, X 5 and X 6 Yes, X 6 and X 7 Yes, X 7 and X 8 Each of the pairs can independently form with the carbon atom to which they are attached a (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 can 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 and (C3-C8)cycloalkyl; or R 2 is (6-10 membered) heterocycloalkyl or (6-10 membered) heteroaryl, wherein said (6-10 membered) heterocycloalkyl or (6-10 membered) heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, -OR 3 , halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl and (3-6 membered)heterocycloalkyl;

[0014] When R a1 、R a2 、R a3 and R 1 When at least one of them is -CN; or when R a3 and R 1 Together with the carbon atoms to which they are attached, they form a (C4-C9)cycloalkenyl, a (4-9-membered)heterocycloalkyl or a (5-10-membered)heteroaryl, wherein said (4-9-membered)heterocycloalkyl 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 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C8)cycloalkyl, R 2 for: where X 4 、X 5 、X 6 、X 7 、X 8 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, and X 4 、X 5 、X 6 、X 7 、X 8 At least two of them are not -H at the same time; or X 4 and X 5 Yes, X 5 and X 6 Yes, X 6 and X 7 Yes, X 7 and X 8 Each of the pairs can independently form with the carbon atom to which they are attached a (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 can 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; or R 2is (6-10 membered) heterocycloalkyl or (6-10 membered) heteroaryl, wherein said (6-10 membered) heterocycloalkyl or (6-10 membered) heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, -OR 3 , halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl and (3-6 membered)heterocycloalkyl;

[0015] 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 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 to which it is attached, it 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;

[0016] 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;

[0017] Each R 3bare 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;

[0018] 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;

[0019] Each R 4R 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 to which it is attached, it 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;

[0020] Each R 5 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 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, it 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, -CN, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl and (C3-C8) cycloalkyl.

[0021] In another preferred embodiment, wherein in the general formula (1), R a1 、R a2 、R a3 and R 1Each 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 is each independently 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; or R a3 and R 1 Together with the carbon atom to which they are attached, they form a (C3-C8 membered)cycloalkyl, (4-8 membered)heterocycloalkyl, phenyl or (5-6 membered)heteroaryl group, wherein said (C3-C8 membered)cycloalkyl, (4-8 membered)heterocycloalkyl, phenyl or (5-6 membered)heteroaryl group may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl.

[0022] In another preferred embodiment, wherein in the general formula (1), R a1 、R a2 、R a3 and R 1 Each is independently: -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, -OCH2CH3, -OCH(CH3)2,

[0023] In another preferred embodiment, wherein in the general formula (1), R a3 and R 1 Together with the carbon atoms to which they are attached, they form the following structural units:

[0024] In another preferred embodiment, wherein in the general formula (1), when R a1 、R a2 、R a3 and R 1 When neither is -CN, R 2 for: where X 4 、X 5 、X 6 、X 7 、X 8 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, and X 4 、X 5 、X 6 、X 7 、X 8 4 of them are not -H at the same time; or X 4 and X 5 Yes, X 5 and X 6 Yes, X 6 and X 7 Yes, X 7 and X 8 Each of the pairs can independently form, together with the carbon atom to which they are attached, a (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 can 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; or R 2is (6-10 membered)heterocycloalkyl or (6-10 membered)heteroaryl, wherein said (6-10 membered)heterocycloalkyl or (6-10 membered)heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -F, -C1, -Br, -I, -OH, -OCH3, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl and (3-6 membered)heterocycloalkyl.

[0025] In another preferred embodiment, wherein in the general formula (1), when R a1 、R a2 、R a3 and R 1 When neither is -CN, R 2 for:

[0026] In another preferred embodiment, wherein in the general formula (1), when R a1 、R a2 、R a3 and R 1 When at least one of them is -CN; or when R a3 and R 1 Together with the carbon atoms to which they are attached, they form a (C4-C9)cycloalkenyl, (4-9-membered)heterocycloalkyl or (5-10-membered)heteroaryl group, wherein said (C4-C9)cycloalkenyl, (4-9-membered)heterocycloalkyl 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, R 2 for: where X 4 、X 5 、X 6 、X 7 、X 8 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, and X 4 、X 5 、X 6 、X 7 、X 8 At least 4 of them are not -H at the same time; or X 4 and X5 Yes, X 5 and X 6 Yes, X 6 and X 7 Yes, X 7 and X 8 Each of the pairs can independently form with the carbon atom to which they are attached a (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 can 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- or R2 is (6-10 membered)heterocycloalkyl or (6-10 membered)heteroaryl, wherein said (6-10 membered)heterocycloalkyl or (6-10 membered)heteroaryl may each independently be optionally substituted with 1, 2, 3 or 4 of -H, -F, -Cl, -Br, -I, -OH, -OCH3, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl and (3-6 membered)heterocycloalkyl.

[0027] In another preferred embodiment, wherein in the general formula (1), when R a1 、R a2 、R a3 and R 1 When at least one of them is -CN; or when R a3 and R 1 Together with the carbon atoms to which they are attached, they form a (C4-C9)cycloalkenyl, (4-9-membered)heterocycloalkyl or (5-10-membered)heteroaryl group, wherein said (C4-C9)cycloalkenyl, (4-9-membered)heterocycloalkyl 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, R 2 for:

[0028] 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.

[0029] In another preferred embodiment, wherein in the general formula (1), each R 3 Independently: -H, -CF3, -CH2CF3, -SO2CH3, -SO2CH2CH3 or -SO2CH(CH3)2.

[0030] 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.

[0031] In another preferred embodiment, wherein in the general formula (1), each R 3a Independently: -CF3, -CH2CF3,

[0032] 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.

[0033] 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,

[0034] 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.

[0035] In another preferred embodiment, in the general formula (1), each Q is independently:

[0036] 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.

[0037] In another preferred embodiment, wherein in the general formula (1), each R 4 are independently: -H, -OCH3, -OCH2CH3, -OCH(CH3)2, -CF3, -CH2CF3,

[0038] 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, -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, -C1, -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, -C1, -Br, -I, -OH, -CN, (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C3) haloalkyl, (C2-C4) alkenyl, (C2-C4) alkynyl and (C3-C6) cycloalkyl.

[0039] In another preferred embodiment, wherein in the general formula (1), each R 5 Independently: -H, -CF3, -CH2CF3, -SO2CH3, -SO2CH2CH3 or -SO2CH(CH3)2.

[0040] In another specific embodiment of the present invention, the compound of formula (1) has one of the following structures:

[0041] 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.

[0042] 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.

[0043] 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.

[0044] By synthesizing and carefully studying a variety of new compounds with MYT1 inhibitory effects, the inventors found that among the compounds of formula (1), the compounds unexpectedly have strong MYT1 inhibitory activity.

[0045] 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.

[0046] Synthesis of compounds

[0047] 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.

[0048] 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.

[0049] 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:

[0050] General reaction scheme 1

[0051] An embodiment of the compound of formula (1) can be prepared according to the general reaction scheme 1, wherein R 1 、R 2 、X 1 and X 3 As defined above, X represents iodine or bromine, N represents nitrogen, O represents oxygen, and Br represents bromine. As shown in General Reaction Scheme 1, compound 1-1 and compound 1-2 undergo a coupling reaction in the presence of Pd2(dba)3 to produce compound 1-3. Compound 1-3 and compound 1-4 undergo a coupling reaction in the presence of Pd(dppf)Cl2 to produce compound 1-5. The cyano group of compound 1-5 undergoes hydrolysis under acidic conditions to produce amide compound 1-6. In some cases, compound 1-6 is deprotected to produce compound 1-7. In some cases, compound 1-7 is subjected to chiral resolution to obtain atropisomers 1-7-A and 1-7-B.

[0052] Further forms of compounds

[0053] "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.

[0054] 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, including, but not limited to, those found in Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use. stAcids and Bases in Ed., (Wiley, 2002).

[0055] 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.

[0056] 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.

[0057] In another aspect, the 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, atropisomers and cis-trans isomers. Each chiral center or axial chirality will independently produce two optical isomers or atropisomers, and all possible optical isomers, atropisomers, 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.

[0058] 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( 14C). 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.

[0059] the term

[0060] 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.

[0061] Unless otherwise specified, "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. Preferred are lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3, CH3CH2, CF3, CHF2, CF3CH2, CF3(CH3)CH, i Pr, n Pr, i Bu, n Bu or t Bu.

[0062] 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.

[0063] Unless otherwise specified, "alkenyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon double bond, including straight or branched chain groups of 1 to 14 carbon atoms. Preferably, the lower alkenyl group contains 1 to 4 carbon atoms, such as vinyl, 1-propenyl, 1-butenyl or 2-methylpropenyl.

[0064] Unless otherwise specified, "alkenylene" refers to a divalent alkenyl group as defined above.

[0065] Unless otherwise specified, "alkynyl" refers to an unsaturated aliphatic hydrocarbon group containing a carbon-carbon triple bond, including straight and branched chain groups of 1 to 14 carbon atoms. Preferably, the lower alkynyl group contains 1 to 4 carbon atoms, such as ethynyl, 1-propynyl or 1-butynyl.

[0066] Unless otherwise specified, "alkynylene" refers to a divalent alkynyl group as defined above.

[0067] Unless otherwise specified, "cycloalkyl" refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic). If the carbocyclic ring contains at least one double bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkenyl group", or if the carbocyclic ring contains at least one triple bond, the partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl group". Cycloalkyl groups may include monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) groups and spirocycles. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. The ring-forming carbon atoms of the cycloalkyl group may optionally be oxidized to form an oxo or 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.

[0068] Unless otherwise specified, "cycloalkylene" refers to a divalent cycloalkyl group as defined above.

[0069] 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.

[0070] 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.

[0071] 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.

[0072] Unless otherwise specified, "arylene" refers to a divalent aromatic radical as defined above. Examples of arylene radicals include, but are not limited to, phenylene, naphthylene, and phenanthrenylene.

[0073] Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S, or N), preferably an aromatic group containing 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen, and more preferably an aromatic group containing 1-2 heteroatoms selected from oxygen, sulfur, or nitrogen. Heteroaryl groups can be monocyclic or polycyclic. For example, a monocyclic heteroaryl ring is fused to one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, benzopyridinyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-c]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl,

[0074] Unless otherwise specified, "heteroarylene" refers to a divalent heteroaryl group as defined above.

[0075] Unless otherwise specified, "heterocycloalkyl" refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, having at least one heteroatom ring member independently selected from boron, phosphorus, nitrogen, sulfur, oxygen and phosphorus, 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 1-2 heteroatoms selected from oxygen, sulfur or nitrogen. If the heterocycloalkyl contains at least one double bond, the partially unsaturated heterocycloalkyl may be referred to as a "heterocycloalkenyl", or if the heterocycloalkyl contains at least one triple bond, the partially unsaturated heterocycloalkyl may be referred to as a "heterocycloalkynyl". Heterocycloalkyl may include monocyclic, bicyclic, spirocyclic or polycyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. The ring-forming carbon atoms and heteroatoms of 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 ... oxazolo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrolactamyl, valerolactamyl, imidazolinyl, hydantoinyl, dioxolane, phthalimide, pyrimidine-2,4(1H,3H)-dione, 1,4-dioxane, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazinyl, pyranyl, pyridonyl, 3-pyrrolinyl, thiopyranyl, pyranonyl, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolinyl,

[0076] Unless otherwise specified, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as defined above.

[0077] 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" ”.

[0078] 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.

[0079] 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.

[0080] "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.

[0081] 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.

[0082] 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:

[0083] When the number of a linking group is 0, such as -(CH2)0-, it means that the linking group is a single bond.

[0084] 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.

[0085] The term "membered ring" includes any cyclic structure. The term "membered" refers to the number of atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thiopyranyl are six-membered rings, while cyclopentyl, pyrrolyl, furanyl, and thiophenyl are five-membered rings.

[0086] 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.

[0087] 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.

[0088] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a wavy line Indicates a wedge-shaped solid key or dotted wedge key

[0089] Unless otherwise stated, Indicates a single bond or a double bond.

[0090] Specific pharmaceutical and medical terms

[0091] 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.

[0092] 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.

[0093] "Active ingredient" refers to the compound of formula (1), and the pharmaceutically acceptable inorganic or organic salt 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, atropisomers. 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, atropisomers and diastereomeric mixtures and 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] Therapeutic uses

[0099] 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.

[0100] 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, endometrial cancer, ovarian cancer, uterine carcinosarcoma, ovarian carcinosarcoma, pancreatic ductal adenocarcinoma, lung cancer, intestinal cancer, colorectal cancer, and esophageal cancer.

[0101] Route of administration

[0102] 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.

[0103] "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.

[0104] The compounds of the present invention may be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), or topically.

[0105] 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.

[0106] 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.

[0107] 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, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0108] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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

[0114] 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.

[0115] In all embodiments, 1 H-NMR was recorded on a Varian Mercury 400 nuclear magnetic resonance instrument, and chemical shifts are expressed in δ (ppm). Silica gel used for separation was 200-300 mesh unless otherwise specified, and the eluent ratios were by volume.

[0116] 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 hydride; 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.

[0117] Example 1 Synthesis of Compound 1

[0118] Step 1: Synthesis of compound int_1-3:

[0119] 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 mixed solvent 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 that 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%).

[0120] 1 H NMR: (400MHz, CHLOROFORM-d) δ6.94 (t, J=9.0Hz, 1H), 2.24-2.13 (m, 6H).

[0121] Step 2: Synthesis of compound int_1-4:

[0122] 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 reacted at 80°C for 2 hours. Additional MeONa (3.85 g, 21.37 mmol, 30% purity) was added, and the reaction mixture was reacted at 80°C for 8 hours. Additional MeONa (4.81 g, 26.7 mmol, 30% purity) was added, and the reaction mixture was reacted at 80°C for 10 hours. TLC monitoring indicated that 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.

[0123] 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).

[0124] Step 3: Synthesis of compound int_1-5:

[0125] Int_1-4 (880 mg, 4.42 mmol) was dissolved in ethanol (3 mL) and water (2 mL), and 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 (730 mg, yield: 97.7%).

[0126] 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).

[0127] ESI-MS m / z: 170 [M+H] + .

[0128] Step 4: Synthesis of compound int_1-7:

[0129] Int_1-5 (700 mg, 4.14 mmol) and int_1-6 (1.10 g, 4.14 mmol) were dissolved in DME (10 mL), and Cs2CO3 (3.24 g, 9.93 mmol), Xantphos (239 mg, 414 umol), and Pd2(dba)3 (379 mg, 414 umol) were added. The reaction solution was nitrogen-purged three times and heated to 90°C for 16 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, PE / EtOAc=10 / 1) to obtain a solid (1.2 g, yield: 82.1%).

[0130] 1H NMR: (400MHz, CHLOROFORM-d) δ7.45 (s, 1H), 6.55 (d, J=11.4Hz, 1H), 6.20 (br s, 1H), 3.82 (s, 3H), 2.24-2.11 (m, 6H), 2.05 (d, J=2.8Hz, 6H).

[0131] ESI-MS m / z: 353 [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 h. To the reaction mixture were added int_1-7 (300 mg, 849 umol), CuI (80.9 mg, 425 umol), and DMEDA (37.4 mg, 425 umol). The reaction mixture was purged with nitrogen three times and heated to 90°C for 16 h. The reaction was monitored by LC-MS. After cooling to room temperature, water (50 mL) was added to the reaction mixture. 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 obtain a solid (270 mg, yield: 94.0%).

[0134] 1 H NMR: (400MHz, CHLOROFORM-d) δ7.51 (s, 1H), 6.78 (d, J=11.1Hz, 1H), 4.53 (s, 2 H), 3.87 (s, 3H), 2.39 (s, 3H), 2.33 (s, 3H), 1.82 (d, J=2.0Hz, 3H), 1.80 (s, 3H).

[0135] ESI-MS m / z: 339[M+H] + .

[0136] Step 6: Synthesis of compound int_1-10:

[0137] Sulfuric acid (4 mL) was slowly added to int_1-9 (220 mg, 650 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 (160 mg, yield: 69.1%).

[0138] 1 H NMR: (400MHz, CHLOROFORM-d) δ7.38 (s, 1H), 6.77 (d, J=11.2Hz, 1H), 5.89 (br s, 2H), 5.43 (br s, 2H), 3.87 (s, 3H), 2.38 (d, J=19.8Hz, 6H), 1.88-1.78 (m, 6H).

[0139] MS (ESI): 357 [M+H] + .

[0140] Step 7: Synthesis of compound 1:

[0141] Under nitrogen, int_1-10 (80.0 mg, 224 μmol) was dissolved in dichloromethane (2 mL). BBr (562 mg, 2.24 mmol, 216 μL) 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 NaHPO (1.5 g) were slowly added to the reaction mixture. The aqueous phase was adjusted to pH 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 the crude product, which was then purified by column chromatography to yield compound 1 (70 mg, yield: 91.3%).

[0142] 1 H NMR (400MHz, DMSO-d6) δ10.03 (br s, 1H), 7.83 (s, 1H), 6.84 (s, 2H), 6.79 (d, J=11.3Hz, 1H), 6.65 (br s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.63 (s, 3H), 1.61 (s, 3H).

[0143] MS (ESI): 343 [M+H] + .

[0144] Example 2 Synthesis of Compound 2 and Compound 3

[0145] Compound 1 (120 mg, 0.35 mmol) was subjected to preparative SFC chiral separation (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); mobile phase: A: CO2, B: EtOH (0.1% NH3H2O); B%: 50%-50%, min) to obtain compound 3 (20 mg, yield: 33.3%) and compound 2 (20 mg, yield: 33.3%).

[0146] Compound 2: 1 H NMR (400MHz, DMSO-d6) δ 10.03 (br s, 1H), 7.83 (s, 1H), 6.84 (s, 2H), 6.79 (d, J=11.3Hz, 1H), 6.65 (br s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.65 (s, 3H), 1.61 (s, 3H).

[0147] MS (ESI): 343 [M+H] + .

[0148] Analysis SFC retention time: 2.129min (Instrument: Waters UPCC with PDA Detector; Column: Cellulose-2, 100x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 2.8mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0149] Compound 3: 1 H NMR (400MHz, DMSO-d6) δ9.98 (br s, 1H), 7.84 (s, 1H), 6.85 (s, 2H), 6.79 (d, J=11.3Hz, 1H), 6.66 (br s, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 1.65 (s, 3H), 1.62 (s, 3H).

[0150] MS (ESI): 343 [M+H] + .

[0151] Analysis SFC retention time: 2.708min (Instrument: Waters UPCC with PDA Detector; Column: Cellulose-2, 100x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Isocratic: 40% B; Flow rate: 2.8mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0152] Example 3 Synthesis of Compound 5

[0153] Step 1: Synthesis of compound int_5-2:

[0154] Int_5-1 (23.0 g, 163 mmol) was dissolved in acetonitrile (400 mL), NBS (72.5 g, 407 mmol) was slowly added thereto, and the reaction solution was stirred at room temperature for 5 hours. TLC monitoring showed that the reaction was complete. Water (500 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (500 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-10% THF / Petroleum ether gradient) to give an orange solid (7 g, yield: 14.4%).

[0155] ESI-MS m / z: 299 [M+H] + .

[0156] Step 2: Synthesis of compound int_5-3:

[0157] Int_5-2 (7.00 g, 23.4 mmol), int_1-2 (4.41 g, 35.1 mmol, 4.91 mL), Pd(dppf)Cl2 (1.71 g, 2.34 mmol) and Cs2CO3 (22.9 g, 70.3 mmol) were dissolved in a mixed solvent of 1,4-dioxane (80 mL) and water (8 mL), replaced with nitrogen three times, and the mixture was heated to 100 ° C and stirred for 12 hours. TLC monitoring showed that the reaction was complete. Water (100 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (200 mLX3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-50% THF / Petroleum ether gradient) to give a white solid (2.2 g, yield: 55.5%).

[0158] ESI-MS m / z: 170 [M+H] + .

[0159] Step 3: Synthesis of compound int_5-4:

[0160] Int_5-3 (2.00 g, 11.8 mmol) and int_1-6 (3.44 g, 13.0 mmol) were dissolved in DME (25 mL), and Cs2CO3 (9.24 g, 28.4 mmol), Xantphos (684 mg, 1.18 mmol) and Pd2(dba)3 (1.08 g, 1.18 mmol) were added. The reaction solution was replaced with nitrogen three times, and the temperature was raised to 90 ° C. for 16 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-50% THF / Petroleum ether gradient) to obtain a solid (3.8 g, yield: 91.3%).

[0161] 1 H NMR: (400MHz, DMSO-d6) δ7.59 (s, 1H), 7.32 (s, 1H), 7.00 (d, J=12.0Hz, 1H), 3.78 (s, 3H), 2.08 (s, 3H), 2.06 (s, 6H), 2.02 (s, 3H).

[0162] ESI-MS m / z: 353 [M+H] + .

[0163] Step 4: Synthesis of compound int_5-5:

[0164] Int_1-8 (823 mg, 12.5 mmol, 784 uL) and Cs2CO3 (3.69 g, 11.3 mmol) were dissolved in DMF (20 mL), the reaction solution was heated to 40 ° C for 0.5 hours, and int_5-4 (2.00 g, 5.66 mmol), CuI (324 mg, 1.70 mmol) and (1R, 2R)-N1, N2-dimethylcyclohexane-1, 2-diamine (242 mg, 1.70 mmol) were added to the reaction solution. The reaction solution was replaced with nitrogen three times, and the temperature was raised to 100 ° C for 16 hours. The reaction was monitored by LC-MS and the reaction was completed. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-50% THF / Petroleum ether gradient) to obtain a solid (400 mg, yield: 20.9%).

[0165] ESI-MS m / z: 339[M+H] + .

[0166] Step 5: Synthesis of compound int_5-6:

[0167] At 0°C, sulfuric acid (6 mL) was slowly added to int_5-5 (0.500 g, 1.48 mmol), and the reaction solution was reacted at 25°C for 2 hours. The reaction was completed after LC-MS monitoring. Ice water (30 mL) was slowly added to the reaction solution, and the pH value of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate (50 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-80% EA / Petroleum ether gradient) to obtain a solid (300 mg, yield: 57%).

[0168] MS (ESI): 357 [M+H] + .

[0169] Step 6: Synthesis of compound 5:

[0170] Under nitrogen protection, int_1-10 (0.300 g, 842 umol) was dissolved in dichloromethane (3 mL). BBr3 (2.11 g, 8.42 mmol, 811 uL) was added to the reaction solution at 0 ° C. The reaction solution was reacted at 0 ° C for 2 hours under nitrogen protection. The reaction was completed by LC-MS monitoring. The pH value of the reaction solution was adjusted to 7 with saturated sodium carbonate aqueous solution, extracted with ethyl acetate (40 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-10% MeOH / DCM gradient) to give compound 5 (150 mg, yield: 52.1%).

[0171] 1 H NMR (400MHz, DMSO-d6) δ7.83 (s, 1H), 7.10 (d, J=11.5Hz, 1H), 6.86-6.77 (m, 2H), 6.65 (br s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.76 (s, 3H), 1.71 (s, 3H).

[0172] MS (ESI): 343 [M+H] + .

[0173] Example 4 Synthesis of Compound 6 and Compound 7

[0174] Compound 5 (150 mg, 438 umol) was subjected to preparative SFC chiral separation (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um); mobile phase: A: CO2, B: EtOH (0.1% NH3H2O); B%: 25%-25%, min) to give compound 6 (30 mg, yield: 40%) and compound 7 (30 mg, yield: 40%).

[0175] Compound 7: 1 H NMR (400MHz, DMSO-d6) δ9.56 (bf s, 1H), 7.83 (s, 1H), 7.10 (d, J=11.5Hz, 1H), 6.82 (br s, 2H), 6.65 (br s, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.76 (s, 3H), 1.71 (s, 3H).

[0176] MS (ESI): 343 [M+H] + .

[0177] Analytical SFC retention time: 3.545min (Instrument: Waters UPCC with PDA Detector; Column; Chiralpak AD-3, 150x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4min and from 40% to 5% of B in 0.2min, then hold 5% of B for 1.8min; Flow rate: 2.5mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0178] Compound 6: 1 H NMR (400MHz, DMSO-d6) δ9.55 (d, J=1.3Hz, 1H), 7.83 (s, 1H), 7.10 (d, J=11.5Hz, 1H), 6.85-6.77 (m, 2H), 6.65 (br s, 2H), 2.27 (s, 3H), 2.25 (s, 3H), 1.76 (s, 3H), 1.71 (s, 3H).

[0179] MS (ESI): 343 [M+H] + .

[0180] Analytical SFC retention time: 3.727min (Instrument: Waters UPCC with PDA Detector; Column: Chiralpak AD-3, 150x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4min and from 40% to 5% of B in 0.2min, then hold 5% of B for 1.8min; Flow rate: 2.5mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0181] Example 5 Synthesis of Compound 9

[0182] Step 1: Synthesis of compound int_9-2:

[0183] Int_9-1 (7.30 g, 41.0 mmol) was dissolved in THF (25 mL), and NBS (7.30 g, 41.0 mmol) was slowly added to the reaction solution. The reaction solution was heated to 60 ° C and stirred for 9.5 hours. TLC monitoring showed that the reaction was complete. Water (30 mL) was added to the reaction solution, and solid precipitated. The reaction solution was filtered, and the filter cake was washed with water (10 mL). The filter cake was collected and dried under vacuum to obtain a crude product (6.05 g, yield: 69.3%). The crude product was used directly in the next reaction.

[0184] 1 H NMR: (400MHz, DMSO-d6) δ12.91 (br s, 1H), 8.19 (s, 1H), 2.38 (s, 3H).

[0185] Step 2: Synthesis of compound int_9-3:

[0186] POBr3 (81.4 g, 284 mmol, 28.9 mL) was heated to 60°C, and then int_9-2 (6.05 g, 28.4 mmol) was slowly added to POBr3. The reaction solution was heated to 100°C and reacted for 1 hour. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution (800 mL) was added to the reaction solution to adjust the pH value to 8. The aqueous phase was extracted with ethyl acetate (500 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, PE / EtOAc=10 / 1) to obtain a solid (6.1 g, yield: 77.9%).

[0187] 1 H NMR: (400MHz, CHLOROFORM-d) δ8.03 (s, 1H), 2.72 (s, 3H).

[0188] Step 3: Synthesis of compound int_9-5:

[0189] Int_9-3 (3.80 g, 13.8 mmol) and int_9-4 (2.50 g, 16.5 mmol) were dissolved in toluene (40 mL), and Cs2CO3 (4.71 g, 14.5 mmol), Xantphos (797 mg, 1.38 mmol) and Pd2(dba)3 (1.26 g, 1.38 mmol) were added. The reaction solution was nitrogen-purged three times and heated to 80°C for 16 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (100 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (200 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, PE / EtOAc=30 / 1) to give a solid (1.2 g, yield: 25.1%).

[0190] 1 H NMR: (400MHz, CHLOROFORM-d) δ7.81 (s, 1H), 7.07 (d, J=8.4Hz, 1H), 6.79 (d, J=8.5Hz, 2H), 3.84 (s, 3H), 2.42 (s, 3H), 2.12 (s, 3H), 2.05 (s, 3H).

[0191] Step 4: Synthesis of compound int_9-7:

[0192] Int_9-6 (859 mg, 8.66 mmol, 767 μL) was dissolved in DME (12 mL). The reaction solution was cooled to -30°C. Under nitrogen, NaH (693 mg, 17.3 mmol, 60% purity) was slowly added to the reaction solution. The reaction solution was heated to 0°C for 0.5 hours. Then, int_9-5 (500 mg, 1.44 mmol) and Pd(dppf)Cl2·CH2Cl2 (118 mg, 144 μmol) were added to the reaction solution at 0°C. The reaction solution was heated to 90°C under nitrogen for 1 hour. The reaction was monitored by LC-MS. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (423 mg, yield: 80.7%).

[0193] 1H NMR: (400MHz, CHLOROFORM-d) δ8.16 (br s, 1H), 7.22 (d, J=8.5Hz, 1H), 6.97 (d, J=8.4Hz, 1H), 5.72 (br s, 2H), 3.95 (s, 3H), 3.88 (s, 3H), 2.63 (s, 3H), 1.90 (s, 3H), 1.83 (s, 3H).

[0194] ESI-MS m / z: 365[M+H] + .

[0195] Step 5: Synthesis of compound int_9-8:

[0196] Int_9-7 (335 mg, 919 μmol) and NaOH (4 M, 6.89 mL) were dissolved in a mixed solvent of methanol (6 mL) and tetrahydrofuran (6 mL). The reaction mixture was heated to 50°C for 24 hours. TLC monitoring indicated that the reaction was complete. The reaction mixture was cooled to room temperature, tetrahydrofuran (10 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure to obtain a solid. The solid was dissolved in DMSO (10 mL) and filtered. The filter cake was washed with water (10 mL) and dried under vacuum to obtain a crude product (128 mg, yield: 40%). The crude product was used directly in the next reaction.

[0197] ESI-MS m / z: 351[M+H] + .

[0198] Step 6: Synthesis of compound int_9-9:

[0199] Int_9-8 (385 mg, 1.10 mmol), PMBNH2 (756 mg, 5.51 mmol, 716 μL), and TEA (893 mg, 8.82 mmol, 1.23 mL) were dissolved in a mixture of acetonitrile (15 mL) and DMSO (15 mL). HATU (1.47 g, 3.86 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was then heated to 20°C for 16 hours. LC-MS monitoring indicated the reaction was complete. Water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 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 (SiO2, PE / EtOAc = 2 / 1) to obtain a solid (150 mg, yield: 29%).

[0200] 1H NMR: (400MHz, CHLOROFORM-d) δ7.71 (s, 1H), 7.38 (d, J=8.6Hz, 2H), 7.24 (d, J=8.4Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 6.96 (br d, J=8.6Hz, 2H), 6.10 (br s, 2H), 5.77 (s, 1H), 4.66 (d, J=5.5Hz, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.62 (s, 3H), 1.92 (s, 3H), 1.85 (s, 3H).

[0201] ESI-MS m / z: 470 [M+H] + .

[0202] Step 7: Synthesis of compound int_9-10:

[0203] Int_9-9 (150 mg, 319 μmol) and TFA (3 mL) were dissolved in acetonitrile (1 mL), and the reaction mixture was heated to 50°C for 4 hours. LC-MS monitoring indicated the reaction was complete. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, and the aqueous phase was 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 purified by preparative plate chromatography (SiO2, PE / EtOAc = 2 / 3) to obtain a solid (53 mg, yield: 47.7%).

[0204] ESI-MS m / z: 350 [M+H] + .

[0205] Step 8: Synthesis of compound 9:

[0206] Under nitrogen protection, int_9-10 (53.1 mg, 152 μmol) was dissolved in dichloromethane (3 mL). BBr3 (653 mg, 2.60 mmol, 251 μL) was added to the reaction solution at 0°C. The reaction solution was reacted at 0°C under nitrogen protection for 3 hours. The reaction was monitored by LC-MS. Ice water (20 mL) was slowly added to the reaction solution. The pH value of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The solution was extracted with ethyl acetate (30 mL*3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 2) to obtain compound 9 (40 mg, yield: 78.5%).

[0207] 1H NMR: (400MHz, DMSO-d6) δ9.62 (br s, 1H), 8.41 (s, 1H), 7.15 (s, 2H), 7.08 (d, J = 8.1Hz, 1H), 6.93 (d, J = 8.4Hz, 1H), 6.91 (br s, 2H), 2.54 (s, 3H), 1.74 (s, 3H), 1.65 (s, 3H).

[0208] MS (ESI): 336 [M+H] + .

[0209] Example 6 Synthesis of Compound 10 and Compound 11

[0210] Compound 9 (40 mg, 119 umol) was subjected to preparative SFC chiral separation (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 um); mobile phase: A: CO2, B: EtOH (0.1% NH3H2O); B%: 30%-30%, min) to give compound 10 (9 mg, yield: 45%) and compound 11 (10 mg, yield: 50%).

[0211] Compound 10: 1 H NMR: (400MHz, DMSO-d6) δ9.62 (br s, 1H), 8.41 (s, 1H), 7.15 (s, 2H), 7.08 (d, J = 8.1Hz, 1H), 6.93 (d, J = 8.4Hz, 1H), 6.91 (br s, 2H), 2.54 (s, 3H), 1.74 (s, 3H), 1.65 (s, 3H).

[0212] MS (ESI): 336 [M+H] + .

[0213] Analytical SFC retention time: 3.941min (Instrument: Waters UPCC with PDA Detector; Column: Chiralcel OJ-3, 150x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4min and hold 40% for 2min, then 5% of B for 2min; Flow rate: 2.5mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0214] Compound 11: 1 H NMR: (400MHz, DMSO-d6) δ9.61 (s, 1H), 8.41 (s, 1H), 7.15 (s, 2H), 7.08 (d, J = 8.4Hz, 1H), 6.93 (d, J = 8.1Hz, 1H), 6.91 (br s, 2H), 2.58-2.52 (m, 3H), 1.74 (s, 3H), 1.65 (s, 3H).

[0215] MS (ESI): 336 [M+H] + .

[0216] Analysis SFC retention time: 4.240min (Instrument: Waters UPCC with PDA Detector; Column: Chiralcel OJ-3, 150x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4min and hold 40% for 2min, then 5% of Bfor 2min; Flow rate: 2.5mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0217] Example 7 Synthesis of Compound 12

[0218] Step 1: Synthesis of compound int_12-2:

[0219] Int_12-1 (40.0 g, 174 mmol) was dissolved in DCM (1500 mL), and m-CPBA (106 g, 522 mmol, 85.0% purity) was slowly added to the reaction solution at 0 ° C. The reaction solution was heated to room temperature and stirred for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was filtered to remove excess m-CPBA, the filtrate was collected, and the filtrate was added to a saturated Na2S2O3 solution and stirred for 1 hour. The aqueous phase was extracted with ethyl acetate (200 mLX3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-30% EA / Petroleum ether gradient) to obtain a solid (17 g, yield: 39.7%).

[0220] 1 H NMR (400 MHz, CHLOROFORM-d) δ = 8.18 (d, J = 0.6 Hz, 1H), 7.23 (s, 1H), 7.20 (s, 1H), 3.94 (s, 3H), 2.22 (s, 3H).

[0221] Step 2: Synthesis of compound int_12-3:

[0222] Int_12-2 (16.0 g, 65.0 mmol) was dissolved in DMF (200 mL), and TFAA (150 g, 715 mmol, 99.4 mL) was slowly added to the reaction solution at 20 ° C. The reaction solution was stirred at room temperature for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was poured into ice water and neutralized by adding saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (200 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-10% EA / Petroleum ether gradient) to obtain a solid (12 g, yield: 75%).

[0223] Step 3: Synthesis of compound int_12-4:

[0224] Int_12-3 (4.00 g, 16.3 mmol) was slowly added to POBr3 (46.6 g, 163 mmol, 16.5 mL), and the reaction solution was heated to 90 ° C for 4 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, poured into ice water, the aqueous phase was extracted with dichloromethane (100 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-10% EA / Petroleum ether gradient) to obtain a solid (3 g, yield: 59.7%).

[0225] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.87 (s, 1H), 3.99 (s, 3H), 3.52 (s, 1H), 2.56 (s, 3H).

[0226] Step 4: Synthesis of compound int_12-5:

[0227] Int_12-4 (2.00 g, 6.47 mmol) and int_9-4 (979 mg, 6.47 mmol) were dissolved in DME (30.0 mL), and Cs2CO3 (4.22 g, 13.0 mmol), Xantphos (375 mg, 647 μmol) and Pd2(dba)3 (593 mg, 647 μmol) were added. The reaction solution was replaced with nitrogen three times, and the temperature was raised to 95 ° C. for 16 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mLX3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-10% EA / Petroleum ether gradient) to obtain a solid (1 g, yield: 40.7%).

[0228] ESI-MS m / z: 379[M+H] + .

[0229] Step 5: Synthesis of compound int_12-6:

[0230] Int_12-5 (1.00 g, 2.64 mmol) was dissolved in aqueous ammonia (20.0 mL), and the reaction mixture was heated to 55°C for 16 hours. LC-MS monitoring showed that the reaction was complete. After the reaction mixture was cooled to room temperature, the aqueous phase 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 a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-20% EA / Petroleum ether gradient) to obtain a solid (0.6 g, yield: 62.5%).

[0231] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.68 (s, 1H), 7.32-7.23 (m, 2H), 7.09 (d, J = 8.4Hz, 1H), 6 .77 (d, J=8.4Hz, 1H), 6.37 (s, 1H), 3.86 (s, 3H), 2.60 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H).

[0232] ESI-MS m / z: 364[M+H] + .

[0233] Step 6: Synthesis of compound int_12-7:

[0234] Int_12-6 (0.600 g, 1.65 mmol) was dissolved in tetrahydrofuran (10 mL), and TEA (1.08 g, 10.7 mmol, 1.49 mL) and TFAA (900 mg, 4.28 mmol, 595 μL) were slowly added to the reaction solution at 0 ° C. The reaction solution was heated to room temperature and stirred for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was poured into ice water, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-20% EA / Petroleum ether gradient) to give a solid (550 mg, yield: 96.4%).

[0235] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.71 (s, 1H), 7.13-7.03 (m, 1H), 6.84-6.73 (m , 1H), 6.54-6.41(m, 1H), 3.87(s, 3H), 2.40(s, 3H), 2.15(s, 3H), 2.08(s, 3H).

[0236] ESI-MS m / z: 346 [M+H] + .

[0237] Step 7: Synthesis of compound int_12-8:

[0238] Int_9-6 (1.22 g, 8.66 mmol, 1.24 mL) was dissolved in DME (15 mL), and the reaction solution was cooled to -30 ° C. Under nitrogen protection, NaH (693 mg, 17.3 mmol, 60.0% purity) was slowly added to the reaction solution, and the reaction solution was heated to 0 ° C for 0.5 hours. Then, int_12-7 (500 mg, 1.44 mmol) and Pd (dppf) Cl2 · CH2Cl2 (118 mg, 144 μmol) were added to the reaction solution at 0 ° C. The reaction solution was heated to 90 ° C for 1 hour under nitrogen protection. The reaction was completed by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-100% EA / Petroleum ether gradient) to obtain a solid (500 mg, yield: 95.2%).

[0239] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.93-7.84 (m, 1H), 7.28 (s, 2H), 7.23 (d, J = 8.3Hz, 1H), 6.9 9 (d, J=8.4Hz, 1H), 3.98 (s, 3H), 3.90 (s, 3H), 2.61 (s, 3H), 1.95-1.89 (m, 3H), 1.85 (s, 3H).

[0240] ESI-MS m / z: 365[M+H] + .

[0241] Step 8: Synthesis of compound int_12-9:

[0242] Int_12-8 (400 mg, 1.10 mmol) and NaOH (4.00 M, 8.23 ​​mL) were dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (5 mL), and the reaction solution was heated to 50 ° C for 72 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a solid. The solid was dissolved in water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×3). The aqueous phase was then neutralized with 1 M hydrochloric acid aqueous solution to a pH of 5-6, and the aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phases at this time were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (208 mg, yield: 54%). The crude product can be used directly in the next reaction.

[0243] ESI-MS m / z: 351[M+H] + .

[0244] Step 9: Synthesis of compound int_12-10:

[0245] Int_12-9 (223 mg, 639 μmol), PMBNH2 (263 mg, 1.92 mmol, 249 μL) and TEA (323 mg, 3.20 mmol, 445 μL) were dissolved in a mixed solvent of acetonitrile (5 mL) and DMSO (5 mL). HATU (851 mg, 2.24 mmol) was slowly added to the reaction solution at 0 ° C. The reaction solution was then heated to 20 ° C. and reacted for 16 hours. LC-MS monitoring showed that the reaction was complete. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-10% EA / Petroleum ether gradient) to give a solid (160 mg, yield: 53.3%).

[0246] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.43-7.36 (m, 3H), 7.26-7.20 (m, 1H), 6.96 (br d, J=8.6Hz, 3H), 6.44-6.10 (m, 1H), 5.95-5.81 (m, 1H), 4.71-4.66 (m, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 2.59 (s, 3H), 1.92 (s, 4H), 1.85 (s, 4H).

[0247] ESI-MS m / z: 470 [M+H] + .

[0248] Step 10: Synthesis of compound int_12-11:

[0249] Int_12-10 (100 mg, 213 μmol) was dissolved in TFA (11.5 g, 101 mmol, 7.50 mL). The reaction mixture was heated to 80°C under nitrogen for 16 hours. LC-MS monitoring indicated the reaction was complete. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, and the aqueous phase was 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 purified by preparative plate chromatography (SiO2, PE / EtOAc = 1 / 2) to obtain a solid (40 mg, yield: 53.8%).

[0250] ESI-MS m / z: 350 [M+H] + .

[0251] Step 11: Synthesis of compound 12:

[0252] Under nitrogen, int_12-11 (35.0 mg, 100 μmol) was dissolved in dichloromethane (3 mL). BBr3 (376 mg, 1.50 mmol, 145 μL) was added to the reaction solution at 0°C. The reaction solution was incubated at 0°C under nitrogen for 1 hour and monitored by LC-MS. Ice water (20 mmol) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 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 purified by preparative plate chromatography (SiO2, PE / EtOAc = 1 / 4) to obtain compound 12 (5.7 mg, yield: 17%).

[0253] 1 H NMR (400MHz, CHLOROFORM-d) δ = 9.57 (s, 1H), 7.93 (s, 1H), 7.17 (br s, 2H), 7.13-7.04 (m, 3H), 6.94 (d, J = 8.3Hz, 1H), 6.84 (br s, 2H), 2.61 (s, 3H), 1.79 (s, 3H), 1.70 (s, 3H).

[0254] MS (ESI): 336 [M+H] + .

[0255] Example 8 Synthesis of Compound 15

[0256] Step 1: Synthesis of compound int_15-2:

[0257] Int_15-1 (15.0 g, 82.8 mmol) was dissolved in DCM (150 mL). Under nitrogen protection, BBr3 (31.1 g, 124 mmol, 12.0 mL) was slowly added to the reaction solution at 0°C. The reaction solution was heated to room temperature and stirred for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to 0°C, methanol (100 mL) was added to the reaction solution, and the reaction solution was continued to stir at room temperature for 2 hours and then concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-80% EA / Petroleum ether gradient) to obtain a solid (12 g, yield: 86.7%).

[0258] Step 2: Synthesis of compound int_15-3:

[0259] Int_15-2 (16.0 g, 65.0 mmol) and K2CO3 (18.2 g, 132 mmol) were dissolved in acetonitrile (100 mL). Bromomethyl methyl ether (9.87 g, 78.9 mmol, 6.45 mL) was slowly added to the reaction solution at 20 ° C. The reaction solution was heated to 50 ° C and stirred for 2 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-30% EA / Petroleum ether gradient) to obtain a solid (10 g, yield: 72.9%).

[0260] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.12-7.05 (m, 2H), 7.97 (s, 1H), 5.22 (s, 2H), 3.5 0(s, 3H), 2.19-2.55(d, 6H), 5.10(s, 2H), 4.81(s, 2H), 1.76(s, 3H), 1.67(s, 3H).

[0261] Step 3: Synthesis of compound int_15-4:

[0262] Int_15-3 (10.0 g, 47.4 mmol) and Pd / C (5 g, 10% purity) were dissolved in methanol (100 mL). The reaction solution was stirred at room temperature under a hydrogen atmosphere (50 psi) for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was filtered to remove palladium carbon, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-30% EA / Petroleum ether gradient) to give a solid (8 g, yield: 93.2%).

[0263] ESI-MS m / z: 182 [M+H] + .

[0264] Step 4: Synthesis of compound int_15-6:

[0265] Int_15-5 (50.0 g, 256 mmol) was dissolved in methanol (500 mL), and Br2 (81.9 g, 512 mmol, 26.4 mL) was slowly added to the reaction solution at 0 ° C. The reaction solution was heated to 55 ° C and stirred for 48 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was diluted with ammonia water and the pH value was adjusted to 8. The aqueous phase was extracted with ethyl acetate (300 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-50% EA / Petroleum ether gradient) to obtain a solid (56 g, yield: 79.8%).

[0266] ESI-MS m / z: 274 [M+H] + .

[0267] Step 5: Synthesis of compound int_15-7:

[0268] Under nitrogen protection, int_15-6 (30.0 g, 109 mmol) was dissolved in ethanol (350 mL). NaBH4 (24.9 g, 657 mmol) was slowly added to the reaction solution at 0°C, and then CaCl2 (10.9 g, 98.5 mmol) was slowly added. The reaction solution was heated to room temperature and stirred for 16 hours. LC-MS monitoring showed that the reaction was complete. 2N hydrochloric acid aqueous solution was added to the reaction solution to adjust the pH value to 2-3. The reaction solution was continued to stir at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a solid. The solid was neutralized with saturated sodium bicarbonate aqueous solution and the pH was adjusted to 7. The aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-80% EA / Petroleum ether gradient) to obtain a solid (15 g, yield: 62.9%).

[0269] ESI-MS m / z: 217 [M+H] + .

[0270] Step 6: Synthesis of compound int_15-8:

[0271] Under nitrogen protection, int_15-7 (15.0 g, 68.8 mmol) was dissolved in DMF (200 mL), and NaH (16.5 g, 413 mmol, 60% purity) was slowly added to the reaction solution at 0 ° C. The reaction solution was stirred at 0 ° C for 0.5 hours, and TosCl (13.1 g, 68.8 mmol) was added to the reaction solution at 0 ° C. The reaction solution was warmed to room temperature and reacted for 16 hours. LC-MS monitoring showed that the reaction was complete. Water (700 mL) was added to the reaction solution to quench the reaction, the aqueous phase was extracted with ethyl acetate (600 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-30% EA / Petroleum ether gradient) to obtain a solid (2.5 g, yield: 18.2%).

[0272] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.70 (s, 1H), 5.02 (m, 2H), 4.92 (m, 2H).

[0273] Step 7: Synthesis of compound int_15-9:

[0274] Int_15-8 (5.00 g, 25.0 mmol) was dissolved in DCM (100 mL). m-CPBA (15.39 g, 25.0 mmol, 80% purity) was slowly added to the reaction solution at 0°C. The reaction solution was warmed to room temperature and stirred for 16 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-100% EA / Petroleum ether gradient) to obtain a solid (5 g, yield: 92.6%).

[0275] ESI-MS m / z: 216 [M+H] + .

[0276] Step 8: Synthesis of compound int_15-10:

[0277] Int_15-9 (1.00 g, 4.63 mmol) was slowly added to POBr3 (7.00 g, 24.4 mmol, 2.48 mL), and the reaction mixture was heated to 70°C for 2 hours. LC-MS monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain a crude product, which was first purified by column chromatography ( The product was purified by silica flash column (eluting with 0-30% EA / petroleum ether gradient) and preparative SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [Neu-EtOH]; B%: 30%-30%, min) to give a solid (0.3 g, yield: 23.2%).

[0278] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.73 (s, 1H), 5.15-5.02 (m, 2H), 4.92-4.91 (m, 2H).

[0279] Step 9: Synthesis of compound int_15-11:

[0280] Int_15-10 (0.300 g, 1.08 mmol) and int_15-4 (292 mg, 1.61 mmol) were dissolved in DME (10.0 mL), and Cs2CO3 (701 mg, 2.15 mmol), Xantphos (62.2 mg, 108 umol) and Pd2(dba)3 (98.5 mg, 108 umol) were added. The reaction solution was replaced with nitrogen three times, and the temperature was raised to 90 ° C. for 3 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-20% EA / Petroleum ether gradient) to obtain a solid (0.3 g, yield: 73.6%).

[0281] ESI-MS m / z: 379[M+H] + .

[0282] Step 10: Synthesis of compound int_15-12:

[0283] Int_1-8 (83.6 mg, 1.27 mmol, 79.6 uL) was dissolved in DME (5 mL), and the reaction solution was cooled to -30 ° C. Under nitrogen protection, NaH (236 mg, 5.91 mmol, 60% purity) was slowly added to the reaction solution, and the reaction solution was heated to 0 ° C for 0.5 hours. Then, int_15-11 (0.160 g, 422 umol) and Pd (dppf) Cl2 · CH2Cl2 (34.45 mg, 42.19 umol) were added to the reaction solution at 0 ° C. The reaction solution was heated to 80 ° C for 1 hour under nitrogen protection. The reaction was monitored by LC-MS and the reaction was completed. After the reaction solution was cooled to room temperature, water (10 mL) was added to the reaction solution, the aqueous phase was extracted with dichloromethane (10 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-50% EA / Petroleum ether gradient) to give a solid (110 mg, yield: 71.6%).

[0284] 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.64 (s, 1H), 7.25-7.18 (m, 2H), 5.31-5.19 (m, 4H), 5.01 (s, 2H), 4.62 (s, 2H), 3.54 (s, 3H), 1.92 (d, J = 19.2Hz, 6H).

[0285] ESI-MS m / z: 365[M+H] + .

[0286] Step 11: Synthesis of compound int_15-13:

[0287] Int_15-12 (80.0 mg, 220 μmol) and LiOH.H2O (64.48 mg, 1.54 mmol) were dissolved in a mixed solution of ethanol (6 mL) and water (2 mL). H2O2 (360 mg, 2.85 mmol, 305 μL, 27% purity) was added dropwise to the reaction solution at 20°C. The reaction solution was heated to 60°C for 0.5 hours and monitored by LC-MS. The reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-100% EA / Petroleum ether gradient) to give a solid (65 mg, yield: 77.4%).

[0288] MS (ESI): 383 [M+H] + .

[0289] Step 12: Synthesis of compound 15:

[0290] Under nitrogen, int_15-13 (60.0 mg, 157 μmol) was dissolved in dichloromethane (3 mL). HCl / dioxane solution (4 M, 3.00 mL) was added to the reaction mixture at 0°C. The reaction mixture was incubated at 20°C under nitrogen for 0.5 hours. The reaction was monitored by LC-MS. Ice water (20 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 dichloromethane (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 purified by preparative column chromatography (SiO2, DCM / MeOH = 10 / 1) to obtain compound 15 (35 mg, yield: 65.9%).

[0291] 1 H NMR (400MHz, DMSO-d6) δ = 9.53 (s, 1H), 7.97 (s, 1H), 7.06 (d, J = 8.1Hz, 1H), 6.96 -6.87(m, 3H), 6.74(s, 2H), 5.10(s, 2H), 4.81(s, 2H), 1.76(s, 3H), 1.67(s, 3H).

[0292] MS (ESI): 339 [M+H] + .

[0293] Example 9 Synthesis of Compound 16 and Compound 17

[0294] Compound 15 (35 mg, 103 umol) was subjected to preparative SFC chiral separation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: A: CO2, B: MeOH (0.1% NH3H2O); B%: 30%-30%, min) to give compound 16 (7 mg, yield: 40%) and compound 17 (8 mg, yield: 45.7%).

[0295] Compound 17: 11H NMR (400 MHz, DMSO-d6) δ = 9.50 (s, 1H), 7.94 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.93 - 6.84 (m, 3H), 6.71 (s, 2H), 5.07 (s, 2H), 4.78 (s, 2H), 1.73 (s, 3H), 1.64 (s, 3H).

[0296] MS (ESI): 339 [M+H] + .

[0297] SFC retention time analysis: 3.457 min (Instrument: Waters UPCC with PDADetector; Column: Chiralpak IG-3, 100x4.6 mm, I.D., 3 um; Mobile phase: A: CO2, B: Methanol (0.05% DEA); Gradient: from 5% to 40% of B in 4 min and hold 40% for 0.5 min, then hold 5% of B for 1.5 min; Flow rate: 2.8 mL / min; Column temp.: 35 °C; ABPR: 1500 psi).

[0298] Compound 16: 1 1H NMR (400 MHz, DMSO-d6) δ = 9.52 (s, 1H), 7.96 (s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.95 - 6.86 (m, 3H), 6.73 (s, 2H), 5.09 (s, 2H), 4.80 (s, 2H), 1.75 (s, 3H), 1.66 (s, 3H).

[0299] MS (ESI): 339 [M+H] + .

[0300] Analytical SFC retention time: 3.663min (Instrument: Waters UPCC with PDADetector; Column: Chiralpak IG-3, 100x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Methanol (0.05% DEA); Gradient: from 5% to 40% of B in 4min and hold 40% for 0.5min, then hold 5% of B for 1.5min; Flow rate: 2.8mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0301] Example 10 Synthesis of Compound 96

[0302] Step 1: Synthesis of compound int_96-3:

[0303] Int_96-1 (40.0 g, 201 mmol), int_96-2 (21.4 g, 301 mmol, 25.1 mL), and TsOH.H2O (3.82 g, 20.1 mmol) were dissolved in toluene (400 mL). Under nitrogen, the reaction mixture was heated to 100°C and allowed to react for 16 hours. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to 0°C and concentrated under reduced pressure to obtain a crude product (50 g, 98.7% yield), which was used directly in the next reaction.

[0304] Step 2: Synthesis of compound int_96-5:

[0305] Int_96-3 (50.0 g, 198 mmol) and int_96-4 (20.5 g, 297 mmol) were dissolved in toluene (500 mL). The reaction mixture was heated to 100°C and stirred for 10 hours. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography (SiO2, DCM:MeOH = 96:4) to obtain a solid (18.7 g, yield: 37.9%).

[0306] 1H NMR (400MHz, CHLOROFORM-d) δ 1.49 (s, 9H) 2.76 (br t, J = 5.56Hz, 2H) 3.67 (br t, J = 5.50Hz, 2H) 4.32 (br s, 2H) 6.45 (d, J = 9.29Hz, 1H) 7.21 (d, J = 9.17Hz, 1H).

[0307] ESI-MS m / z: 251[M+H] + .

[0308] Step 3: Synthesis of compound int_96-6:

[0309] Int_96-5 (10.0 g, 40.0 mmol) was dissolved in dichloromethane (100 mL). Py.Br (14.1 g, 44.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. TLC monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography (SiO, DCM:EtOAc = 7:3) to obtain a solid (2.7 g, yield: 20%).

[0310] 1 H NMR (400MHz, CHLOROFORM-d) δ 1.49 (s, 9H) 2.78 (br s, 2H) 3.68 (br s, 2H) 4.34 (br s, 2H) 7.61 (s, 1H).

[0311] ESI-MS m / z: 329 [M+H] + .

[0312] Step 4: Synthesis of compound int_96-7:

[0313] Int_96-6 (2.70 g, 8.20 mmol) was dissolved in HCl / dioxane solution (30.0 mL) and stirred at 0°C for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction mixture was filtered, and the filter cake was collected and dried under vacuum to afford the crude product (1.6 g, 85.5% yield). The crude product was used directly in the next reaction.

[0314] ESI-MS m / z: 229 [M+H] + .

[0315] Step 5: Synthesis of compound int_96-8:

[0316] Int_96-7 (2.00 g, 7.53 mmol, hydrochloride) was dissolved in formic acid (20 mL). HCHO (905 mg, 9.04 mmol, 830 μL, 30.0% purity) was added to the reaction solution. The reaction solution was heated to 100°C and stirred for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product (1.3 g, yield: 73.5%), which was used directly in the next reaction.

[0317] ESI-MS m / z: 243 [M+H] + .

[0318] Step 6: Synthesis of compound int_96-9:

[0319] Int_96-8 (1.00 g, 4.11 mmol) was slowly added to POBr (11.8 g, 41.1 mmol, 4.18 mL). The reaction mixture was heated to 90°C for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (80 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 purified by preparative plate chromatography (SiO, DCM / MeOH = 10 / 1) to obtain a solid (230 mg, yield: 18.4%).

[0320] ESI-MS m / z: 305 [M+H] + .

[0321] Step 7: Synthesis of compound int_96-10:

[0322] Int_96-9 (220 mg, 719 μmol) and int_9-4 (109 mg, 719 μmol) were dissolved in toluene (3.0 mL), and Cs2CO3 (469 mg, 1.44 mmol), Xantphos (41.6 mg, 71.9 μmol) and Pd2(dba)3 (65.8 mg, 71.9 μmol) were added. The reaction solution was nitrogen-purged three times and heated to 100°C for 3 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, DCM:MeOH=95:5) to obtain a solid (227 mg, yield: 84%).

[0323] ESI-MS m / z: 376[M+H]+ .

[0324] Step 8: Synthesis of compound int_96-11:

[0325] Int_1-8 (87.8 mg, 1.33 mmol, 83.6 uL) was dissolved in DME (3 mL). The reaction solution was cooled to -30°C and, under nitrogen, NaH (266 mg, 6.64 mmol, 60.0% pudty) was slowly added. The reaction solution was heated to 0°C and reacted for 0.5 hours. Then, int_96-10 (250 mg, 664 umol) and Pd(dppf)Cl2·CH2Cl2 (54.3 mg, 66.4 umol) were added to the reaction solution at 0°C. The reaction solution was reacted at 0°C under nitrogen for 2 hours. The reaction was monitored by LC-MS. Water (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, DCM:MeOH=1:0-20:1) to give a solid (201 mg, yield: 84.1%).

[0326] 1 H NMR (400MHz, CHLOROFORM-d) δ1.84 (s, 3H) 1.90 (s, 3H) 2.54 (s, 3H) 2.83 (br s, 2H) 2.95-3.03 (m, 2H) 3.75 (br s, 2H) 3.88 (s, 3H) 6.95 (d, J=8.36Hz, 1H) 7.20 (d, J=8.58Hz, 1H) 7.40 (s, 1H).

[0327] ESI-MS m / z: 362[M+H] + .

[0328] Step 9: Synthesis of compound int_96-12:

[0329] Sulfuric acid (3 mL) was slowly added to int_96-11 (220 mg, 609 μmol) at 0°C. The reaction mixture was allowed to react at 25°C for 2 hours, monitored by LC-MS. Ice water (10 mL) was slowly added to the reaction mixture, and the aqueous phase was adjusted to pH 8 with saturated sodium bicarbonate solution. The mixture 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, DCM:MeOH = 10:1) to afford a solid (179 mg, yield: 77.8%).

[0330] MS (ESI): 380 [M+H] + .

[0331] Step 10: Synthesis of compound 96:

[0332] Under nitrogen, int_96-12 (200 mg, 527 μmol) was dissolved in dichloromethane (3 mL). BBr (660 mg, 2.64 mmol, 254 μL) was added to the reaction mixture at 0°C. The reaction mixture was incubated at 0°C under nitrogen for 1 hour and monitored by LC-MS. Ice water (30 mL) was slowly added to the reaction mixture. The pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (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 purified by preparative column chromatography to afford compound 96 (103 mg, 53.5% yield).

[0333] 1 H NMR (400MHz, DMSO-d6) δ1.66 (s, 3H) 1.75 (s, 3H) 2.39 (s, 3H) 2.64-2.70 (m, 2H) 2.72 (br d, J = 3.96Hz, 2H) 3.60 (br s, 2H) 6.66 (br s, 2H) 6.82 (br s, 2H) 6.90 (d, J=8.36Hz, 1H) 7.05 (d, J=8.36Hz, 1H) 7.72 (s, 1H) 9.5l (s, 1H).

[0334] MS (ESI): 366 [M+H] + .

[0335] Example 11 Synthesis of Compound 97 and Compound 98

[0336] Compound 96 (103 mg, 281 umol) was subjected to preparative SFC chiral separation (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); mobile phase: A: CO2, B: MeOH (0.1% NH3H2O); B%: 50%-50%, min) to obtain compound 97 (23 mg, yield: 44.6%) and compound 98 (29 mg, yield: 56.3%).

[0337] Compound 97: 11H NMR (400 MHz, DMSO-d6) δ 1.66 (s, 3H), 1.75 (s, 3H), 2.39 (s, 3H), 2.64 - 2.70 (m, 2H), 2.72 (br d, J = 3.96 Hz, 2H), 3.60 (br s, 2H), 6.66 (br s, 2H), 6.82 (br s, 2H), 6.90 (d, J = 8.36 Hz, 1H), 7.05 (d, J = 8.36 Hz, 1H), 7.72 (s, 1H), 9.51 (s, 1H).

[0338] MS (ESI): 366 [M + H] + .

[0339] Analysis of SFC retention time: 3.501 min (Instrument: Agilent 1260 with DAD detector; Column: Cellulose-4, 100 x 4.6 mm, I.D., 3 um; Mobile phase: A: CO2, B: Methanol (0.05% DEA); Gradient: 40% of B; Flow rate: 2.8 mL / min; Column temp.: 40 °C; ABPR: 100 bar).

[0340] Compound 98: 1 1H NMR (400 MHz, DMSO-d6) δ 1.66 (s, 3H), 1.75 (s, 3H), 2.35 (s, 3H), 2.62 (br d, J = 5.28 Hz, 2H), 2.70 (br d, J = 5.50 Hz, 2H), 3.54 (s, 2H), 6.65 (br s, 2H), 6.80 (br s, 2H), 6.91 (d, J = 8.14 Hz, 1H), 7.04 (d, J = 8.36 Hz, 1H), 7.70 (s, 1H), 9.42 - 9.82 (m, 1H).

[0341] MS (ESI): 366 [M + H] + .

[0342] Analysis SFC retention time: 4.702min (Instrument: (Agilent 1260 with DAD detector; Column: Cellulose-4, 100x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Methanol (0.05% DEA); Gradient: 40% of B; Flow rate: 2.8mL / min; Column temp.: 40℃; ABPR: 100bar).

[0343] Example 12 Synthesis of Compound 115

[0344] Step 1: Synthesis of compound int_115-2:

[0345] Int_115-1 (20.0 g, 99.5 mmol) was dissolved in acetonitrile (200 mL). NIS (33.6 g, 149 mmol) and TFA (17.0 g, 149 mmol, 11.1 mL) were added to the reaction mixture at room temperature. Under nitrogen, the reaction mixture was heated to 70°C for 16 hours. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to 0°C and concentrated under reduced pressure to obtain a solid. The solid was dissolved in dichloromethane (100 mL), washed with water (50 mL x 2), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (26.3 g, yield: 80.9%), which was used directly in the next reaction.

[0346] 1 HNMR (400MHz, DMSO-d6) δ7.75 (d, J=8.8Hz, 1H), 6.83 (d, J=8.8Hz, 1H), 3.79 (s, 3H), 2.34 (s, 3H).

[0347] Step 2: Synthesis of compound int_115-4:

[0348] Int_115-2 (25.0 g, 76.5 mmol), int_115-3 (17.3 g, 76.5 mmol), Pd(dppf)Cl2 (5.59 g, 7.65 mmol) and Cs2CO3 (2 M, 76.46 mL) were dissolved in 1,4-dioxane (250 mL). The reaction solution was replaced with nitrogen three times, and the reaction solution was heated to 100 ° C and stirred for 3 hours. TLC monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( 330g Silica Flash Column, Eluent of 0-10% Ethyl acetate / Petroleum ether gradient) to obtain a solid (12 g, yield: 52.5%).

[0349] Step 3: Synthesis of compound int_115-5:

[0350] Int_115-4 (12.0 g, 40.1 mmol) and acetic acid (241 mg, 4.01 mmol, 229 uL) were dissolved in ethyl acetate (100 mL). Pd / C (10.0 g, 401 mmol, 10% purity) was added to the reaction solution, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was replaced with hydrogen three times and the reaction solution was allowed to react at room temperature under a hydrogen atmosphere (50 PSI) for 3 hours. TLC monitoring showed that the reaction was complete. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product (12 g, yield: 99.3%), which was used directly in the next reaction.

[0351] 1 H NMR (400MHz, CHLOROFORM-d) δ7.09 (d, J=8.3Hz, 1H), 6.76 (d, J=8.3Hz, 1H), 4.23-4.09 (m, 3H) , 3.88-3.79 (m, 4H), 3.06 (t, J=7.8Hz, 2H), 2.68-2.55 (m, 3H), 2.35 (s, 3H), 1.36-1.21 (m, 5H).

[0352] Step 4: Synthesis of compound int_115-6:

[0353] Int_115-5 (12.0 g, 39.8 mmol) was dissolved in methanol (80.0 mL). NaOH (1 M, 79.7 mL) was added to the reaction mixture at 0°C. The reaction mixture was allowed to warm to room temperature for 16 hours. LC-MS monitoring indicated the reaction was complete. 1N HCl aqueous solution was added dropwise to the reaction mixture at 0°C to adjust the pH to 3-4. The aqueous phase was extracted with ethyl acetate (300 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (10 g, yield: 91.9%), which was used directly in the next reaction.

[0354] Step 5: Synthesis of compound int_115-7:

[0355] Int_115-6 (10.0 g, 36.6 mmol) was dissolved in toluene (150 mL). SOCl2 (8.71 g, 73.23 mmol, 5.31 mL) was added to the reaction mixture. The mixture was heated to 110°C and stirred for 3 hours. TLC monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a crude product (10.7 g, 100% yield), which was used directly in the next reaction.

[0356] Step 6: Synthesis of compound int_115-8:

[0357] Int_115-7 (10.7 g, 36.6 mmol) was dissolved in dichloromethane (150 mL). AlCl₃ (4.88 g, 36.6 mmol) was added to the reaction mixture at 0°C. The reaction mixture was allowed to warm to room temperature and react for 1 hour. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and poured into ice water (100 mL). The aqueous phase was extracted with dichloromethane (200 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (8 g, yield: 85.6%), which was used directly in the next reaction.

[0358] Step 7: Synthesis of compound int_115-9:

[0359] Int_115-8 (8.00 g, 31.4 mmol) was dissolved in TFA (100 mL). Triethylsilane (36.46 g, 313.59 mmol, 50.09 mL) was added to the reaction mixture at 0°C. The reaction mixture was heated to 75°C and allowed to react for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to yield a solid. The solid was diluted with water (100 mL) and the pH was adjusted to 8-9 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (300 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to yield the crude product, which was then purified by column chromatography (SiO2, PE:EtOAc = 1 / 0 to 3 / 1) to yield the product (6 g, yield: 79.4%).

[0360] 1 H NMR (400MHz, CHLOROFORM-d) δ 6.72 (s, 1H), 3.89-3.79 (m, 4H), 3.05-3.00 (m, 2H), 2.93 (t, J = 7.5Hz, 2H), 2.31 (s, 3H), 2.15-2.05 (m, 2H).

[0361] Step 8: Synthesis of compound int_115-11:

[0362] Under nitrogen, int_115-9 (1.00 g, 4.15 mmol) and int_115-10 (1.13 g, 6.22 mmol, 1.04 mL) were dissolved in 1,4-dioxane (20 mL). Sodium tert-butoxide (797 mg, 8.29 mmol) and XantPhos Pd G3 (393 mg, 415 μmol) were added to the reaction solution at room temperature. The reaction solution was nitrogen-purged three times and heated to 110°C for 3 hours. LC-MS monitoring indicated the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product (2.5 g, crude product), which was used directly in the next step.

[0363] Step 9: Synthesis of compound int_115-12:

[0364] Under nitrogen, int_115-11 (2.5 g, 7.32 mmol) was dissolved in a mixture of tetrahydrofuran (20 mL) and water (10 mL). Aqueous HCl (13 M, 21.52 mL) was added to the reaction mixture at room temperature, and the reaction mixture was allowed to react for 16 hours. LC-MS monitoring indicated the reaction was complete. The reaction mixture was concentrated under reduced pressure to yield a solid, which was diluted with water (20 mL) and adjusted to pH 8-9 with aqueous ammonia. The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to yield the crude product, which was then purified by column chromatography (SiO2, PE:EtOAc = 1 / 0 to 3 / 1) to afford the product (1 g, yield: 77.5%).

[0365] Step 10: Synthesis of compound int_115-13:

[0366] Int_115-12 (800 mg, 4.51 mmol) and int_1-6 (358.76 mg, 1.35 mmol) were dissolved in DME (4.0 mL), and Cs2CO3 (2.94 g, 9.03 mmol), Xantphos (261.16 mg, 451.36 umol), and Pd2(dba)3 (413 mg, 451 umol) were added. The reaction solution was nitrogen-purged three times and heated to 110°C for 3 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, PE:EtOAc = 1 / 0 to 3 / 1) to obtain the product (600 mg, yield: 36.8%).

[0367] ESI-MS m / z: 361[M+H] + .

[0368] Step 11: Synthesis of compound int_115-14:

[0369] Int_1-8 (252 mg, 3.82 mmol, 240 uL) and int_115-13 (0.6 g, 1.66 mmol) were dissolved in DMF (20 mL). Under nitrogen protection, CuI (158 mg, 830 umol), Cs2CO3 (1.62 g, 4.98 mmol) and (1R, 2R)-N1, N2-dimethylcyclohexane-1, 2-diamine (47.3 mg, 332 umol) were added to the reaction solution. Under nitrogen protection, the reaction solution was heated to 120 ° C for 16 hours. The reaction was monitored by LC-MS and the reaction was completed. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( 20g Silica Flash Column, Eluent of 0-50% Ethyl acetate / Petroleum ether gradient) to obtain the product (150 mg, yield: 26.1%).

[0370] 1 H NMR (400MHz, CHLOROFORM-d) δ7.50 (s, 1H), 6.94 (s, 1H), 4.67 (s, 2H), 3.88 (s, 3H), 3.04-2 .98 (m, 2H), 2.58-2.50 (m, 2H), 2.40 (s, 3H), 2.33 (s, 3H), 2.10-2.02 (m, 2H), 1.86 (s, 3H).

[0371] ESI-MS m / z: 347 [M+H] + .

[0372] Step 12: Synthesis of compound int_115-15:

[0373] At 0°C, sulfuric acid (8.28 g, 84.4 mmol, 4.50 mL) was slowly added to int_115-14 (0.15 g, 433 μmol). The reaction mixture was allowed to react at 25°C for 1 hour, monitored by LC-MS. Ice water (20 mL) was slowly added to the reaction mixture, and the pH of the aqueous phase was adjusted to 8-9 with aqueous ammonia. The mixture 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 a crude product, which was then purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to yield a solid (80 mg, yield: 50.7%).

[0374] MS (ESI): 365 [M+H] + .

[0375] Step 13: Synthesis of compound 115:

[0376] Under nitrogen protection, int_115-15 (0.06 g, 164 umol) was dissolved in dichloromethane (3 mL). At 0 ° C, BBr3 (412.45 mg, 1.65 mmol, 158.64 uL) was added to the reaction solution. The reaction solution was heated to room temperature under nitrogen protection for 3 hours. The reaction was completed after LC-MS monitoring. Ice water (30 mL) was slowly added to the reaction solution, and the pH value of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate aqueous solution. It was extracted with dichloromethane (50 mL * 3) and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative column chromatography ( 4g Silica Flash Column, Eluent of 0-100% Ethyl acetate / Petroleum ether gradient) to give compound 115 (37 mg, yield: 64.4%).

[0377] 1 H NMR (400MHz, DMSO-d6) δ9.40 (s, 1H), 7.81 (s, 1H), 6.87 (s, 1H), 6.73 (br s, 2H), 6.62 (br s, 2H), 2.88 (brt, J=8.1Hz, 3H), 2.26 (d, J=5.3Hz, 8H), 1.93 (br d, J=6.6Hz, 2H), 1.67 (s, 3H).

[0378] MS (ESI): 351 [M+H] + .

[0379] Example 13 Synthesis of Compound 116 and Compound 117

[0380] Compound 115 (37 mg, 100 umol) was subjected to preparative SFC chiral separation (column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 um); mobile phase: A: CO2, B: EtOH (0.1% NH3H2O); B%: 30%-30%, min) to give compound 116 (9 mg, yield: 48.6%) and compound 117 (8 mg, yield: 43.2%).

[0381] Compound 116: 1 H NMR (400MHz, DMSO-d6) δ9.40 (s, 1H), 7.81 (s, 1H), 6.87 (s, 1H), 6.73 (br s, 2H), 6.62 (br s, 2H), 2.88 (br t, J=8.1Hz, 2H), 2.26 (d, J=5.3Hz, 6H), 1.93 (br d, J=6.6Hz, 2H), 1.67 (s, 3H).

[0382] MS (ESI): 351 [M+H] + .

[0383] Analytical SFC retention time: 3.738min (Instrument: (Waters UPCC with PDA Detector; Column: Chiralpak AS-3, 150x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4min and from 40% to 5% of B in 0.2min, then hold 5% for 1.8min; Flow rate: 2.5mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0384] Compound 117: 1H NMR (400MHz, DMSO-d6) δ9.40 (s, 1H), 7.81 (s, 1H), 6.87 (s, 1H), 6.73 (br s, 2H), 6.62 (br s, 2H), 2.88 (br t, J=8.1Hz, 2H), 2.26 (d, J=5.3Hz, 6H), 1.93 (br d, J=6.6Hz, 2H), 1.67 (s, 3H).

[0385] MS (ESI): 351 [M+H] + .

[0386] Analytical SFC retention time: 4.344min (Instrument: (Waters UPCC with PDA Detector; Column: Chiralpak AS-3, 150x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4min andfrom 40% to 5% of B in 0.2min, then hold 5% for 1.8min; Flow rate: 2.5mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0387] Example 14 Synthesis of Compound 137

[0388] Step 1: Synthesis of compound int_137-1:

[0389] Int_9-3 (3.3 g, 12 mmol) and int_1-5 (2.45 g, 14.5 mmol) were dissolved in toluene (40 mL), and Cs2CO3 (4.71 g, 14.5 mmol), Xantphos (694 mg, 1.2 mmol) and Pd2(dba)3 (1.09 g, 1.2 mmol) were added. The reaction solution was nitrogen-purged three times and heated to 80°C for 16 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (100 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (200 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, PE / EtOAc=30 / 1) to give a solid (1.1 g, yield: 25.1%).

[0390] ESI-MS m / z: 364[M+H]+ .

[0391] Step 2: Synthesis of compound int_137-2:

[0392] Int_9-6 (859 mg, 8.66 mmol, 767 μL) was dissolved in DME (12 mL). The reaction solution was cooled to -30°C. Under nitrogen, NaH (693 mg, 17.3 mmol, 60% purity) was slowly added to the reaction solution. The reaction solution was heated to 0°C for 0.5 hours. Then, int_137-1 (524 mg, 1.44 mmol) and Pd(dppf)Cl2·CH2Cl2 (118 mg, 144 μmol) were added to the reaction solution at 0°C. The reaction solution was heated to 90°C under nitrogen for 1 hour. The reaction was monitored by LC-MS. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. The aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (SiO2, PE / EtOAc = 3 / 1) to obtain a solid (410 mg, yield: 74.4%).

[0393] ESI-MS m / z: 383 [M+H] + .

[0394] Step 3: Synthesis of compound int_137-3:

[0395] Int_137-2 (350 mg, 915 μmol) and NaOH (4 M, 7 mL) were dissolved in a mixture of methanol (6 mL) and tetrahydrofuran (6 mL). The reaction mixture was heated to 50°C for 24 hours. TLC monitoring indicated the reaction was complete. The reaction mixture was cooled to room temperature, tetrahydrofuran (10 mL) was added, and the mixture was concentrated under reduced pressure to obtain a solid. The solid was dissolved in DMSO (10 mL) and filtered. The filter cake was washed with water (10 mL) and dried under vacuum to obtain a crude product (115 mg, yield: 34.1%), which was used directly in the next reaction.

[0396] ESI-MS m / z: 369[M+H] + .

[0397] Step 4: Synthesis of compound int_137-4:

[0398] Int_137-3 (368 mg, 1 mmol), PMBNH2 (756 mg, 5.51 mmol, 716 μL), and TEA (893 mg, 8.82 mmol, 1.23 mL) were dissolved in a mixture of acetonitrile (15 mL) and DMSO (15 mL). HATU (1.47 g, 3.86 mmol) was slowly added to the reaction mixture at 0°C. The reaction mixture was then heated to 20°C and allowed to react for 16 hours. LC-MS monitoring indicated the reaction was complete. Water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with ethyl acetate (100 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 (SiO2, PE / EtOAc = 2 / 1) to afford a solid (178 mg, yield: 36.5%).

[0399] ESI-MS m / z:488[M+H] + .

[0400] Step 5: Synthesis of compound int_137-5:

[0401] Int_137-4 (170 mg, 348 μmol) and TFA (3 mL) were dissolved in acetonitrile (1 mL). The reaction mixture was heated to 50°C for 4 hours. LC-MS monitoring indicated the reaction was complete. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, and the aqueous phase was 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 purified by preparative plate chromatography (SiO2, PE / EtOAc = 2 / 3) to afford a solid (60 mg, yield: 46.8%).

[0402] ESI-MS m / z: 368[M+H] + .

[0403] Step 5: Synthesis of compound 137:

[0404] Under nitrogen, int_137-5 (60 mg, 163 μmol) was dissolved in dichloromethane (3 mL). BBr3 (653 mg, 2.60 mmol, 251 μL) was added to the reaction solution at 0°C. The reaction solution was incubated at 0°C under nitrogen for 3 hours and monitored by LC-MS. Ice water (20 mL) was slowly added to the reaction solution. The aqueous phase was adjusted to pH 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 the crude product, which was purified by preparative column chromatography (SiO2, PE / EtOAc = 1 / 2) to obtain compound 137 (39 mg, yield: 67.5%).

[0405] MS (ESI): 354 [M+H] + .

[0406] Example 15 Synthesis of Compound 143

[0407] Step 1: Synthesis of compound int_143-1:

[0408] Int_12-4 (2.00 g, 6.47 mmol) and int_1-5 (1.09 g, 6.47 mmol) were dissolved in DME (30.0 mL), and Cs2CO3 (4.22 g, 13.0 mmol), Xantphos (375 mg, 647 μmol) and Pd2(dba)3 (593 mg, 647 μmol) were added. The reaction solution was replaced with nitrogen three times, and the temperature was raised to 95 ° C. for 16 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-10% EA / Petroleum ether gradient) to obtain a solid (1.5 g, yield: 58.3%).

[0409] ESI-MS m / z: 397 [M+H] + .

[0410] Step 2: Synthesis of compound int_143-2:

[0411] Int_143-1 (993 mg, 2.5 mmol) was dissolved in aqueous ammonia (20.0 mL), and the reaction mixture was heated to 55°C for 16 hours. LC-MS monitoring showed that the reaction was complete. After the reaction mixture was cooled to room temperature, the aqueous phase 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 a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-20% EA / Petroleum ether gradient) to obtain a solid (0.7 g, yield: 73.2%).

[0412] ESI-MS m / z: 382[M+H] + .

[0413] Step 3: Synthesis of compound int_143-3:

[0414] Int_143-2 (0.700 g, 1.83 mmol) was dissolved in tetrahydrofuran (10 mL), and TEA (1.08 g, 10.7 mmol, 1.49 mL) and TFAA (900 mg, 4.28 mmol, 595 μL) were slowly added to the reaction solution at 0 ° C. The reaction solution was heated to room temperature and stirred for 16 hours. TLC monitoring showed that the reaction was complete. The reaction solution was poured into ice water, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-20% EA / Petroleum ether gradient) to obtain a solid (500 mg, yield: 75%).

[0415] ESI-MS m / z: 364[M+H] + .

[0416] Step 4: Synthesis of compound int_143-4:

[0417] Int_9-6 (1.22 g, 8.66 mmol, 1.24 mL) was dissolved in DME (15 mL), and the reaction solution was cooled to -30 ° C. Under nitrogen protection, NaH (693 mg, 17.3 mmol, 60.0% purity) was slowly added to the reaction solution, and the reaction solution was heated to 0 ° C for 0.5 hours. Then, int_143-3 (546 mg, 1.5 mmol) and Pd (dppf) Cl2 · CH2Cl2 (122 mg, 150 μmol) were added to the reaction solution at 0 ° C. The reaction solution was heated to 90 ° C for 1 hour under nitrogen protection. The reaction was completed by LC-MS monitoring. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-100% EA / Petroleum ether gradient) to give a solid (510 mg, yield: 88.9%).

[0418] ESI-MS m / z: 383 [M+H] + .

[0419] Step 5: Synthesis of compound int_143-5:

[0420] Int_143-4 (382 mg, 1 mmol) and NaOH (4.00 M, 8.23 ​​mL) were dissolved in a mixed solvent of methanol (10 mL) and tetrahydrofuran (5 mL), and the reaction solution was heated to 50 ° C for 72 hours. TLC monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a solid. The solid was dissolved in water (30 mL), and the aqueous phase was extracted with ethyl acetate (30 mL×3). The aqueous phase was then neutralized with 1 M hydrochloric acid aqueous solution to a pH of 5-6, and the aqueous phase was extracted with ethyl acetate (30 mL×3). The organic phases at this time were combined and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product (205 mg, yield: 55.6%). The crude product can be used directly in the next step reaction.

[0421] ESI-MS m / z: 369[M+H] + .

[0422] Step 6: Synthesis of compound int_143-6:

[0423] Int_143-5 (235 mg, 640 μmol), PMBNH2 (263 mg, 1.92 mmol, 249 μL) and TEA (323 mg, 3.20 mmol, 445 μL) were dissolved in a mixed solvent of acetonitrile (5 mL) and DMSO (5 mL). HATU (851 mg, 2.24 mmol) was slowly added to the reaction solution at 0 ° C. The reaction solution was then heated to 20 ° C. and reacted for 16 hours. LC-MS monitoring showed that the reaction was complete. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-10% EA / Petroleum ether gradient) to give a solid (175 mg, yield: 56%).

[0424] ESI-MS m / z:488[M+H] + .

[0425] Step 7: Synthesis of compound int_143-7:

[0426] Int_143-6 (100 mg, 205 μmol) was dissolved in TFA (11.5 g, 101 mmol, 7.50 mL). The reaction mixture was heated to 80°C under nitrogen for 16 hours. LC-MS monitoring indicated the reaction was complete. Saturated aqueous sodium bicarbonate (20 mL) was added to the reaction mixture, and the aqueous phase was 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 the crude product, which was purified by preparative plate chromatography (SiO2, PE / EtOAc = 1 / 2) to obtain a solid (53 mg, yield: 70.3%).

[0427] ESI-MS m / z: 368[M+H] + .

[0428] Step 8: Synthesis of compound 143:

[0429] Under nitrogen, int_143-7 (53 mg, 144 μmol) was dissolved in dichloromethane (3 mL). BBr (653 mg, 2.60 mmol, 251 μL) was added to the reaction solution at 0°C. The reaction solution was incubated at 0°C under nitrogen for 3 hours. The reaction was monitored by LC-MS. Ice water (20 mL) was slowly added to the reaction solution. The pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution. The solution 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 purified by preparative column chromatography (SiO, PE / EtOAc = 1 / 2) to obtain compound 143 (35 mg, yield: 68.7%).

[0430] MS (ESI): 354 [M+H] + .

[0431] Example 16 Synthesis of Compound 149

[0432] Step 1: Synthesis of compound int_149-2:

[0433] Int_149-1 (34.0 g, 281 mmol) was dissolved in a mixed solvent of toluene (300 mL) and water (30.0 mL). I2 (71.2 g, 281 mmol) and NaHCO3 (35.4 g, 421 mmol) were added to the reaction solution at room temperature. Under nitrogen protection, the reaction solution was reacted at room temperature for 18 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was washed with saturated Na2S2O3 solution (350 mL×2), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by preparative column chromatography ( Silica Flash Column, Eluent of 0-5% EA / Petroleum ether gradient) to obtain the product (60 g, yield: 86.5%).

[0434] 1 H NMR (400MHz, CHLOROFORM-d) δ7.39-7.37 (m, 1H), 7.29-7.28 (m, 1H), 6.88-6.85 (m, 1H), 2.24-2.22 (m, 3H), 2.21-2.20 (m, 3H).

[0435] Step 2: Synthesis of compound int_149-3:

[0436] Int_149-2 (60.0 g, 243 mmol), CuI (4.62 g, 24.3 mmol), Pd(PPh3)2Cl2 (3.41 g, 4.86 mmol) and ethynyl(trimethyl)silane (28.6 g, 291 mmol, 40.4 mL) were dissolved in triethylamine (500 mL), the reaction solution was replaced with nitrogen three times, and the reaction solution was stirred at room temperature for 18 hours. TLC monitoring showed that the reaction was complete. The reaction solution was diluted with water (500 mL), the aqueous phase was extracted with ethyl acetate (500 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient) to obtain a solid (35 g, yield: 66.3%).

[0437] MS (ESI): 218 [M+H] + .

[0438] Step 3: Synthesis of compound int_149-4:

[0439] Int_149-3 (1.65 g, 7.59 mmol) and CuI (2.89 g, 15.2 mmol) were dissolved in DMF (40 mL). The reaction solution was purged with nitrogen three times and heated to 100°C for 2.5 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradient) to obtain the product (0.4 g, yield: 36.3%).

[0440] 1 H NMR (400MHz, CHLOROFORM-d) δ 8.06-7.93 (m, 1H), 7.35-7.31 (m, 1H), 7.23-7.18 (m, 1H), 6.88 (s, 1H), 6.56-6.48 (m, 1H), 2.54-2.43 (m, 6H).

[0441] MS (ESI): 146 [M+H] + .

[0442] Step 4: Synthesis of compound int_149-5:

[0443] Int_149-4 (11.0 g, 75.8 mmol) was dissolved in acetic acid (100 mL), and NaBH3CN (9.52 g, 152 mmol) was added to the reaction solution at 0°C. The reaction solution was warmed to room temperature and reacted for 2 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was diluted with water (300 mL), the aqueous phase was extracted with ethyl acetate (300 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column. Eluent of 0-30% Ethyl acetate / Petroleum ether gradient) to obtain the product (7.3 g, yield: 65.5%).

[0444] 1 H NMR (400MHz, CHLOROFORM-d) δ 6.76-6.69 (m, 1H), 6.65-6.55 (m, 1H), 3.51-3.39 (m, 2H), 3.39-3.28 (m, 1H), 2.96-2.88 (m, 2H), 2.18-1.98 (m, 6H).

[0445] MS (ESI): 148 [M+H] + .

[0446] Step 5: Synthesis of compound int_149-6:

[0447] At 0°C, int_149-5 (1.00 g, 6.79 mmol) was dissolved in H2SO4 (20.0 mL), and HNO3 (611 mg, 6.79 mmol, 437 uL, 70.0% purity) was added dropwise to the reaction solution at 0°C. The reaction solution was heated to 20°C and stirred for 1 hour. LC-MS monitoring showed that the reaction was complete. The reaction solution was poured into ice water (150 mL), and the pH value of the aqueous phase was adjusted to 8-9 with 6N NaOH. The aqueous phase was extracted with dichloromethane (200 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient) to obtain the product (1.1 g, yield: 84.3%).

[0448] MS (ESI): 193 [M+H] + .

[0449] Step 6: Synthesis of compound int_149-7:

[0450] Int_149-6 (1.10 g, 5.72 mmol) was dissolved in dichloromethane (20 mL), and DMAP (140 mg, 1.14 mmol), TEA (1.74 g, 17.2 mmol, 2.39 mL) and Boc2O (2.50 g, 11.5 mmol, 2.63 mL) were added to the reaction solution at 0 ° C, and the reaction solution was warmed to room temperature for 8 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was diluted with water (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL * 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, and the crude product was purified by column chromatography ( Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient) to obtain the product (1 g, yield: 59.8%).

[0451] MS (ESI): 293 [M+H] + .

[0452] Step 7: Synthesis of compound int_149-8:

[0453] Int_149-7 (0.90 g, 3.08 mmol) was dissolved in a mixed solvent of methanol (20 mL) and water (20 mL). Fe (2.58 g, 46.2 mmol) and NH4Cl (1.65 g, 30.8 mmol) were added to the reaction solution, and the reaction solution was heated to 80°C for 8 hours. LC-MS monitoring showed that the reaction was complete. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a solid. The solid was diluted with water (100 mL), the aqueous phase was extracted with ethyl acetate (100 mL*3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography ( Silica Flash Column, Eluent of 0-20% Ethyl acetate / Petroleum ether gradient) to obtain the product (0.7 g, yield: 86.8%).

[0454] 1H NMR (400MHz, DMSO-d6) δ6.69 (s, 1H), 3.34-3.33 (m, 6H), 2.06-2.02 (m, 3H), 1.93 (s, 3H), 1.45 (s, 9H).

[0455] MS (ESI): 263 [M+H] + .

[0456] Step 8: Synthesis of compound int_149-9:

[0457] Int_149-8 (0.65 g, 2.48 mmol) and int_1-6 (722 mg, 2.73 mmol) were dissolved in 1,4-dioxane (20 mL). Cs2CO3 (1.61 g, 4.96 mmol), Xantphos (215 mg, 372 umol), and Pd2(dba)3 (340 mg, 372 umol) were added. The reaction mixture was nitrogen-purged three times and heated to 110°C for 5 hours. LC-MS monitoring indicated the reaction was complete. After the reaction mixture was cooled to room temperature, water (50 mL) was added to the reaction mixture. 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 a crude product, which was then purified by column chromatography (SiO2, PE:THF = 1 / 0 to 9 / 1) to obtain the product (730 mg, yield: 66%).

[0458] 1 H NMR (400MHz, CHLOROFORM-d) δ7.48-7.43 (m, 1H), 7.00-6.95 (m, 1H), 6.24-6.06 (m, 1H), 4.1 6-4.08 (m, 2H), 3.01-2.94 (m, 2H), 2.24-2.16 (m, 6H), 2.16-2.10 (m, 6H), 1.57-1.52 (m, 9H).

[0459] ESI-MS m / z: 446[M+H] + .

[0460] Step 9: Synthesis of compound int_149-10:

[0461] Int_1-8 (370 mg, 5.60 mmol, 353 uL) and int_149-9 (0.50 g, 1.12 mmol) were dissolved in DMF (7 mL). Under nitrogen protection, CuI (427 mg, 2.24 mmol), Cs2CO3 (1.09 g, 3.36 mmol) and (1R, 2R)-N1, N2-dimethylcyclohexane-1, 2-diamine (31.9 mg, 224 umol) were added to the reaction solution. The reaction solution was heated to 140 ° C under nitrogen protection for 3 hours. The reaction was completed by LC-MS monitoring. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography ( 20g Silica Flash Column, Eluent of 0-30% Ethyl acetate / Petroleum ether gradiem) to obtain the product (50 mg, yield: 10.4%).

[0462] ESI-MS m / z: 432[M+H] + .

[0463] Step 10: Synthesis of compound 149:

[0464] Sulfuric acid (1 mL) was slowly added to int_149-10 (45.0 mg, 104 μmol) at 0°C. The reaction mixture was allowed to react at 20°C for 1 hour, monitored by LC-MS. Ice water (20 mL) was slowly added to the reaction mixture, and the pH of the aqueous phase was adjusted to 8-9 with triethylamine. The mixture was extracted with ethyl acetate (20 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 to obtain a solid (30 mg, yield: 82.6%).

[0465] 1 H NMR (400MHz, DMSO-d6) δ7.83-7.75(m, 1H), 6.96-6.92(m, 1H), 6.70-6.57(m, 4H), 5.33(br s, 1H), 3.55-3.47 (m, 2H), 3.07-2.92 (m, 2H), 2.29-2.22 (m, 6H), 1.75-1.67 (m, 3H), 1.62-1.55 (m, 3H).

[0466] MS (ESI): 350 [M+H] + .

[0467] Example 17 Synthesis of Compound 150 and Compound 151

[0468] Compound 149 (50 mg, 143 umol) was subjected to preparative SFC chiral separation (column: Phenomenex-Cellulose-2 (250 mm*30 mm, 10 um); mobile phase: A: CO2, B: EtOH (0.1% NH3H2O); B%: 60%-60%, min) to give compound 150 (8 mg, yield: 32%) and compound 151 (8 mg, yield: 32%).

[0469] Compound 150: 1 H NMR (400MHz, DMSO-d6) δ7.83-7.75(m, 1H), 6.96-6.92(m, 1H), 6.70-6.57(m, 4H), 5.33(br s, 1H), 3.55-3.47 (m, 2H), 3.07-2.92 (m, 2H), 2.29-2.22 (m, 6H), 1.75-1.67 (m, 3H), 1.62-1.55 (m, 3H).

[0470] MS (ESI): 350 [M+H] + .

[0471] Analysis SFC retention time: 3.482min (Instrument: (Waters UPCC with PDA Detector; Column: Cellulose-2, 100x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: 40% of B; Flow rate: 2.8mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0472] Compound 151: 1 H NMR (400MHz, DMSO-d6) δ7.81 (s, 1H), 7.01-6.91 (m, 1H), 6.69-6.55 (m, 4H), 5.37- 5.28 (m, 1H), 3.55-3.49 (m, 2H), 3.08-2.92 (m, 2H), 2.30-2.23 (m, 6H), 1.71 (s, 3H), 1.61-1.56 (m, 3H). MS(ESI):350[M+H] + .

[0473] Analysis SFC retention time: 4.748min (Instrument: (Waters UPCC with PDA Detector; Column: Cellulose-2, 100x4.6mm, ID, 3um; Mobile phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: 40% of B; Flow rate: 2.8mL / min; Column temp.: 35℃; ABPR: 1500psi).

[0474] Example 18 Synthesis of Compound 153

[0475] Step 1: Synthesis of compound 153:

[0476] Int_149 (0.16 g, 461 μmol) was dissolved in tetrahydrofuran (5 mL). DDQ (105 mg, 461 μmol) was added to the reaction solution at room temperature. The reaction solution was reacted at room temperature for 3 hours under nitrogen protection. LC-MS monitoring showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative column chromatography ( Silica Flash Column, Eluent of 0-65% EA / Petroleum ether gradient) to obtain the product (120 mg, yield: 74.9%).

[0477] 1 H NMR (400MHz, DMSO-d6) δ11.21 (br s, 1H), 7.85-7.81 (m, 1H), 7.44 (t, J=2.8Hz, 1H), 7.41-7.39 (m, 1H), 6.77-6.68 (m, 2H), 6.63 (br s, 2H), 6.48-6.46 (m, 1H), 2.27 (s, 3H), 2.23-2.20 (m, 3H), 2.05-2.03 (m, 3H), 1.89-1.86 (m, 3H).

[0478] MS (ESI): 348 [M+H] + .

[0479] Example 19 Synthesis of Compound 176

[0480] Step 1: Synthesis of compound int_176-2:

[0481] Int_176-1 (1.2 g, 7.89 mmol) and int_1-6 (2.51 g, 9.47 mmol) were dissolved in DME (50 mL), and Cs2CO3 (3.7 g, 11.364 mmol), Xantphos (456 mg, 0.789 mmol) and Pd2(dba)3 (722 mg, 0.789 mmol) were added. The reaction solution was nitrogen-purged three times and heated to 90°C for 16 hours. LC-MS monitoring showed that the reaction was complete. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (50 mL×3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a solid (1.4 g, yield: 52.8%).

[0482] ESI-MS m / z: 336[M+H] + .

[0483] Step 2: Synthesis of compound int_176-3:

[0484] Int_1-8 (283 mg, 4.28 mmol) was dissolved in DME (30 mL). The reaction solution was cooled to -30°C. Under nitrogen, NaH (214 mg, 5.355 mmol, 60.0% purity) was slowly added to the reaction solution. The reaction solution was heated to 0°C for 0.5 hours. Then, int_176-2 (1.2 g, 3.57 mmol) and Pd(dppf)Cl2 (261 mg, 0.357 mmol) were added to the reaction solution at 0°C. The reaction solution was heated to 90°C under nitrogen for 12 hours. The reaction was monitored by LC-MS. After the reaction solution was cooled to room temperature, water (50 mL) was added to the reaction solution. 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 a crude product, which was purified by column chromatography to obtain a solid (670 mg, yield: 58.7%).

[0485] ESI-MS m / z: 322 [M+H] + .

[0486] Step 3: Synthesis of compound int_176-4:

[0487] Int_176-3 (670 mg, 2.09 mmol), potassium carbonate (577 mg, 4.17 mmol), and 30% aqueous hydrogen peroxide (711 mg, 6.27 mmol) were dissolved in a mixture of DMSO (10 mL) and water (2 mL). The reaction mixture was allowed to react at 25°C for 2 hours, monitored by LC-MS. Water (100 mL) was added to the reaction mixture, and the aqueous phase was extracted with dichloromethane (100 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, which was then purified by column chromatography to obtain a solid (120 mg, yield: 16.9%).

[0488] MS (ESI): 340 [M+H] + .

[0489] Step 4: Synthesis of compound 176:

[0490] Under nitrogen, int_176-4 (50 mg, 0.147 mmol) was dissolved in dichloromethane (15 mL). BBr (626 mg, 2.5 mmol) was added to the reaction mixture at 0°C. The reaction mixture was incubated at 0°C under nitrogen for 2 hours and monitored by LC-MS. The pH of the reaction mixture was adjusted to 7 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (40 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, which was then purified by column chromatography to obtain compound 176 (12 mg, yield: 25.5%).

[0491] 1 H NMR (400MHz, DMSO-d6) δ9.92 (s, 1H), 8.13 (s, 1H), 7.83 (s, 1H), 6.95 (s, 2H), 6.67 (s, 2H), 2.24 (s, 3H), 2.22 (s, 3H), 1.92 (s, 3H), 1.69 (s, 3H).

[0492] MS (ESI): 326 [M+H] + .

[0493] By using the above synthesis method and different starting materials, target compounds 4, 8, 18-95, 99-114, 118-136, 140-142, 144-148, 152, 154-175 and 177-225 in Table 1 can be obtained.

[0494] Table 1

[0495] Biological Example 1 In vitro inhibition test of MYT1 kinase activity by the compounds of the present invention

[0496] 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.

[0497] Table 2. Inhibitory activity of the compounds of the present invention against recombinant protein MYT1 (IC 50 , nM)

[0498] +++ indicates IC 50 Less than or equal to 200nM

[0499] ++ indicates IC 50 200nM to 500nM

[0500] + indicates IC 50 Greater than 500nM

[0501] Biological Example 2 In vitro antiproliferative activity of the compounds of the present invention on MIA PaCa-2 cells

[0502] 3000 MIA PaCa-2 cells 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.

[0503] Table 3 Antiproliferative activity of the compounds of the present invention on MIA PaCa-2 cells

[0504] Reference compound RP-6306 is compound 182 in WO2021195781A1.

[0505] 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.

[0506] Biological Example 3 In vitro antiproliferative activity of the compound of the present invention combined with gemcitabine on MIA PaCa-2 cells

[0507] 3000 MIAPaCa-2 cells / well were plated in a 384-well plate and treated with 20 nM Gemcitabine. After overnight attachment, DMSO or compound was added at a maximum concentration of 1000 nM 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 achieved by the compound compared to the DMSO group was calculated, and the IC was then calculated. 50 The results are shown in Table 4 below.

[0508] Table 4 In vitro antiproliferative activity of the compounds of the present invention combined with gemcitabine on MIA PaCa-2 cells

[0509] From the data in Table 4, it can be seen that the compound of the present invention combined with gemcitabine has a strong in vitro anti-proliferative activity against MIA PaCa-2 cells, and the anti-proliferative activity of the compound 2 of the present invention combined with gemcitabine is stronger than that of RP-6306.

[0510] Biological Example 4 In vivo pharmacokinetic study of the compounds of the present invention

[0511] 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. The 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, the intravenous group of animals was given a single injection of the corresponding compound via the tail vein with a dosing volume of 10 mL / kg. The oral group of animals was given a single injection of the corresponding compound via gavage with a dosing volume of 10 mL / kg. The animals were weighed before administration and the dosing volume was calculated based on the body weight. Sample collection times were: 0.083 (injection group), 0.167, 0.5, 1, 2, 4, 8, and 24 hours. Approximately 200 uL 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 PK sample was collected at the last time point. Phoenix WinNonlin was used. TMPlasma 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.

[0512] Table 5 In vivo pharmacokinetic evaluation results of the compounds of the present invention

[0513] As can be seen from the data in Table 5, in the mouse pharmacokinetic experiment, compared with RP-6306, the half-life T 1 / 2 The longer duration of the reaction indicates that Compound 2 has better metabolic stability in vivo. Furthermore, compared to RP-6306, Compound 2 exhibits a significantly higher Vdss, indicating that Compound 2 distributes less in plasma and more in other tissues, potentially offering a significant advantage in treating solid tumors. Therefore, Compound 2 exhibits unexpectedly improved pharmacokinetic properties compared to RP-6306.

[0514] Biological Example 5 In vitro permeability test of the compounds of the present invention

[0515] 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) transport and basolateral to apical (B to A, BA) transport of the corresponding compound were measured, and the permeation rate (apparent permeability) of the test compound (P app x 10 -6 cm / sec) and efflux ratio (P app (BA) / P app (AB)). Digoxin, metoprolol, and atenolol were used as controls. The results of the in vitro permeability experiments are shown in Table 6 below.

[0516] Table 6 In vitro permeability test results of the compounds of the present invention

[0517] As can be seen from the data in Table 6, compared with RP-6306, the transport rate of compound 2 in the apical to basolateral (A to B, AB) of MDCK and MDCK-MDR1 cells is faster, and the efflux ratio (P app (BA) / P app(AB)) was lower, indicating that compound 2 had better permeability than RP-6306.

[0518] Biological Example 6 In vitro solubility and stability test of the compounds of the present invention

[0519] 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.

[0520] 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.

[0521] The results of in vitro solubility and stability tests of the compounds of the present invention are shown in Table 7 below.

[0522] Table 7 In vitro solubility test results of the compounds of the present invention

[0523] ND means not tested

[0524] As can be seen from the data in Table 7, compared with RP-6306, Compound 2 of the present invention has higher solubility in various solvents (FaSSIF, FeSSIF, SGF, water, methanol and tetrahydrofuran), and Compound 2 is more stable than RP-6306 in FaSSIF, FeSSIF and water.

[0525] Biological Example 7 In vivo efficacy study - mouse HT29 subcutaneous transplant tumor model

[0526] HT29 is a colon cancer cell line. Each nude mouse was subcutaneously inoculated with 5×10 6 HT29 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).

[0527] The test results show that the compound of the present invention has good activity in the mouse HT29 subcutaneous transplant tumor model.

[0528] Biological Example 8 In vivo efficacy study - mouse HCC1569 subcutaneous transplant tumor model

[0529] 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).

[0530] The test results show that the compound of the present invention has good activity in the mouse HCC1569 subcutaneous transplant tumor model.

[0531] Biological Example 9 In vivo efficacy study - mouse OVCAR-3 subcutaneous transplant tumor model

[0532] 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).

[0533] The test results show that the compound of the present invention has good activity in the mouse OVCAR-3 subcutaneous transplant tumor model.

[0534] Biological Example 10 In vitro manual patch clamp assay to detect the inhibitory activity of compounds on hERG ion channels

[0535] HEK-293 cells stably expressing hERG potassium channel were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418 at 37°C and a carbon dioxide concentration of 5%.

[0536] Cell passaging: Remove old culture medium and wash once with PBS, then add 1 mL of TrypLE TM Express solution, incubate at 37°C for about 0.5 minutes. When the cells detach from the bottom of the dish, add about 5 mL of complete culture medium preheated at 37°C. Gently pipette the cell suspension to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, inoculate the cells in a 6 cm cell culture dish with 2.5 × 10 cells per cell culture dish. 5 cells (final volume: 5 mL). To maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.

[0537] Fluids used for electrophysiological recordings:

[0538] Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH.

[0539] Intracellular solution: 20 mM KCl, 115 mM K-Aspartic acid, 1 mM MgCl2·6H2O, 5 mM EGTA, 10 mM HEPES, 2 mM Na2-ATP, pH adjusted to 7.2 with KOH.

[0540] Patch clamp assay: Before the experiment, cells were treated with TrypLE TM Express separation, 4×10 3 Cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the experiment was tested. The voltage stimulation protocol for whole-cell patch clamp recording of hERG potassium currents was as follows: after the whole-cell seal was formed, the cell membrane voltage was clamped at -80 mV. The clamping voltage was depolarized from -80 mV to -50 mV for 0.5 s (as a leak current detection), then stepped to 30 mV for 2.5 s, and then quickly restored to -50 mV for 4 s to stimulate the tail current of the hERG channel. Data were repeatedly collected every 10 s to observe the effect of drugs on the hERG tail current. A 0.5 s stimulation of -50 mV was used as a leak current detection. The experimental data were acquired by an EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0541] Recording electrodes are drawn from capillary glass tubes using a microelectrode puller. Under an inverted microscope, the recording electrode is placed in contact with the cell using the microelectrode manipulator. Negative pressure is applied to create a GΩ seal. After the GΩ seal is established, rapid capacitance compensation is performed. Continued negative pressure is applied to rupture the cell membrane, establishing whole-cell recording mode. Slow capacitance compensation is then performed, and membrane capacitance and series resistance are recorded. No leakage compensation is applied.

[0542] When the hERG current recorded by the whole cell is stable, the drug is administered. After each drug concentration is applied for 5 minutes (or the current is stable), the next concentration is detected. Multiple concentrations are detected for each test compound. The coverslip with cells is placed in the recording bath in an inverted microscope. The test compound and the external solution without the compound are flowed through the recording bath in sequence from low concentration to high concentration using gravity perfusion to act on the cells. A vacuum pump is used for liquid exchange during the recording. The current detected in the external solution without the compound for each cell serves as its own control group. Multiple cells are tested independently and repeatedly. All electrophysiological experiments are performed at room temperature.

[0543] Data analysis: First, the current after each drug concentration was normalized with the blank control current. Then calculate the inhibition rate corresponding to each drug concentration The mean and standard error were calculated for each concentration, and the half-inhibitory concentration (CI) of each compound was calculated using the following equation:

[0544] The above equation was used to perform a nonlinear fit for the dose-dependent effect, where C represents the test sample concentration, IC50 is the half-inhibitory concentration, and h represents the Hill coefficient. 50 The calculations were performed using IGOR software.

[0545] Conclusion: The compounds of the present invention have no obvious hERG inhibitory activity.

[0546] Biological Example 11 Cytochrome P450 Isozyme Inhibition Study

[0547] Experimental operation: First, dilute the test compound (10.0mM) to prepare a working solution (100× final concentration) with a working solution concentration of 1.00mM. At the same time, prepare the working solutions of each positive inhibitor of P450 isoenzyme (CYP2C9 (using Diclofenac as a probe substrate), CYP2D6 (using Dextromethorphan as a probe substrate) and CYP3A (using Midazolam or Testosterone as a probe substrate)) and its specific probe substrate; thaw the human liver microsomes stored in a refrigerator below -80°C on ice, wait until the human liver microsomes are completely dissolved, dilute with potassium phosphate buffer (PB), and prepare a working solution of a certain concentration (0.127mg / mL). First, add 20.0μL of probe substrate to the reaction plate (add 20.0μl to the Blank well). PB), then 158 μL of human liver microsome working solution was added to the reaction plate, and the reaction plate was placed on ice for use; at this time, 2.00 μL of test compound (N=1) and specific inhibitor (N=2) were added to the corresponding wells, and the group without inhibitor (test compound or positive inhibitor) added the corresponding organic solvent. The organic phase of the test compound control sample and the positive control sample was 1:1 DMSO:MeOH and 1:9 DMSO:MeOH, respectively; after pre-incubation in a 37°C water bath for 10 minutes, 20.0 μL of coenzyme factor (NADPH) solution was added to the reaction plate. For the CYP3A metabolic reaction with midazolam as the probe substrate, the reaction time was 3 minutes; for the CYP2D6 reaction with dextromethorphan as the probe substrate, the reaction time was 20 minutes, and the other reactions were all 10 minutes; then 400 μL of pre-cooled acetonitrile solution (containing 200 ng / mL The reaction was terminated with the addition of tolbutamide and labetalol as internal standards; the reaction plate was placed on a shaker and vortexed for 10 minutes; the plate was then centrifuged at 4°C, 4000 rpm for 20 minutes; 200 μL of the supernatant was added to 100 μL of water for sample dilution; the plate was sealed, vortexed, and mixed before LC / MS / MS analysis.

[0548] Data analysis: XL fit was used to plot the percentage of control group versus test compound concentration and for nonlinear regression analysis of the data. 50 The values ​​are determined using a 3- or 4-parameter logistic equation:

[0549] 3-parameter logistic equation: 4-parameter logistic equation:

[0550] Conclusion: The compounds of the present invention have no significant inhibitory effect on any subtype of CYP enzymes.

[0551] Biological Example 12 Hepatocyte Metabolic Stability

[0552] Prepare several 96-well sample precipitation plates, named T0, T15, T30, T60, T90, T0-MC, T90-MC and blank matrix. Take out the recovery culture medium and incubation culture medium in advance and place them in a 37°C water bath to preheat. Take out the frozen hepatocytes from the liquid nitrogen tank and immediately immerse them in a 37°C water bath (about 90 seconds). After the frozen part is melted and loosened, pour them into centrifuge tubes containing 40mL of recovery culture medium, and gently invert to resuspend the cells in the recovery culture medium. Centrifuge at 100×g for 5 minutes at room temperature, remove the supernatant, resuspend the hepatocytes with an appropriate volume of incubation culture medium, and calculate the cell viability by trypan blue staining. Add 198μL of hepatocyte suspension (0.51×10 6 cells / mL) were added to the preheated incubation plates. For the culture medium control group, 198 μL of incubation medium without hepatocytes was added to the T0-MC and T90-MC incubation plates. All incubation plates were pre-incubated in a 37°C incubator for 10 minutes.

[0553] Then, add 2 μL of the test compound and control compound working solutions, mix thoroughly, and immediately place the incubation plate on a plate shaker in the incubator. Start the timer to begin the reaction. Prepare two replicates for each compound at each time point. Incubate at 37°C, saturated humidity, and 5% CO2.

[0554] In the test system, the final concentration of the test substance was 1 μM, the final concentration of the control substance was 3 μM, and the final concentration of the hepatocytes was 0.5×10 6 cells / mL, with a final concentration of 0.96% total organic solvent, including 0.1% DMSO. At the end of the incubation at the corresponding time point, the incubation plate was removed, and 25 μL of the mixture of compound and control compound with cells was added to a sample plate containing 125 μL of acetonitrile stop solution (containing 200 ng / mL Tolbutamide and Labetalol as internal standards). For the blank sample plate, 25 μL of incubation medium without hepatocytes was directly added. After sealing all sample plates, shake them on a plate shaker at 600 rpm for 10 minutes and centrifuge at 3220 × g for 20 minutes. The supernatants of the test and control samples were diluted with ultrapure water at a ratio of 1:3. All samples were mixed and analyzed by LC / MS / MS.

[0555] Data Analysis: The percentage of compound remaining after incubation was calculated using the following equation:

[0556] Calculate t using the following first-order kinetic equation 1 / 2 and Clint:

[0557] C t =C0·e-k·t ,when

[0558] CLint(hep)=k / million cells per mL.

[0559] Conclusion: The compound of the present invention has good metabolic stability in hepatocytes.

[0560] 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): R A -C(O)NH(R 4 )、-C(O)(R 3a ) or -SO2R 3a ; R B is -H or -N(R 3 )2; X 1 CR a1 or N; X 2 CR a2 or N; X 3 CR a3 or N; R a1 、R a2 、R a3 and R 1 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 R a3 and R 1 Together with the carbon atoms to which they are attached, they 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 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 and (C3-C8)cycloalkyl; When R a1 、R a2 、R a3 and R 1 When neither is -CN, R 2 for: where X 4 、X 5 、X 6 、X 7 、X 8 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, and X 4 、X 5 、X 6 、X 7 、X 8 4 of them are not -H at the same time; or X 4 and X 5 Yes, X 5 and X 6 Yes, X 6 and X 7 Yes, X 7 and X 8 Each of the pairs can independently form with the carbon atom to which they are attached a (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 can 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 and (C3-C8)cycloalkyl; or R 2 is (6-10 membered) heterocycloalkyl or (6-10 membered) heteroaryl, wherein said (6-10 membered) heterocycloalkyl or (6-10 membered) heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, -OR 3 , halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl and (3-6 membered)heterocycloalkyl; When R a1 、R a2 、R a3 and R 1 When at least one of them is -CN; or when R a3 and R 1 Together with the carbon atoms to which they are attached, they form a (C4-C9)cycloalkenyl, a (4-9-membered)heterocycloalkyl or a (5-10-membered)heteroaryl, wherein said (4-9-membered)heterocycloalkyl 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 5 、-N(R 5 )2, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl and (C3-C8)cycloalkyl, R 2 for: where X 4 、X 5 、X 6 、X 7 、X 8 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, and X 4 、X 5 、X 6 、X 7 、X 8 At least 2 of them are different at the same time -H; or X 4 and X 5 Yes, X 5 and X 6 Yes, X 6 and X 7 Yes, X 7 and X 8 Each of the pairs can independently form with the carbon atom to which they are attached a (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 can 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; or R 2 is (6-10 membered) heterocycloalkyl or (6-10 membered) heteroaryl, wherein said (6-10 membered) heterocycloalkyl or (6-10 membered) heteroaryl may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -H, -OH, -OR 3 , halogen, -CN, (C1-C6)alkyl, (C1-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl and (3-6 membered)heterocycloalkyl; 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 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 to which it is attached, it 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; 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; 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; 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 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 to which it is attached, it 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; Each R 5 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 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, it 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, -CN, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C2-C6) alkenyl, (C2-C6) alkynyl and (C3-C8) cycloalkyl.

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 a1 、R a2 、R a3 and R 1 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 is each independently 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; or R a3 and R 1 Together with the carbon atom to which they are attached, they form a (C3-C8 membered)cycloalkyl, (4-8 membered)heterocycloalkyl, phenyl or (5-6 membered)heteroaryl group, wherein said (C3-C8 membered)cycloalkyl, (4-8 membered)heterocycloalkyl, phenyl or (5-6 membered)heteroaryl group may each independently be optionally substituted by 1, 2, 3 or 4 of the following groups: -F, -Cl, -Br, -I, -OH, -OCH3, -NH2, -N(CH3)2, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl.

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 a1 、R a2 、R a3 and R 1 Each is independently: -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, -OCH2CH3, -OCH(CH3)2, 4. The compound according to claim 2 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R a3 and R 1 Together with the carbon atoms to which they are attached, they form the following structural units:

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), when R a1 、R a2 、R a3 and R 1 When neither is -CN, R 2 for: where X 4 、X 5 、X 6 、X 7 、X 8 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, and X 4 、X 5 、X 6 、X 7 、X 8 4 of them are not -H at the same time; or X 4 and X 5 Yes, X 5 and X 6 Yes, X 6 and X 7 Yes, X 7 and X 8 Each of the pairs can independently form, together with the carbon atom to which they are attached, a (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 can 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; or R 2 is (6-10 membered)heterocycloalkyl or (6-10 membered)heteroaryl, wherein said (6-10 membered)heterocycloalkyl or (6-10 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, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl and (3-6 membered)heterocycloalkyl.

6. The compound according to claim 5 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when R a1 、R a2 、R a3 and R 1 When neither is -CN, R 2 for:

7. 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), when R a1 、R a2 、R a3 and R 1 When at least one of them is -CN; or when R a3 and R 1 Together with the carbon atoms to which they are attached, they form a (C4-C9)cycloalkenyl, (4-9-membered)heterocycloalkyl, phenyl or (5-10-membered)heteroaryl group, wherein said (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, R 2 for: where X 4 、X 5 、X 6 、X 7 、X 8 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, and X 4 、X 5 、X 6 、X 7 、X 8 At least 4 of them are not -H at the same time; or X 4 and X 5 Yes, X 5 and X 6 Yes, X 6 and X 7 Yes, X 7 and X 8 Each of the pairs can independently form, together with the carbon atom to which they are attached, a (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 can 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; or R 2 is (6-10 membered)heterocycloalkyl or (6-10 membered)heteroaryl, wherein said (6-10 membered)heterocycloalkyl or (6-10 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, -CN, (C1-C3)alkyl, (C1-C3)haloalkyl, (C2-C4)alkenyl, (C2-C4)alkynyl, (C3-C6)cycloalkyl and (3-6 membered)heterocycloalkyl.

8. The compound according to claim 7 or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), when R a1 、R a2 、R a3 and R 1 When at least one of them is -CN; or when R a3 and R 1 Together with the carbon atoms to which they are attached, they form a (C4-C9)cycloalkenyl, (4-9-membered)heterocycloalkyl or (5-10-membered)heteroaryl group, wherein said (C4-C9)cycloalkenyl, (4-9-membered)heterocycloalkyl 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, R 2 for:

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 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.

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 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.

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: -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 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.

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 crystal 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, (3-6 membered) heterocycloalkylene, phenylene or (5-6 membered) heteroarylene, wherein the (C1-C3) alkylene, (C2-C4) alkenylene, (C2-C4) alkynylene, (C3-C6) cycloalkylene Alkyl, phenylene, (5-6 membered)heteroarylene or (3-6 membered)heterocycloalkylene 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.

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:

17. The compound according to any one of claims 1 to 16, or 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 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.

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, -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.

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 isomer, crystal form, pharmaceutically acceptable salt, hydrate or solvate thereof, 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 a blood cancer and a solid tumor.

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