Polycyclic nitrogen-containing heterocyclic compound and application thereof

Abstract

The invention relates to a polycyclic nitrogen-containing heterocyclic compound and application thereof, and belongs to the field of medicines. The compound can be used for regulating CDK7 kinase activity or preventing and / or treating abnormal CDK7 related diseases, and has good pharmaceutical activity. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of medicine, and in particular relates to a polycyclic nitrogen-containing heterocyclic compound and a use thereof. Background Art

[0002] Cyclin dependent kinases (CDKs) are a class of serine / threonine kinases that play a key role in cell cycle regulation and cell transcription. Twenty CDKs have been discovered, divided into two subfamilies: one is cell cycle-related CDKs, including CDK1-7 and 14-18; the other is transcription-related CDKs, including CDK7-13, 19 and 20. CDKs need to form a complex with cell cycle proteins to regulate the cell cycle and other biological functions.

[0003] CDK7 is the most unique member of the CDK family, with dual functions of regulating cell cycle and transcription. On the one hand, CDK7, Cyclin H, and MAT1 form CDK-activated kinase (CAK), which regulates the cell cycle by phosphorylating CDK1, 2, 4, and / or 6. On the other hand, CDK7 can phosphorylate Ser5 and Ser7 sites on the C-terminal domain (CTD) of RNA polymerase II, and can also phosphorylate and activate CDK9, thereby phosphorylating the Ser2 site of CTD. Therefore, CDK7 directly or indirectly participates in regulating the initiation and elongation of intracellular transcription by phosphorylating the CTD domain. The unique dual function of CDK7 makes it play an important role in the occurrence and development of tumors, and it is a potential target for anti-tumor drugs. Studies have confirmed that CDK7 inhibitors can inhibit the dual mechanism of oncogene transcription and cell cycle progression to exert anti-tumor effects, and have shown significant anti-tumor activity in vitro and in vivo against a variety of malignant tumors such as triple-negative breast cancer, ovarian cancer, prostate cancer, colon cancer, pancreatic cancer, and acute myeloid leukemia. In addition, preclinical studies have found that CDK7 inhibitors are effective against breast cancer that is resistant to CDK4 / 6 inhibitors. These studies suggest that CDK7 inhibitors have great potential as anti-tumor drugs, especially in the field of tumor diseases with huge clinical needs, such as triple-negative breast cancer, pancreatic cancer, castration-resistant prostate cancer, and colon cancer. Therefore, the development of new CDK7 inhibitors is particularly important.

[0004] Although some CDK7 inhibitors have been reported, the CDK7 inhibitors with faster research progress (such as SY-5609 and CT7001) are still in the early clinical stage, and no CDK7 inhibitor has been approved for clinical treatment. Therefore, there is still an urgent need for more effective small molecule CDK7 inhibitors to enrich the clinical pipeline and address unmet clinical needs. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides the following technical solutions.

[0006] In a first aspect, the present invention employs a compound.

[0007] (1) a compound selected from the group consisting of a compound of formula (I) or a deuterated substance thereof or a pharmaceutically acceptable salt thereof or a solvate thereof or a hydrate thereof or a prodrug thereof or an optical isomer thereof or an atropisomer thereof,

[0008]

[0009] in, is a single bond or a double bond;

[0010] X is selected from -(CH2) n1 -、-(CH2) n1 O-, -(CH2) n2 C(R 5a )(R 5b )(CH2) n3 - or -CH=CH-;

[0011] L is -NH- or -NH(CH2) n4 -; Preferably, L is -NH-;

[0012] n1 is 1, 2, 3 or 4; preferably, n1 is 2;

[0013] n2 is 0, 1, 2 or 3; preferably, n2 is 0, 1 or 2;

[0014] n3 is 0, 1, 2 or 3; preferably, n3 is 0 or 1;

[0015] n4 is 1, 2, 3, 4, 5 or 6;

[0016] R 5a , R 5b are each independently selected from H, halogen, substituted or unsubstituted C 1- C6 alkyl (e.g., substituted or unsubstituted C1 alkyl, substituted or unsubstituted C2 alkyl, substituted or unsubstituted C3 alkyl, substituted or unsubstituted C4 alkyl, substituted or unsubstituted C5 alkyl, substituted or unsubstituted C6 alkyl), substituted or substituted C 2- C6 alkene group (e.g., substituted or substituted C2 alkene group, substituted or unsubstituted C3 alkene group, substituted or unsubstituted C4 alkene group, substituted or unsubstituted C5 alkene group, substituted or unsubstituted C6 alkene group), substituted or unsubstituted C 2-C6 alkynyl (e.g., substituted or unsubstituted C2 alkynyl, substituted or unsubstituted C3 alkynyl, substituted or unsubstituted C4 alkynyl, substituted or unsubstituted C5 alkynyl, substituted or unsubstituted C6 alkynyl), or R 5a , R 5b Together with the carbon atoms adjacent to them, they form a C3-C6 cycloalkyl group (e.g., a C3 cycloalkyl group, a C4 cycloalkyl group, a C5 cycloalkyl group, or a C6 cycloalkyl group);

[0017] R1 is selected from the following groups: substituted or unsubstituted C1-C6 alkyl, such as substituted or unsubstituted C1 alkyl, substituted or unsubstituted C2 alkyl, substituted or unsubstituted C3 alkyl, substituted or unsubstituted C4 alkyl, substituted or unsubstituted C5 alkyl, substituted or unsubstituted C6 alkyl), substituted or unsubstituted C3-C8 cycloalkyl, such as substituted or unsubstituted C3 cycloalkyl, substituted or unsubstituted C4 cycloalkyl, substituted or unsubstituted C5 cycloalkyl, substituted or unsubstituted C6 cycloalkyl, substituted or unsubstituted C7 cycloalkyl, substituted or unsubstituted C8 cycloalkyl), substituted or unsubstituted 4-12 membered heterocyclyl (such as substituted or unsubstituted 4 membered heterocyclyl, substituted or unsubstituted 5 membered heterocyclyl, substituted or unsubstituted 6 membered heterocyclyl), substituted or unsubstituted 7-membered heterocyclyl, substituted or unsubstituted 8-membered heterocyclyl, substituted or unsubstituted 9-membered heterocyclyl, substituted or unsubstituted 10-membered heterocyclyl, substituted or unsubstituted 11-membered heterocyclyl, substituted or unsubstituted 12-membered heterocyclyl,), substituted or unsubstituted 5-9-membered heterobridged cycloalkyl (e.g., substituted or unsubstituted 5-membered heterobridged cycloalkyl, substituted or unsubstituted 6-membered heterobridged cycloalkyl, substituted or unsubstituted 7-membered heterobridged cycloalkyl, substituted or unsubstituted 8-membered heterobridged cycloalkyl, substituted or unsubstituted 9-membered heterobridged cycloalkyl), substituted or unsubstituted 5-9-membered bridged cycloalkyl (e.g., substituted or unsubstituted 5-membered bridged cycloalkyl, substituted or unsubstituted 6-membered bridged cycloalkyl, substituted or unsubstituted 7-membered bridged cycloalkyl, substituted or unsubstituted substituted or unsubstituted 6-10 membered heterospirocycloalkyl (e.g. substituted or unsubstituted 6-membered heterospirocycloalkyl, substituted or unsubstituted 7-membered heterospirocycloalkyl, substituted or unsubstituted 8-membered heterospirocycloalkyl, substituted or unsubstituted 9-membered heterospirocycloalkyl, substituted or unsubstituted 10-membered heterospirocycloalkyl), substituted or unsubstituted 6-10 membered spirocycloalkyl (e.g. substituted or unsubstituted 6-membered spirocycloalkyl, substituted or unsubstituted 7-membered spirocycloalkyl, substituted or unsubstituted 8-membered spirocycloalkyl, substituted or unsubstituted 9-membered spirocycloalkyl, substituted or unsubstituted 10-membered spirocycloalkyl), substituted or unsubstituted 6-10 membered heteroparacycloalkyl (e.g. substituted or unsubstituted 6-membered heteroparacycloalkyl, substituted or unsubstituted unsubstituted 7-membered heterocycloalkyl, substituted or unsubstituted 8-membered heterocycloalkyl, substituted or unsubstituted 9-membered heterocycloalkyl, substituted or unsubstituted 10-membered heterocycloalkyl), substituted or unsubstituted 6-10-membered cycloalkyl (e.g., substituted or unsubstituted 6-membered cycloalkyl, substituted or unsubstituted 7-membered cycloalkyl, substituted or unsubstituted 8-membered cycloalkyl, substituted or unsubstituted 9-membered cycloalkyl, substituted or unsubstituted 10-membered cycloalkyl), substituted or unsubstituted 5-10-membered heteroaryl (e.g., substituted or unsubstituted 5-membered heteroaryl, substituted or unsubstituted 6-membered heteroaryl, substituted or unsubstituted 7-membered heteroaryl, substituted or unsubstituted 8-membered heteroaryl, substituted or unsubstituted 9-membered heteroaryl, substituted or unsubstituted 10-membered heteroaryl),Substituted or unsubstituted C6-C, 10 Aryl (e.g., substituted or unsubstituted C6 aryl, substituted or unsubstituted C7 aryl, substituted or unsubstituted C8 aryl, substituted or unsubstituted C9 aryl, substituted or unsubstituted C 10 Aryl);

[0018] Y is selected from CH, NR6, N, O or S;

[0019] R6 is selected from hydrogen, amino, -C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl), C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, -C(=O)-NR 7a R 7b ; The 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S in R6 contains 1-7 carbon atoms in the ring;

[0020] R 7a , R 7b Each independently selected from hydrogen or C1-C6 alkyl;

[0021] Z1 and Z2 are each independently selected from C or N;

[0022] Z3 is selected from N or C(R8);

[0023] Z4 is selected from N or C(R9);

[0024] R9 is selected from H or halogen;

[0025] R8, R 10 , R 10 'are each independently selected from H, F, Cl, Br, I, cyano, or substituted or unsubstituted C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, halogenated C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, 3-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, 3-8 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, -NR 11-C(=O)-O-(C1-C6 alkyl), -OC(=O)-R 12 , -C(=O)-R 12 ,

[0026] R 11 , R 12 , R 13 , R 13 '、R 14 , R 14 '、R 15 , R 15 '、R 16 , R 16 'are independently selected from: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 independently selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, substituted or unsubstituted 3-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O, S, C6-C 10 Aryl, 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; or R 13 , R 13 'Connected to their adjacent P to form a 4-6 membered ring; or R 12 , R 16 ' are independently selected from methyl, ethyl, cyclopropyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S; or R 16 is methyl;

[0027] In some embodiments of (1), R8, R 10 , R 10 The 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1 to 7 carbon atoms in the ring.

[0028] In some embodiments of (1), R8, R 10 , R 10 The 3-8 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1 to 7 carbon atoms in the ring.

[0029] In some embodiments of (1), R 11 , R 12 , R 13 , R 13 '、R 14 , R 14 '、R 15 , R15 '、R 16 , R 16 The substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S contains 1 to 7 carbon atoms in the ring.

[0030] In some embodiments of (1), the substituted or unsubstituted 4-12 membered heterocyclic group in R1 contains 1-11 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2.

[0031] In some embodiments of (1), the substituted or unsubstituted 5-9 membered heterobridged cycloalkyl in R1 contains 1-8 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2.

[0032] In some embodiments of (1), the substituted or unsubstituted 6-10 membered spirocycloalkyl in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0033] In some embodiments of (1), the substituted or unsubstituted 6-10 membered heterocycloalkyl group in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2.

[0034] In some embodiments of (1), the substituted or unsubstituted 5-10 membered heteroaryl group in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring.

[0035] In some embodiments of (1), the R 5a , R 5b In each substituted or unsubstituted, one or more hydrogen atoms are substituted independently by methyl groups; preferably, R 5a , R 5b It is H or methyl.

[0036] In some embodiments of (1), the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C2-C6 alkene group, C2-C6 alkynyl group, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl, -NH-(3-6 membered cycloalkyl) or -NH-R2; or the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, fluorine atom, chlorine atom, hydroxymethyl, hydroxyethyl, methyl, ethyl, -C H2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl, -NH-(3-membered cycloalkyl) or -NH-R2 are substituted; preferably, the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl.

[0037] In some embodiments of (1), R2 is selected from hydrogen, substituted or unsubstituted amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, substituted or unsubstituted -C(=O)-NR 2a R 2b .

[0038] In some embodiments of (1), the substituted or unsubstituted 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S in R2 contains 1-7 carbon atoms in the ring.

[0039] In some embodiments of (1), R 2a , R 2b Each is independently selected from hydrogen or C1-C6 alkyl.

[0040] In some embodiments of (1), R8, R 10 , R 10The substitution in the substituted or unsubstituted 'independently represents that one or more hydrogen atoms are replaced by =O or methyl; preferably, R8 is selected from F, Cl, Br, -C(=O)-R 12 , and / or

[0041] In some embodiments of (1), the substitution in the substituted or unsubstituted 3-8 membered heterocyclic group in R1 is that one or more H atoms are replaced by methyl or =O.

[0042] In some embodiments of (1), the C1-C6 alkyl group includes a C1 alkyl group, a C2 alkyl group, a C3 alkyl group, a C4 alkyl group, a C5 alkyl group or a C6 alkyl group.

[0043] In some embodiments of (1), the halogenated C1-C6 alkyl group includes a halogenated C1 alkyl group, a halogenated C2 alkyl group, a halogenated C3 alkyl group, a halogenated C4 alkyl group, a halogenated C5 alkyl group or a halogenated C6 alkyl group.

[0044] In some embodiments of (1), the C3-C8 cycloalkyl group includes C3 cycloalkyl, C4 cycloalkyl, C5 cycloalkyl, C6 cycloalkyl, C7 cycloalkyl or C8 cycloalkyl.

[0045] In some embodiments of (1), the substituted or unsubstituted 4-12 membered heterocyclic group includes a substituted or unsubstituted 4-membered heterocyclic group containing 1, 2, 3 or 4 independently selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 5-membered heterocyclic group containing 1, 2, 3 or 4 independently selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 6-membered heterocyclic group containing 1, 2, 3 or 4 independently selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 7-membered heterocyclic group containing 1, 2, 3 or 4 independently selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 1, 2, 3 or 4 8-membered heterocyclyl groups independently selected from N, O, S, S(O) or S(O)2, substituted or unsubstituted 9-membered heterocyclyl groups independently selected from N, O, S, S(O) or S(O)2, substituted or unsubstituted 10-membered heterocyclyl groups independently selected from N, O, S, S(O) or S(O)2, substituted or unsubstituted 11-membered heterocyclyl groups independently selected from N, O, S, S(O) or S(O)2, or substituted or unsubstituted 12-membered heterocyclyl groups independently selected from N, O, S, S(O) or S(O)2.

[0046] In some embodiments of (1), the C 2- The C6 alkene group includes a C2 alkene group, a C3 alkene group, a C4 alkene group, a C5 alkene group or a C6 alkene group.

[0047] In some embodiments of (1), the C 2- The C6 alkynyl group includes a C2 alkynyl group, a C3 alkynyl group, a C4 alkynyl group, a C5 alkynyl group or a C6 alkynyl group.

[0048] In some embodiments of (1), the substituted or unsubstituted 5-9 membered bridged cycloalkyl group includes a substituted or unsubstituted 5-membered bridged cycloalkyl group, a substituted or unsubstituted 6-membered bridged cycloalkyl group, a substituted or unsubstituted 7-membered bridged cycloalkyl group, a substituted or unsubstituted 8-membered bridged cycloalkyl group or a substituted or unsubstituted 9-membered bridged cycloalkyl group.

[0049] In some embodiments of (1), the substituted or unsubstituted 5-9 membered hetero-bridged cycloalkyl includes a substituted or unsubstituted 5-membered hetero-bridged cycloalkyl containing 1, 2, 3 or 4 selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 6-membered hetero-bridged cycloalkyl containing 1, 2, 3 or 4 selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 7-membered hetero-bridged cycloalkyl containing 1, 2, 3 or 4 selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 8-membered hetero-bridged cycloalkyl containing 1, 2, 3 or 4 selected from N, O, S, S(O) or S(O)2, or a substituted or unsubstituted 9-membered hetero-bridged cycloalkyl containing 1, 2, 3 or 4 selected from N, O, S, S(O) or S(O)2.

[0050] In some embodiments, the substituted or unsubstituted 6-10 membered spirocycloalkyl includes substituted or unsubstituted 6-membered spirocycloalkyl, substituted or unsubstituted 7-membered spirocycloalkyl, substituted or unsubstituted 8-membered spirocycloalkyl, substituted or unsubstituted 9-membered spirocycloalkyl or substituted or unsubstituted 10-membered spirocycloalkyl.

[0051] In some embodiments of (1), the substituted or unsubstituted 6-10 membered heterospirocycloalkyl includes a substituted or unsubstituted 6-membered heterospirocycloalkyl containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 7-membered heterospirocycloalkyl containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 8-membered heterospirocycloalkyl containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 9-membered heterospirocycloalkyl containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, or a substituted or unsubstituted 10-membered heterospirocycloalkyl containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2.

[0052] In some embodiments of (1), the substituted or unsubstituted 6-10 membered cycloalkyl group includes a substituted or unsubstituted 6-membered cycloalkyl group, a substituted or unsubstituted 7-membered cycloalkyl group, a substituted or unsubstituted 8-membered cycloalkyl group, a substituted or unsubstituted 9-membered cycloalkyl group or a substituted or unsubstituted 10-membered cycloalkyl group.

[0053] In some embodiments of (1), the substituted or unsubstituted 6-10 membered heterocycloalkyl group includes a substituted or unsubstituted 6-membered heterocycloalkyl group containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 7-membered heterocycloalkyl group containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 8-membered heterocycloalkyl group containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 9-membered heterocycloalkyl group containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, or a substituted or unsubstituted 10-membered heterocycloalkyl group containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2.

[0054] In some embodiments of (1), the C6-C 10 The aryl group includes a C6 aryl group, a C7 aryl group, a C8 aryl group, a C9 aryl group or a C 10 Aryl.

[0055] In some embodiments of (1), the substituted or unsubstituted 5-10 membered heteroaryl group includes a substituted or unsubstituted 5-membered heteroaryl group containing 1, 2, 3 or 4 selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 6-membered heteroaryl group containing 1, 2, 3 or 4 selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 1, 2, 3 or 4 selected from N, O, S, S(O) or S(O)2, O) or S(O)2, a substituted or unsubstituted 7-membered heteroaryl containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 8-membered heteroaryl containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, a substituted or unsubstituted 9-membered heteroaryl containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2, or a substituted or unsubstituted 10-membered heteroaryl containing 1, 2, 3 or 4 groups selected from N, O, S, S(O) or S(O)2.

[0056] In some embodiments of (1), the substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S includes a substituted or unsubstituted 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, a substituted or unsubstituted 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, a substituted or unsubstituted 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, a substituted or unsubstituted 7-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, a substituted or unsubstituted 8-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, a substituted or unsubstituted 9-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, and a substituted or unsubstituted 10-membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S.

[0057] In some embodiments of (1), the substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S includes a substituted or unsubstituted 3-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N, O, S, a substituted or unsubstituted 4-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, a substituted or unsubstituted 5-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, a substituted or unsubstituted 6-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, a substituted or unsubstituted 7-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, and a substituted or unsubstituted 8-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S.

[0058] (2) The compound according to (1), wherein Y is N or NH;

[0059] Z1 and Z2 are each independently selected from C or N;

[0060] Z3 is selected from N or C(R8);

[0061] Z4 is selected from C(R9);

[0062] R9 is selected from H or halogen;

[0063] L is -NH-;

[0064] X is selected from -(CH2) n1 -or-(CH2) n2 C(R 5a )(R 5b )(CH2) n3-; Preferably, X is selected from: -CH2-, -CH2CH2-, -CH2CH2CH2-, -(CH2)4-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2C(CH3)2CH2-, -CF2CH2-, -CH=CH-, More preferably, X is selected from: -CH2CH2-, -C(CH3)2CH2-, -CH2C(CH3)2CH2-.

[0065] (3) The compound according to any one of the above (1) and (2), wherein the compound of formula (I) is selected from the group consisting of a compound of formula (II), a compound of formula (III), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (III-1), a compound of formula (IV-1), a compound of formula (V-1), a compound of formula (VI-1), a compound of formula (VI-2), a compound of formula (VI-3) or a compound of formula (VII-1),

[0066]

[0067] The definitions of the symbols are as described in any of the above (1), (2), and (3).

[0068] (4) The compound according to any one of (1), (2) and (3), wherein R 5a , R 5b is H or methyl. (5) According to the compound described in (4), the compound of formula (I) is selected from:

[0069] ① The compound of formula (I) is selected from the compound of formula (III),

[0070]

[0071] in,

[0072] Z3 is selected from N or C(R8);

[0073] R8 is H, F, Cl, -C(=O)-CH3 or

[0074] R 10 , R 10 'are each independently selected from H, cyano, methyl, F, Cl, Br, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, -C(=O)-R 12 , or R10 ' is H, methyl, Br or chlorine atom, R 10 is selected from H, cyano, methyl, F, Cl, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, -C(=O)-R 12 ,

[0075] Other symbols are as described in any of the above (1), (2) and (3);

[0076] Optionally, the substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1-7 carbon atoms in the ring;

[0077] or

[0078] ② The compound of formula (I) is selected from the compound of formula (VI-2),

[0079] Wherein n2 is 2, R8 is selected from -C(=O)-CH3 or R 10 is selected from H, cyano, methyl, F, Cl, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, -C(=O)-R 12 ,

[0080] Other symbols are as described in any of the above (1), (2) and (3);

[0081] Optionally, the substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1-7 carbon atoms in the ring;

[0082] or

[0083] ③ The compound of formula (I) is selected from the compound represented by formula (II),

[0084] Among them, R 10 is selected from H, cyano, methyl, F, Cl, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, -C(=O)-R 12 ,

[0085] Other symbols are as described in any of the above (1), (2) and (3);

[0086] Optionally, the substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1-7 carbon atoms in the ring;

[0087] or

[0088] ④ The compound of formula (I) is selected from the compound represented by formula (V),

[0089] Among them, R 10 , R 10 'are each independently selected from H, cyano, methyl, fluorine atom, chlorine atom, Br, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, -C(=O)-R 12 , or R 10 ' is H, methyl, Br or chlorine atom, R 10 is selected from H, cyano, methyl, fluorine atom, chlorine atom, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, -C(=O)-R 12 ,

[0090] n2 is 0 or 1, n3 is 0 or 1, and n2 and n3 are not 0 at the same time;

[0091] Other symbols are as described in any of the above (1), (2) and (3);

[0092] Optionally, the substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1-7 carbon atoms in the ring.

[0093] (6) The compound according to any one of (1), (2), (3), (4) and (5), wherein

[0094] The substituted or unsubstituted C1-C6 alkyl group in R1 is selected from the following groups:

[0095]

[0096] or

[0097]

[0098] p2 is 0 or 1; p3 is 1, 2 or 3;

[0099] and / or

[0100] The substituted or unsubstituted C3-C8 cycloalkyl group in R1 is selected from the following groups:

[0101]

[0102] and / or

[0103] The substituted or unsubstituted 6-10 membered spirocycloalkyl group in R1 is selected from the following groups:

[0104] and / or

[0105] The substituted or unsubstituted 4-12 membered heterocyclic group in R1 is selected from the following groups:

[0106]

[0107] ; R3 and R4 are each independently selected from: H, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3 and R4 are connected to form a 3-6 membered cycloalkyl;

[0108] and / or

[0109] The substituted or unsubstituted 5-9 membered hetero-bridged cycloalkyl group in R1 is selected from the following groups:

[0110] and / or

[0111] The substituted or unsubstituted 5-9 membered bridged cycloalkyl group in R1 is selected from the following groups:

[0112]

[0113] ; and / or

[0114] The substituted or unsubstituted 6-10 membered heterospirocycloalkyl group in R1 is selected from the following groups:

[0115]

[0116] and / or

[0117] The substituted or unsubstituted 6-10 membered heterocycloalkyl group in R1 is selected from the following groups:

[0118]

[0119] and / or

[0120] R2 is independently selected from the following groups: hydrogen, substituted or unsubstituted amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, substituted or unsubstituted -C(=O)-NR 2a R 2b ;

[0121] Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S in R2 contains 1 to 9 carbon atoms in the ring;

[0122] Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S in R2 contains 1-7 carbon atoms in the ring; and / or

[0123] Optionally, R 2a , R 2b Each is independently selected from hydrogen or C1-C6 alkyl.

[0124] (7) The compound according to any one of (1), (2), (3), (4), (5) and (6), wherein

[0125] R 10 , R 10 ' are each independently selected from: H, -CN, methyl, F, Cl, Br,

[0126] ; or R 10 ' is H, methyl, Br or chlorine atom; R 10 Selected from H, -CN, methyl, F, Cl,

[0127] R8 is selected from H, F, Cl, -C(=O)-CH3 or

[0128] R1 is selected from the following groups:

[0129]

[0130] or

[0131]

[0132]

[0133] in,

[0134] R2 is H;

[0135] R3 and R4 are each independently selected from: H, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3 and R4 are linked to form a 3-6 membered cycloalkyl;

[0136] p1 is 0, 1, 2 or 3; p2 is 0 or 1; p3 is 1, 2 or 3.

[0137] (8) The compound according to any one of the above (1), (2), (3), (4), (5), (6) and (7), wherein the compound of formula (I) is selected from:

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147] In a second aspect, the present invention provides a pharmaceutical composition.

[0148] (9) A pharmaceutical composition comprising the compound according to any one of (1) to (8) of the first aspect, and a pharmaceutically acceptable excipient, diluent or carrier.

[0149] In a third aspect, the present invention provides uses of the aforementioned compound or the aforementioned pharmaceutical composition.

[0150] (10) Use of the compound described in any one of (1) to (8) of the first aspect or the pharmaceutical composition described in the second aspect in the preparation of a drug for inhibiting CDK7 kinase activity or a drug for preventing and / or treating diseases related to increased CDK7 kinase activity.

[0151] In some embodiments, the diseases associated with increased CDK7 kinase activity include cancer, inflammation, cardiovascular disease, infectious disease, immune disease or metabolic disease.

[0152] In some embodiments, the cancer comprises breast cancer, ovarian cancer, colorectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, pancreatic cancer, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, intestinal cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer, or uterine cancer.

[0153] In some embodiments, the cancer comprises estrogen receptor (ER)-positive breast cancer, triple-negative breast cancer, ovarian cancer, castration-resistant prostate cancer, colorectal cancer, pancreatic cancer, liver cancer, lung cancer, or acute myeloid leukemia.

[0154] Beneficial Effects

[0155] Compared with the prior art, the present invention has at least one of the following technical effects:

[0156] (A) The compounds provided by the present invention have good CDK7 kinase inhibitory activity and can be used to regulate CDK7 kinase activity or to prevent and / or treat abnormal CDK7-related diseases.

[0157] (B) The compounds provided by the present invention have good anti-tumor activity, especially good inhibitory activity against human colorectal cancer.

[0158] Definition of terms

[0159] Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings:

[0160] "Compounds of the present invention" means compounds of formula I or pharmaceutically acceptable salts, tautomers, polymorphs, isomers and solvates thereof. Similarly, the phrase "compounds of formula I" means compounds of the formula and pharmaceutically acceptable salts, tautomers, polymorphs, isomers and solvates thereof.

[0161] In the present invention, expressions such as "compound I" and "compound represented by formula I" refer to the same compound.

[0162] "V / V" means volume ratio. IC 50 It represents the half inhibitory concentration.

[0163] The term "plurality" means at least 2, for example 2, 3, 4 or 5 etc.

[0164] In the present invention, the meanings of the atoms in the compound structure are as follows: F represents fluorine, Cl represents chlorine, and D represents deuterium.

[0165] The term "and / or" should be understood to mean any one of the optional items or a combination of any two or more of the optional items.

[0166] The term "optional", "optional" or "optionally" means that the event or situation described later may but does not necessarily occur. For example, "optionally, the heteroatom in the heterocycle includes at least one selected from nitrogen, oxygen, and sulfur" means that the situation of "the heteroatom in the heterocycle includes at least one selected from nitrogen, oxygen, and sulfur" may exist or not exist.

[0167] In the present invention, "room temperature" refers to ambient temperature, which is from about 10°C to about 40°C. In some embodiments, "room temperature" refers to a temperature from about 20°C to about 30°C; in other embodiments, "room temperature" refers to a temperature from about 25°C to about 30°C; in still other embodiments, "room temperature" refers to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, etc.

[0168] "Alkyl" is a hydrocarbon containing positive carbon atoms, secondary carbon atoms, tertiary carbon atoms, or cyclic carbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), 1 to 10 carbon atoms (i.e., C1-C 10alkyl), 1 to 8 carbon atoms (i.e., C1-C8 alkyl), or 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (i-Pr, i-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH (CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl ( -CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH (CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3 or octyl (-(CH2)7CH3).

[0169] The term "alkylene" means a saturated divalent hydrocarbon radical obtained by removing two hydrogen atoms from a saturated straight or branched hydrocarbon radical. Unless otherwise specified, an alkylene group contains 1-12 carbon atoms. In one embodiment, an alkylene group contains 1-6 carbon atoms; in another embodiment, an alkylene group contains 1-4 carbon atoms; in yet another embodiment, an alkylene group contains 1-3 carbon atoms; in yet another embodiment, an alkylene group contains 1-2 carbon atoms. Such examples include methylene (-CH2-), ethylene (-CH2CH2-), isopropylene (-CH(CH3)CH2-), and the like. The alkylene group is optionally substituted with one or more substituents described herein.

[0170] The term "carbocyclyl" or "carbocycle" refers to a monovalent or polyvalent non-aromatic saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3-12 carbon atoms. Bicyclic or tricyclic ring systems may include fused rings, bridged rings and spirocyclic rings. Carbobicyclic groups include spirocarbobicyclic groups and fused carbobicyclic groups. Suitable carbocyclyl groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. In one embodiment, the carbocyclyl contains 3-10 carbon atoms, such as C 3- C 10 In another embodiment, the carbocyclic group contains 3-8 carbon atoms, such as C 3- C8 carbocyclyl; In another embodiment, the carbocyclyl contains 3-6 carbon atoms, such as C 3- In another embodiment, the monocyclic carbocyclic group contains 4-8 carbon atoms, such as C 4- C8 monocyclic carbocyclic group; In another embodiment, the monocyclic carbocyclic group contains 4-6 carbon atoms, such as C 4-C6 monocyclic carbocyclic radical.The example of carbocyclic radical group further comprises, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.Described carbocyclic radical group is optionally substituted by one or more substituents described in the present invention. The example of carbocyclyl group further includes, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc.When the structure clearly needs a linking group, the Markush variable listed for the group should be understood as a linking group.For example, if the structure needs a linking group and the Markush group definition for the variable lists "carbocyclyl", it should be understood that the subcarbocyclyl group connected by the "carbocyclyl" representative.

[0171] The term "cycloalkyl" refers to a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. The bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. In one embodiment, the cycloalkyl contains 3 to 10 carbon atoms, such as C 3- C 10 In another embodiment, the cycloalkyl group contains 3-8 carbon atoms, such as C 3- C8 cycloalkyl; In another embodiment, the cycloalkyl contains 3-6 carbon atoms, such as C 3- C6 cycloalkyl. The cycloalkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.

[0172] The term "alkoxy" means an alkyl group attached to the rest of the molecule via an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein.

[0173] Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), and the like.

[0174] An "alkenyl group" is a group containing at least one unsaturated site, i.e., a carbon-carbon sp 2 For example, an alkenyl group can have 2 to 10 carbon atoms (C2-C 10 alkenyl), 2 to 12 carbon atoms (C2-C 12 The alkenyl group may be optionally substituted with one or more substituents as described herein, including "cis" and "trans" orientations, or "E" and "Z" orientations. Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), allyl (-CH2CH=CH2), cyclopentenyl (-C5H7) 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0175] "Alkynyl" is a hydrocarbon containing a positive carbon atom, a secondary carbon atom, a tertiary carbon atom or a ring carbon atom having at least one unsaturated site, i.e., a carbon-carbon sp triple bond. The alkynyl group may be optionally substituted with one or more substituents described herein. For example, an alkynyl group may have 2 to 10 carbon atoms (C2-C 10 Alkynyl), 2 to 12 carbon atoms (C2-C 12 Examples of suitable alkynyl groups include, but are not limited to, ethynyl (-C=CH), propargyl (-CH2C=CH), or the like.

[0176] The term "aryl" refers to a monocyclic, bicyclic and tricyclic carbon ring system containing 6-20 ring atoms, or 6-14 ring atoms, or 6-12 ring atoms, or 6-10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring consisting of 3-7 atoms. The aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups can include groups derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like. The aryl group is optionally substituted by one or more substituents described herein.

[0177] "Arylalkyl" refers to a radical in which the 3 The term "arylalkyl" refers to an alkyl radical having a carbon atom (carbon atom) and a cycloalkyl radical having a carbon atom (carbon atom). The term "arylalkyl" refers to an alkyl radical having a carbon atom (carbon atom) and a cycloalkyl radical having a carbon atom (carbon atom). Typical arylalkyl includes, but is not limited to, benzyl, 2-phenyl second-1-yl, naphthylmethyl, 2-naphthyl second-1-yl, naphthobenzyl, 2-naphthophenyl second-1-yl and analogue. Arylalkyl can comprise 7 to 20 carbon atoms, for example, alkyl moiety is 1 to 6 carbon atom, and aryl moiety is 6 to 14 carbon atoms.

[0178] The term "substituted" refers to alkyl, aryl, arylalkyl, heterocyclyl, heteroaryl, carbocyclyl, etc., for example, "substituted C1-C 10 Alkyl", "substituted C6-C 20 Aryl", "substituted arylalkyl", "substituted C1-C 20 "Heterocycle" and "substituted carbocyclyl" refer to C1-C2-1, C1-C3-1, C1-C4-1, C1-C6-1, C1-C7-1, C1-C8-1, C1-C9-1, C1-C1 ... 10 Alkyl, C6-C 20 Aryl, Arylalkyl, C1-C 20 Heterocycle, alkylamino, carbocyclyl. Unless otherwise indicated, when the term "substituted" is used in conjunction with a group having two or more moieties capable of substitution, such as arylalkyl, the substituents may be attached to the aryl portion, the alkyl portion, or both.

[0179] The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N,N-dialkylamino", wherein the amino group is independently substituted with one or two alkyl groups, wherein the alkyl group has the meaning as described herein. Suitable alkylamino groups can be monoalkylamino or dialkylamino, such examples include, but are not limited to, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like. The alkylamino group is optionally substituted with one or more substituents as described herein.

[0180] The term "hydroxyalkyl" means an alkyl group substituted with one or more hydroxy groups, wherein the alkyl group has the meaning as described herein; such examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxy-1-propyl, 3-hydroxy-1-propyl, 2,3-dihydroxypropyl and the like.

[0181] The term "cyanoalkyl" means an alkyl group substituted with one or more cyano groups, wherein the alkyl group has the meaning as described herein; such examples include, but are not limited to, cyanomethyl, 2-cyanoethyl, 2-cyano-1-propyl, 3-cyano-1-propyl, 2,3-dicyanopropyl and the like.

[0182] The term "aminoalkyl" means an alkyl group substituted by one or more amino groups, wherein the alkyl group has the meaning described herein; such examples include, but are not limited to, aminomethyl, 2-aminoethyl, 2-amino-1-propyl, 3-amino-1-propyl, 2,3-diaminopropyl and the like.

[0183] The term "haloalkyl" means that an alkyl group is substituted by one or more halogen atoms, wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to, -CHF2, -CF3, -CHFCH2F, -CF2CHF2, -CH2CF3, -CHFCH3, -CH2CH2F, -CF2CH3, -CH2CF2CHF2, etc. In one embodiment, C1-C6 haloalkyl comprises fluorine-substituted C1-C6 alkyl; in another embodiment, C1-C4 haloalkyl comprises fluorine-substituted C1-C4 alkyl; in yet another embodiment, C1-C2 haloalkyl comprises fluorine-substituted C1-C2 alkyl.

[0184] The term "haloalkoxy" means that an alkoxy group is substituted by one or more halogen atoms, wherein the alkoxy group has the meaning as described in the present invention, such examples include, but are not limited to, -OCHF2, -OCF3, -OCHFCH2F, -OCF2CHF2, -OCH2CF3, -OCHFCH3, -OCH2CH2F, -OCF2CH3, -OCH2CF2CHF2, etc. In one embodiment, C1-C6 haloalkoxy comprises fluorine-substituted C1-C6 alkoxy; in another embodiment, C1-C4 haloalkoxy comprises fluorine-substituted C1-C4 alkoxy; in yet another embodiment, C1-C2 haloalkoxy comprises fluorine-substituted C1-C2 alkoxy.

[0185] The term "jk atoms" or "jk-membered" means that the cyclic group is composed of jk ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P; j and k are each independently any non-zero natural number, and k>j; "jk" includes j, k, and any natural number between the two. For example, "3-8 atoms" or "3-8-membered", "3-6 atoms" or "3-6-membered", "5-10 atoms" or "5-10-membered", "5-6 atoms" or "5-6-membered" means that the cyclic group is composed of 3-8 (i.e., 3, 4, 5, 6, 7, or 8), 3-6 (i.e., 3, 4, 5, or 6), 5-10 (i.e., 5, 6, 7, 8, 9, or 10), or 5-6 (i.e., 5 or 6) ring atoms, and the ring atoms include carbon atoms and / or heteroatoms such as O, N, S, and P. For another example, piperidinyl is a 6-atom heterocyclic group or a 6-membered heterocyclic group, and pyridinyl is a 6-atom heteroaryl group or a 6-membered heteroaryl group.

[0186] The term "jk pieces", "jk yuan" or "C j -C k " wherein j and k are independently any non-zero natural numbers, and k>j; for example, "1-4" means 1, 2, 3 or 4, "4-6 yuan" means 4 yuan, 5 yuan or 6 yuan; "C3-C6" means C3, C4, C5 or C6. And so on.

[0187] The terms "(alkoxy)-alkylene", "(alkylamino)-alkylene", "(cycloalkyl)-alkylene", "(heterocyclyl)-alkylene", "(aryl)-alkylene", "(heteroaryl)-alkylene" mean that the alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently connected to the rest of the molecule through an alkylene, wherein the alkoxy, alkylamino, cycloalkyl, heterocyclyl, aryl, heteroaryl and alkylene have the meanings described in the present invention. For example, examples of (cycloalkyl)-alkylene include, but are not limited to, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, cyclohexylmethylene, etc. For another example, examples of (aryl)-alkylene include, but are not limited to, phenylmethylene, phenylethylidene, phenylpropylene, etc. The (alkoxy)-alkylene, (alkylamino)-alkylene, (cycloalkyl)-alkylene, (heterocyclyl)-alkylene, (aryl)-alkylene, (heteroaryl)-alkylene are each independently optionally substituted with one or more substituents described herein.

[0188] As used herein, the term "prodrug" refers to any compound that, when administered to a biological system, produces a drug, i.e., an active ingredient, due to a spontaneous chemical reaction, an enzyme-catalyzed chemical reaction, photolysis, and / or a metabolic chemical reaction. A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.

[0189] As used herein, "heterocycle" or "heterocyclyl" includes, by way of example and without limitation, those heterocycles described in Paquette, Leo A.: Principles of Modern Heterocyclic Chemistry (WA Benjamin, New York, 1968), in particular Chapters 1, 3, 4, 6, 7 and 9: The Chemistry of Heterocyclic Compounds, A Series of Monographs^ (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19 and 28 and J. Am. Chem. Soc. (1960) 82:5566. In a particular embodiment of the invention, "heterocycle" includes "carbocycles" as defined herein, in which one or more (e.g. 1, 2, 3 or 4) carbon atoms have been replaced by heteroatoms (e.g. O, N or S). The term "heterocycle" or "heterocyclyl" includes saturated rings, partially unsaturated rings and aromatic rings (i.e. heteroaromatic rings). Substituted heterocyclyl groups include, for example, heterocycles substituted with any of the substituents disclosed herein including carbonyl.

[0190] The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 ring atoms, wherein the bicyclic or tricyclic ring system may include fused rings, bridged rings and spiro rings. One or more atoms in the ring are independently replaced by heteroatoms, and the heteroatoms have the meanings as described herein. In one embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3-8 ring atoms (1-7 carbon atoms and 1-4 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2); in another embodiment, heterocyclyl is a monocyclic heterocyclyl consisting of 3-6 ring atoms (1-5 carbon atoms and 1-4 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2); in another embodiment, heterocyclyl is a bicyclic heterocyclyl consisting of 7-12 ring atoms (1-11 carbon atoms and 1-4 heteroatoms selected from N, O, P, S, where S or P is optionally substituted by one or more oxygen atoms to give groups like SO, SO2, PO, PO2). The heterocyclyl groups are optionally substituted by one or more substituents described herein.

[0191] The ring atoms of the heterocyclic group can be carbon groups or heteroatom groups. In which the -CH2- group of the ring is optionally replaced by -C(=O)-, the sulfur atom of the ring is optionally oxidized to S-oxide, and the nitrogen atom of the ring is optionally oxidized to N-oxygen compound. Examples of heterocyclic groups include, but are not limited to, oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepine Base, diazepine Base, thiazolin Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinyl, 3,5-dioxopiperidinyl, pyrimidinedione, and the like. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane, thiomorpholinyl 1,1-dioxide, and the like. The heterocyclic group is optionally substituted by one or more substituents described herein.

[0192] Examples of heterocycles include, by way of example and not limitation, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothienyl, thiooxytetrahydrothienyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthyl, indolyl, indolene, quinolyl, isoquinolyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenolic flavinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl pyridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatoyl or bis-tetrahydrofuranyl.

[0193] The term "heteroaryl" refers to monocyclic, bicyclic and tricyclic ring systems containing 5-12 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms, wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring consisting of 5-7 atoms. The heteroaryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the heteroaryl group. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring", "aromatic heterocycle" or "heteroaromatic compound". The heteroaryl group is optionally substituted by one or more substituents described in the present invention. Non-limiting examples of suitable heteroatoms that can be included in the aromatic ring include oxygen, sulfur and nitrogen. Non-limiting examples of heteroaryl rings include all those aromatic rings listed in the definition of "heterocyclyl", including pyridyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothienyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazolyl, etc. In one embodiment, the 5-10 atom heteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

[0194] Examples of heteroaryl groups include, but are not limited to, 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl , 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, pyrazinyl, 1,3,5-triazinyl; also includes the following bicyclic rings, but is by no means limited to these bicyclic rings: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (such as 2-indolyl), purinyl, quinolyl (such as 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (such as 1-isoquinolyl), [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and the like.

[0195] "Prodrug moiety" refers to an unstable functional group that is separated from an active inhibitory compound during metabolism, systemically, intracellularly, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, "Design and Application of Prodrugs" in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academic Publishers, 113-191 pages). Prodrug moieties can be used to enhance solubility, absorption, and lipophilicity to optimize drug delivery, bioavailability, and efficacy.

[0196] The prodrug moiety may include an active metabolite or the drug itself.

[0197] The compound shown in Formula I or its pharmaceutically acceptable salt can exist as different polymorphs or pseudopolymorphs. Crystal polymorphism used herein refers to the ability of a crystalline compound to exist in different crystal structures. Crystal polymorphism can be derived from differences in crystal packing (stacking polymorphism) or packing differences between different conformers of the same molecule (conformational polymorphism). Crystal pseudopolymorphism used herein refers to the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the present invention can exist due to differences in crystal packing (stacking pseudopolymorphism) or due to packing differences between different conformers of the same molecule (conformational pseudopolymorphism). The present invention includes all polymorphs and pseudopolymorphs of Formula I-III compounds and their pharmaceutically acceptable salts.

[0198] The compound shown in formula I or its pharmaceutically acceptable salt can also exist as an amorphous solid. Amorphous solids used herein are such solids, wherein there is no long-range order in the positions of the atoms in the solid. This definition also applies when the crystal size is 2 nanometers or less. Additives including solvents can be used to establish the amorphous form of the present invention. The present invention includes all amorphous forms of compounds of formula I-III and their pharmaceutically acceptable salts.

[0199] The term "treat", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of, or preventing the condition or disorder, or one or more symptoms of such condition or disorder, to which the term applies. The term "treat", as used herein, refers to the act of treating, as "treating" is defined immediately above.

[0200] The compounds described herein also include reference to their physiologically acceptable salts, examples of which include salts derived from suitable bases, such as alkali metals or alkaline earth metals (e.g., Na + , Li + , K + , Ca +2 and Mg +2 ), ammonium and NR4 +(wherein R is as defined herein). Physiologically acceptable salts of nitrogen atoms or amino groups include: (a) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; (b) salts formed with organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalene, and the like. (c) salts with elemental anions, such as chlorine, bromine and iodine. Physiologically acceptable salts of hydroxy compounds include salts of the anions of the compounds with hydroxy groups, such as sodium + and NR4 + A combination of appropriate cations.

[0201] For therapeutic use, the salts of the active ingredients of the compounds of the invention are physiologically acceptable, i.e., they are salts derived from physiologically acceptable acids or bases. However, salts that are not physiologically acceptable acids or bases may also be used, for example, to prepare or purify physiologically acceptable compounds. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of the present invention.

[0202] The compounds described in formula I may have chiral centers, such as chiral carbons. The compounds described in formula I therefore include racemic mixtures of all stereoisomers, including enantiomers, diastereomers and atropisomers. In addition, the compounds described in the present invention include optical isomers enriched or separated at any or all asymmetric chiral atoms. In other words, chiral centers similar to the description are provided in the form of chiral isomers or racemic mixtures. Racemic and diastereomeric mixtures, as well as separate or synthesized, substantially free of their enantiomers or diastereomeric partners, are within the scope of the present invention. Racemic mixtures are separated into their separate, substantially optically pure isomers by known techniques, such as separation of diastereomeric salts formed with optically active auxiliary agents (such as acids or bases), which are then converted back to optically active substances. In most cases, starting from the appropriate stereoisomers of the desired raw materials, the desired optical isomers are synthesized by stereospecific reactions.

[0203] Whenever a compound described herein is represented by more than one of the same designated group (e.g., "R" or "R 1”), it is to be understood that these groups may be the same or different, i.e., each group is independently selected.

[0204] Pharmaceutical preparations

[0205] The compounds of the present invention are formulated with conventional carriers and excipients, which will be selected in accordance with conventional practice. Although the active ingredients can be administered alone, it is preferred that they are formulated into pharmaceutical preparations. The preparations of the present invention, whether for veterinary or human use, contain at least one active ingredient as defined above and one or more acceptable carriers therefor, and optionally contain other therapeutic ingredients, especially those additional therapeutic ingredients as disclosed herein. The carrier must be "acceptable" in the sense that it is compatible with the other components of the formulation and is physiologically harmless to its recipient.

[0206] Preparations include those suitable for the above-mentioned routes of administration. Preparations can be conveniently prepared into unit dosage forms, and can be prepared by any method well-known in the pharmaceutical field. Technology and preparations can generally be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA.). Such methods include the step of mixing the active ingredient with a carrier constituting one or more auxiliary components. In general, the preparation is prepared as follows: by uniformly and closely mixing the active ingredient with a liquid carrier or a finely dispersed solid carrier or both, and then, if necessary, the product is shaped.

[0207] The invention further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary carrier therefor.

[0208] Veterinary carriers are substances useful for the purpose of the veterinary composition and may be solid, liquid or gaseous substances which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

[0209] Route of Administration:

[0210] One or more compounds of the present invention (referred to herein as active ingredients) are administered by any route suitable for the condition being treated. Suitable routes include oral, rectal, nasal, pulmonary, topical (including buccal and sublingual) and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), etc. It should be understood that the preferred route may vary, for example, depending on the condition of the recipient. DETAILED DESCRIPTION

[0211] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0212] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0213] In the present invention, μM means micromoles per liter; mmol means millimole; equiv means equivalent. "Overnight" means 12 hours.

[0214] Example 1: Preparation of (S)-9-(dimethylphosphoryl)-2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indole-10-carbonitrile (Compound A201)

[0215]

[0216] Step 1-1:

[0217]

[0218] Dissolve 2-bromo-3-nitrobenzoic acid (10 g, 40.6 mmol) in anhydrous toluene (80 mL) and anhydrous N,N-dimethylformamide (1.5 mL), add thionyl chloride (15 mL, 207 mmol), reflux for 4 hours, cool to 0 ° C, and slowly pour into cold ammonia water (150 mL). Add ethyl acetate (100 mL × 3) to extract and combine the organic phases, and wash the combined organic phases with saturated sodium chloride solution and dry with anhydrous sodium sulfate. Spin dry to obtain 2-bromo-3-nitrobenzamide (9.8 g, 40 mmol, yellow solid, yield 98.5%).

[0219] Step 1-2:

[0220]

[0221] Dissolve 2-bromo-3-nitrobenzamide (5 g, 20.41 mmol) in phosphorus oxychloride (20 mL), heat at 100 °C and seal the tube overnight. After TLC detection shows that the reaction is complete, add the cooled reaction solution dropwise into cold water (100 mL) and shake continuously. After filtration and drying, a gray solid 2-bromo-3-nitrobenzonitrile can be obtained, which is directly used in the next step.

[0222] 1 H NMR (400MHz, Chloroform-d) δ8.01 (dd, J=8.2, 1.5Hz, 1H), 7.88 (dd, J=7.8, 1.5Hz, 1H), 7.63 (t, J=8.0Hz, 1H).

[0223] Steps 1-3:

[0224]

[0225] 2-Bromo-3-nitrobenzonitrile (4.3 g, 18.94 mmol) was dissolved in anhydrous ethanol (80 mL), stannous chloride (10 g, 52.7 mmol) was added and heated at 80 ° C overnight. After the reaction was complete by TLC monitoring, the solvent was dried and ethyl acetate (100 mL) was added. Under ice bath conditions, 6M sodium hydroxide aqueous solution was added until pH = 10. After filtration through diatomaceous earth, the filtrate was extracted with ethyl acetate (100 mL × 2), the organic phases were combined, and the combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and then dried to obtain a light brown solid 3-amino-2-bromobenzonitrile (3 g, 15.22 mmol, yield 80.4%).

[0226] 1H NMR (400MHz, Chloroform-d) δ7.18 (t, J=7.9Hz, 1H), 7.05 (dd, J=7.6, 1.5Hz, 1H), 6.94 (dd, J=8.2, 1.5Hz, 1H), 4.42-4.27 (s, 2H).

[0227] 13 C NMR (101MHz, CDCl3) δ145.30,128.49,123.82,119.25,117.71,116.30,110.38.

[0228] Steps 1-4:

[0229]

[0230] Dissolve 3-amino-2-bromobenzonitrile (4g, 20.3mmol) in concentrated hydrochloric acid (40mL), cool to 0℃, and slowly drip sodium nitrite (1.69g, 24.5mmol, 4mL) aqueous solution. One hour later, slowly drip stannous chloride (9.67g, 51mmol) in concentrated hydrochloric acid (40mL). After TLC monitoring of the reaction is complete, slowly drip 12M sodium hydroxide aqueous solution pH = 10. After filtration through diatomaceous earth, the filtrate is extracted with ethyl acetate (100mL×2), the organic phases are combined, and the combined organic phases are washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After spin drying and concentration, a light yellow solid 2-bromo-3-hydrazinylbenzonitrile (2.3g, 10.85mmol, yield 53.4%) is obtained.

[0231] Steps 1-5:

[0232]

[0233] 2-Bromo-3-hydrazinobenzonitrile (1.45 g, 6.84 mmol) and cycloheptanone (766 mg, 6.84 mmol) were dissolved in trifluoroacetic acid (15 mL) and heated at 100 °C in a sealed tube overnight. After cooling to room temperature, the reaction solution was concentrated in vacuo using a rotary evaporator, slowly added with saturated sodium bicarbonate solution at 0 °C for neutralization, and extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 20: 1) to obtain 4-bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-3-carbonitrile (1.56 g, 5.40 mmol, light yellow oily liquid, yield: 78.9%).

[0234] 1 H NMR (400MHz, Chloroform-d) δ8.20 (s, 1H), 7.43 (dd, J = 8.3, 0.6Hz, 1H), 7.30 (d, J = 8. 2Hz,1H),2.95-2.90(m,2H),2.80-2.76(m,2H),1.96-1.89(m,2H),1.84-1.73(m,4H).

[0235] 13 C NMR (101MHz, CDCl3) δ143.18,132.76,132.57,123.87,119.16,117.29,116.43,107.60,105.20,31.56,29.64,28.31,27.01,24.71.

[0236] Steps 1-6:

[0237]

[0238] 4-Bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-3-carbonitrile (41 mg, 0.142 mmol) was dissolved in anhydrous N,N-dimethylformamide (1.5 mL) under argon protection, cooled to 0°C, and 60% sodium hydride (11.3 mg, 0.284 mmol) was slowly added. Half an hour later, 2-(trimethylsilyl)ethoxymethyl chloride (50 μL, 0.284 mmol) was added dropwise and stirred at room temperature overnight. After TLC detection, saturated ammonium chloride solution was added dropwise at 0°C to quench the reaction. After removing tetrahydrofuran from the solution by rotary evaporator, ethyl acetate (10 mL×3) was added for extraction, and the organic phases were combined, and the combined organic phases were washed with saturated sodium chloride (10 mL×3) and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=20:1) to give 4-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-3-carbonitrile (48.6 mg, 0.116 mmol, light yellow solid, yield: 81.7%).

[0239] 1 H NMR(400MHz,Chloroform-d)δ7.44(d,J=8.1Hz,1H),7.32(d,J=8.1Hz,1H),5.92(s,2H),3 .57-3.50(m,2H),2.98-2.92(m,2H),2.81-2.75(m,2H),1.91(m,J=5.2,2.4Hz,2H),1.78(m J=24.9,9.0,5.6,2.7Hz,4H),0.91-0.86(m,2H),-0.05(s,9H).

[0240] 13 C NMR (101MHz, CDCl3) δ147.57,135.72,133.51,126.04,121.15,118.77,118.32, 109.87,108.43,72.74,66.38,32.62,29.05,27.94,27.85,25.19,19.49,-0.00.

[0241] Steps 1-7:

[0242]

[0243] 4-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole-3-carbonitrile (860 mg, 2.05 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (Dioxane:H2O (V / V) = 10:1, 11 mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (931 mg, 4.1 mmol) was added, and the mixture was stirred overnight. After the reaction was completed as monitored by TLC, a saturated aqueous sodium bicarbonate solution was added to quench the reaction. The dioxane in the solution was removed by a rotary evaporator, and methyl tert-butyl ether (20 mL×3) was added for extraction. The organic phases were combined, and the combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate, spin-dried, and then the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=6:1) to give 4-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one-3-carbonitrile (550 mg, 1.27 mmol, white solid, yield 62%).

[0244] 1 H NMR(400MHz,Chloroform-d)δ8.51(d,J=8.3Hz,1H),7.49(d,J=8.3Hz,1H),6.00(s,2H),3.63(t,J=8.2Hz,2H),3.20 (t,J=6.1Hz,2H),2.83(t,J=6.2Hz,2H),2.11-2.04(m,2H),2.00-1.91(m,2H),0.92(d,J=8.3Hz,2H),-0.03(s,9H).

[0245] 13 C NMR (101MHz, CDCl3) δ198.13,153.82,133.38,133.33,127.95,122.17,119.12,1 17.10,111.85,107.19,72.18,65.99,43.57,26.23,25.04,21.89,18.41,-1.08.

[0246] Steps 1-8:

[0247]

[0248] 4-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one-3-carbonitrile (90 mg, 0.208 mmol) was dissolved in anhydrous toluene, and ethyl formate (50 μL, 0.624 mmol) and a tetrahydrofuran solution of potassium tert-butoxide (1 mol / L, 620 μL, 0.62 mmol) were added at 0°C. After the reaction was completed as monitored by TLC, a saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate (200 mL×3) was added for extraction. The organic phases were combined, and the combined organic phases were washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to obtain compound 1-8 (58 mg, 0.126 mmol, light yellow solid, yield 60.6%).

[0249] 1 H NMR(400MHz,Chloroform-d)δ16.03(d,J=7.5Hz,1H),8.60(d,J=8.3Hz,1H),7.92(d,J=7.0Hz,1H),7.47(d,J=8.3Hz,1H),5.95(s,2H ),3.64(t,J=8.1Hz,2H),3.23(t,J=6.5Hz,2H),2.45-2.39(m,2H),2.13(dt,J=10.1,6.2Hz,2H),0.93(t,J=8.2Hz,2H),-0.02(s,9H).

[0250] 13 C NMR (101MHz, CDCl3) δ186.45,174.44,150.95,133.41,133.30,127.19,122.88,118.7 8,113.83,113.72,111.73,106.66,71.82,65.65,29.35,27.07,24.95,18.11,-1.40.

[0251] Steps 1-9:

[0252]

[0253] Compound 1-8 (108 mg, 0.23 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (200 μL, 2.3 mmol) was added, and the mixture was refluxed at 90°C for 1 h. After the reaction of the raw material was completed by TLC monitoring, the mixture was cooled to room temperature, and crude (S)-3-guanidine-1-carboxylic acid tert-butyl ester (1.15 mmol) and sodium methoxide (62 mg, 1.15 mmol) were added. The mixture was refluxed at 90°C for 16 hours. After the reaction was completed by mass spectrometry monitoring, the solvent was removed by rotary evaporator, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain compound 1-9 (81 mg, 0.121 mmol, yellow oily liquid, yield 52.8%). MS (ESI): [M+H] + =667.

[0254] Steps 1-10:

[0255]

[0256] Compound 1-9 (81.8 mg, 0.123 mmol), palladium acetate (8.3 mg, 0.037 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (42.6 mg, 0.074 mmol) and potassium phosphate (78 mg, 0.368 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (28.7 mg, 0.368 mmol) in N,N-dimethylformamide (1.2 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Add saturated sodium bicarbonate aqueous solution (5 mL) to quench the reaction, extract with ethyl acetate (10 mL × 3), combine the organic phases, wash the combined organic phases with saturated sodium chloride solution (10 mL × 3), dry with anhydrous sodium sulfate, spin dry, and then filter the residue through a short silica gel column to obtain compound 1-10 (39 mg, 0.059 mmol, yellow solid, yield 47.6%). MS (ESI): [M+H] + =665.

[0257] Steps 1-11:

[0258]

[0259] Add dioxane hydrochloride solution (4 mol / L, 2 mL) to the compound 1-10 (39 mg, 0.059 mmol) obtained in the previous step, heat to 60°C for 10 minutes, until the reaction is complete as monitored by mass spectrometry. Remove the solvent using a rotary evaporator, and purify the residue by preparative HPLC to obtain the target compound (S)-9-(dimethylphosphoryl)-2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indole-10-carbonitrile (Compound A201). MS (ESI): [M+H] + =435. 1 H NMR(400MHz,Chloroform-d)δ8.79(s,1H),7.79(d,J=7.9Hz,1H),7.45(dd,J=7.9Hz,1H),3.7 5(m,1H),3.16(m,1H),2.61-3.01(m,7H),1.91(m,2H),2.12-2.21(m,8H),1.73-1.93(m,4H).

[0260] Example 2: Preparation of (S)-dimethyl (2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrimido [4', 5': 3,4] cyclohepta [1,2-b] indol-9-yl) phosphine oxide (Compound A202)

[0261]

[0262] Step 2-1:

[0263]

[0264] 2-Bromophenylhydrazine hydrochloride (10 g, 44.74 mmol) and cycloheptanone (5 g, 44.57 mmol) were dissolved in acetic acid (200 mL), and the solution was refluxed at 145 ° C for 2 hours. The cooled reaction solution was concentrated in vacuo using a rotary evaporator, neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate (200 mL × 3), the organic phases were combined, and then dried over anhydrous sodium sulfate. Concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether) to obtain 4-bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (10.3 g, 39.02 mmol, light yellow oily liquid, yield 87.2%).

[0265] 1H NMR(400MHz,Chloroform-d)δ7.87(s,1H),7.41(d,J=8.0Hz,1H),7.23(dd,J=7.6,0.9Hz,1H),6.95( t,J=7.8Hz,1H),2.87(t,J=5.8Hz,2H),2.79(t,J=5.6Hz,2H),1.94-1.87(m,2H),1.82-1.74(m,4H).

[0266] 13 C NMR (101MHz, CDCl3) δ138.30,132.81,130.38,122.83,120.17,116.88,115.08,103.86,31.73,29.53,28.60,27.38,24.93.

[0267] Step 2-2:

[0268]

[0269] 4-Bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (5 g, 18.9 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) under argon protection, cooled to 0°C, and 60% sodium hydride (1.52 g, 37.9 mmol) was slowly added. Half an hour later, 2-(trimethylsilyl)ethoxymethyl chloride (6.7 mL, 37.9 mmol) was added dropwise and stirred at room temperature overnight. After TLC detected that the reaction was complete, saturated ammonium chloride solution was added dropwise at 0°C to quench the reaction. After removing tetrahydrofuran in the solution by a rotary evaporator, ethyl acetate (200 mL×3) was added for extraction, and the organic phases were combined. The combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate, and then spin-dried to obtain 4-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (7.4 g, 18.9 mmol, yellow oily liquid, yield 100%).

[0270] 1H NMR (400MHz, Chloroform-d) δ7.41(dd,J=7.8,1.1Hz,1H),7.30(dd,J=7.7,1.1Hz,1H),6.93(t,J=7.7Hz,1H),5.93(s,2H),3.53(t,J =8.0Hz,2H),2.92(t,J=5.6Hz,2H),2.78(t,J=5.6Hz,2H),1.93-1.87(m,2H),1.83-1.74(m,4H),0.87(t,J=8.2Hz,2H),-0.06(s,9H).

[0271] 13 C NMR (101MHz, CDCl3) δ141.40,132.28,131.86,126.74,120.40,116.97,115. 97,103.45,71.17,64.51,31.40,27.92,26.81,26.27,23.97,18.11,-1.42.

[0272] Step 2-3:

[0273]

[0274] Dissolve 4-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (7.63 g, 19.4 mmol) in a mixed solution of tetrahydrofuran and water (THF:H2O (V / V) = 10:1, 150 mL). Cool to 0°C, add 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (8.8 g, 37.9 mmol), and stir for 3 hours. After the reaction was completed as monitored by TLC, saturated aqueous sodium bicarbonate solution was added to quench the reaction. After tetrahydrofuran in the solution was removed by a rotary evaporator, methyl tert-butyl ether (200 mL×3) was added for extraction, the organic phases were combined, and the combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate, spin-dried, and then the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V)=10:1) to obtain 4-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (5.01 g, 12.3 mmol, yellow liquid, yield 63.3%).

[0275] 1H NMR (400MHz, Chloroform-d) δ8.44(dd,J=7.9,1.1Hz,1H),7.44(dd,J=7.7,1.1Hz,1H),7.09(t,J=7.8Hz,1H),6.02(s,2H),3.62(t,J=8 .0Hz,2H),3.18(t,J=6.5,6.0Hz,2H),2.81(t,J=6.4Hz,2H),2.08-2.00(m,2H),1.98-1.90(m,2H),0.91(t,J=8.1Hz,2H),-0.04(s,9H).

[0276] Steps 2-4:

[0277]

[0278] 4-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (7.1 g, 17.4 mmol) was dissolved in anhydrous toluene, and ethyl formate (4.2 mL, 52.2 mmol) and a tetrahydrofuran solution of potassium tert-butoxide (1 mol / L, 52.2 mL, 52.2 mmol) were added at 0°C. After the reaction was completed by TLC monitoring, a saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate (200 mL×3) was added for extraction. The organic phases were combined, and the combined organic phases were washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 20:1) to obtain compound 2-4 (5.01 g, 11.49 mmol, milky white solid, yield 66%)

[0279] 1 H NMR (400MHz, Chloroform-d) δ8.52(d,J=8.0Hz,1H),7.92(d,J=6.7Hz,1H),7.45(d,J=7.7Hz,1H),7.08(t,J=7.9Hz,1H),5.97(s, 2H), 3.64 (t, J = 8.4Hz, 2H), 3.21 (t, J = 6.5Hz, 2H), 2.40 (t, J = 5.0Hz, 2H), 2.14-2.07 (m, 2H), 0.91 (t, J = 8.1Hz, 2H), -0.03 (s, 9H).

[0280] 13C NMR (101MHz, CDCl3) δ188.49,175.41,149.58,134.73,131.89,130.93,124.70,1 23.85,114.99,114.88,104.39,73.05,66.68,30.54,28.71,26.54,19.53,-0.00.

[0281] Steps 2-5:

[0282]

[0283] (S)-1-Boc-3-aminopiperidine (1g, 5mmol) was dissolved in anhydrous acetonitrile (10mL), and N,N-diisopropylethylamine (868μL, 5mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (700mg, 4.76mmol) were added. After reacting at room temperature overnight, acetonitrile was removed by rotary evaporator, and the residual solid was washed with ether three times. After vacuum drying, the crude product of (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester (white solid) was obtained and used directly in the next step. MS (ESI): [M+H] + =243.

[0284] Steps 2-6:

[0285]

[0286] Compound 2-4 (871 mg, 2 mmol) was dissolved in anhydrous ethanol (10 mL), morpholine (966 μL, 10 mmol) was added, and the mixture was refluxed at 90°C for 1 h. After the reaction of the raw materials was completed by TLC monitoring, the mixture was cooled to room temperature, and (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester (5 mmol) and sodium methoxide (270 mg, 5 mmol) were added. The mixture was refluxed at 90°C for 16 hours. After the reaction was completed by mass spectrometry monitoring, the solvent was removed by rotary evaporator, water (40 mL) was added, and the mixture was extracted with ethyl acetate (40 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain compound 2-6 (783 mg, 1.22 mmol, light yellow oily liquid, yield 61%). MS (ESI): [M+H] + =642.

[0287] Steps 2-7:

[0288]

[0289] Compound 2-6 (179 mg, 0.28 mmol), palladium acetate (18.8 mg, 0.084 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (97.5 mg, 0.168 mmol) and potassium phosphate (178 mg, 0.838 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (65.4 mg, 0.842 mmol) in N,N-dimethylformamide (3 mL) was added. The reaction was carried out at 145 ° C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried with anhydrous sodium sulfate, and then the residue was filtered through a short silica gel column to obtain compound 2-7 (160 mg, 0.25 mmol, yield 89.4%). MS(ESI):[M+H] + =641.

[0290] Steps 2-8:

[0291]

[0292] Add dioxane hydrochloride solution (4 mol / L, 3 mL) to compound 2-7 (80 mg, 0.125 mmol), heat to 60 ° C for 10 minutes, until the reaction is complete as monitored by mass spectrometry. Remove the solvent with a rotary evaporator, and purify the residue by preparative HPLC to obtain (S)-dimethyl (2- (piperidin-3-ylamino) -5,6,7,8-tetrahydropyrimido [4', 5': 3,4] cycloheptyl [1,2-b] indol-9-yl) phosphine oxide (compound A202).

[0293] 1 H NMR(400MHz,Methanol-d4)δ8.86(d,J=8.0Hz,1H),8.00(s,1H),7.54(dd,J=13.0,7.5Hz ,1H),7.44(td,J=7.7,2.7Hz,1H),4.55(s,1H),3.67-3.61(m,1H),3.44(t,J=6.6Hz,2H), 3.41-3.37(m,1H),3.31-3.23(m,1H),3.17-3.10(m,1H),2.96-2.81(m,2H),2.42-2.32(m ,1H),2.23-2.09(m,3H),2.03-1.98(m,1H),1.96(s,3H),1.93(s,3H),1.90-1.80(m,1H).

[0294] MS(ESI):[M+H] + =410.2.

[0295] Example 3: Preparation of (S)-(2-((4-hydroxybutan-2-yl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A203)

[0296]

[0297] Step 3-1:

[0298]

[0299] (S)-3-aminobutanol (223 mg, 2.5 mmol) was dissolved in anhydrous acetonitrile, and N,N-diisopropylethylamine (434 μL, 2.5 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (350 mg, 2.38 mmol) were added. After reacting at room temperature overnight, the acetonitrile was removed by rotary evaporator, and the residual solid was washed with ether three times. After vacuum drying, the crude (S)-1-(4-hydroxybutan-2-yl)guanidine (light yellow oily liquid) was obtained and used directly in the next step. MS (ESI): [M+H] + =131.

[0300] Step 3-2:

[0301]

[0302] Compound 2-4 (100 mg, 0.23 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (200 μL, 2.3 mmol) was added, and the mixture was refluxed at 90 ° C for 1 h. After the reaction of the raw material was completed by TLC monitoring, the mixture was cooled to room temperature, and crude (S)-1-(4-hydroxybutyl-2-yl)guanidine (2.5 mmol) and sodium methoxide (135 mg, 2.5 mmol) were added. The mixture was refluxed at 90 ° C for 16 hours. After the reaction was completed by mass spectrometry monitoring, the solvent was removed by rotary evaporator, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 2:1) to obtain compound 3-2 (71 mg, 0.134 mmol, light yellow oily liquid, yield 58%). MS (ESI): [M+H] + =531.

[0303] Step 3-3:

[0304]

[0305] Compound 3-2 (71 mg, 0.134 mmol), palladium acetate (9 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (46.5 mg, 0.08 mmol) and potassium phosphate (84.8 mg, 0.4 mmol) were added to a microwave tube. After replacing argon three times, a solution of deoxygenated dimethylphosphine (31.2 mg, 0.4 mmol) in N,N-dimethylformamide (1.5 mL) was added. The reaction was carried out at 145 ° C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried with anhydrous sodium sulfate, and then the residue was filtered through a short silica gel column to obtain compound 3-3 (59.4 mg, 0.113 mmol, light yellow solid, yield 84%). MS(ESI):[M+H] + =529.

[0306] Step 3-4:

[0307]

[0308] Compound 3-3 (59.4 mg, 0.112 mmol) obtained in the previous step was added to a dioxane hydrochloride solution (4 mol / L, 2 mL), and the mixture was heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by a rotary evaporator, and the residue was purified by preparative HPLC to obtain the target compound (S)-(2-((4-hydroxybutane-2-yl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A203).

[0309] 1 H NMR (400MHz, CD3OD) δ9.00 (s, 1H), 7.86 (d, J = 14.0Hz, 1H), 7.56-7.47 (m, 1H), 7.43-7.37 (m, 1H), 4.58 (m, 1H), 3.76 (t, J =6.1Hz,2H),3.46-3.39(m,2H),2.86-2.79(m,2H),2.23-2.02(m,4H),1.96(s,3H),1.92(s,3H),1.43(d,J=6.5Hz,3H).

[0310] MS(ESI):[M+H] + =399.

[0311] Example 4: Preparation of (2-((3-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A204)

[0312] Step 4-1:

[0313]

[0314] 3-Amino-1-propanol (188 mg, 2.5 mmol) was dissolved in anhydrous acetonitrile, and N,N-diisopropylethylamine (434 μL, 2.5 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (350 mg, 2.38 mmol) were added. After reacting at room temperature overnight, acetonitrile was removed by rotary evaporator, and the residual solid was washed with ether three times. After vacuum drying, a light yellow oily liquid 1-(3-hydroxypropyl)guanidine was obtained, which was directly used in the next step reaction.

[0315] MS(ESI):[M+H] + =76.

[0316] Step 4-2:

[0317]

[0318] Compound 2-4 (100 mg, 0.229 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (200 μL, 2.3 mmol) was added, and the mixture was refluxed at 90 ° C for 1 h. After the reaction of the raw material was completed by TLC monitoring, it was cooled to room temperature, and 1-(3-hydroxypropyl)guanidine (2.5 mmol) and sodium methoxide (135 mg, 2.5 mmol) were added. After reflux at 90 ° C for 16 hours, the reaction was completed after mass spectrometry monitoring, the solvent was removed by rotary evaporator, water (10 mL) was added, and it was extracted with ethyl acetate (10 mL×3), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain compound 4-2 (73 mg, light yellow oily liquid, yield 62%). 1H NMR (400MHz, CDCl3) δ8.65(d,J=8.0Hz,1H),8.00(s,1H),7.43(d,J=7.6Hz,1H),7.05(t,J=7.8Hz,1H),6.00(s,2H),5.24(t,J=6.8Hz,1H),3.6 5(dt,J=15.9,6.4Hz,6H),3.20(t,J=6.8Hz,2H),2.64-2.59(m,2H),2.2 0-2.11(m,2H),1.78(q,J=5.8Hz,2H),0.95-0.88(m,2H),-0.04(s,9H). 13 C NMR (101MHz, CDCl3) δ161.91,156.33,145.12,133.74,130.39,129.02,122.60,122.35,121.71,113.11, 103.18,71.65,65.16,58.52,37.62,33.76,29.14,27.96,26.62,18.28,-1.26.LC-MS(ESI)m / z:517[M+H] + .

[0319] Step 4-3:

[0320]

[0321] Compound 4-2 (73 mg, 0.141 mmol), palladium acetate (9 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (46.5 mg, 0.08 mmol) and potassium phosphate (84.8 mg, 0.4 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (31.2 mg, 0.4 mmol) in N,N-dimethylformamide (1.5 mL) was added. The reaction was carried out at 145 ° C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried with anhydrous sodium sulfate, and then the residue was filtered through a short silica gel column to obtain compound 4-3 (64 mg, 0.125 mmol, light yellow solid, yield 88%). MS(ESI):[M+H] + =515.

[0322] Step 4-4:

[0323]

[0324] Compound 4-3 (60 mg) was added with dioxane hydrochloride solution (4 mol / L, 2 mL), and the mixture was heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to obtain the target compound (2-((3-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A204). MS (ESI): [M+H] + =385. 1 H NMR (400MHz, CDCl3) δ8.97(s,1H),7.86(d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H,1H),7.21(t,J=7.8Hz,1H) ,3.64(m,6H),3.21(t,J=6.4Hz,2H),2.11(s,3H),2.05(s,3H),1.76(q,J=6.2Hz,2H),0.95-0.88(m,2H).

[0325] Example 5: Preparation of (2-(((1-hydroxycyclobutyl)methyl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A205)

[0326] Step 5-1:

[0327]

[0328] 1-(Aminomethyl)cyclobutanol (253 mg, 2.5 mmol) was dissolved in anhydrous acetonitrile, and N,N-diisopropylethylamine (434 μL, 2.5 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (350 mg, 2.38 mmol) were added. After reacting at room temperature overnight, acetonitrile was removed by rotary evaporator, and the residual solid was washed with ether three times. After vacuum drying, 1-(3-hydroxypropyl)guanidine (light yellow oily liquid) was obtained and used directly in the next step. MS (ESI): [M+H] + =144.

[0329] Step 5-2:

[0330]

[0331] Compound 2-4 (100 mg, 0.23 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (200 μL, 2.3 mmol) was added, and the mixture was refluxed at 90 ° C for 1 h. After the reaction of the raw material was completed by TLC monitoring, it was cooled to room temperature, and 1-(3-hydroxypropyl)guanidine (2.5 mmol) and sodium methoxide (134 mg, 2.5 mmol) were added. After reflux at 90 ° C for 16 hours, the reaction was completed by mass spectrometry monitoring, and the solvent was removed by rotary evaporator, water (10 mL) was added, and it was extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The combined organic phases were washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain compound 5-2 (80 mg, 0.148 mmol light yellow oily liquid, yield 64%). MS (ESI): [M+H] + =543.

[0332] Step 5-3:

[0333]

[0334] Compound 5-2 (80 mg, 0.148 mmol), palladium acetate (10 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (51 mg, 0.09 mmol) and potassium phosphate (93 mg, 0.44 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (34 mg, 0.44 mmol) in N,N-dimethylformamide (1.7 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and spin-dried. The residue was then filtered through a short silica gel column to obtain compound 5-3 (63 mg, 0.117 mmol, light yellow solid, yield 79%), MS (ESI): [M+H] + =541.

[0335] Step 5-4:

[0336]

[0337] Add dioxane hydrochloride solution (4 mol / L, 2 mL) to compound 5-3 (58 mg), heat to 60°C for 10 minutes, until the reaction is complete as monitored by mass spectrometry. Remove the solvent using a rotary evaporator, and purify the residue by preparative HPLC to obtain the target compound (2-(((1-hydroxycyclobutyl)methyl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A205).

[0338] 1 H NMR (400MHz, Methanol-d4) δ8.98(s,1H),7.84(s,1H),7.50(dd,J=13.3,7.3Hz,1H),7.37(td,J=7.7,2.6Hz,1H),3.79(s,2H),3 .38(t,J=6.3Hz,2H),2.79(t,J=4.7Hz,2H),2.23-2.07(m,6H),1.94(s,3H),1.90(s,3H),1.85-1.75(m,1H),1.71-1.61(m,1H).

[0339] MS(ESI):[M+H] + =411.

[0340] Example 6: Preparation of (2-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A206)

[0341] Step 6-1:

[0342]

[0343] (1R, 2R)-2-aminocyclohexanol (288 mg, 2.5 mmol) was dissolved in anhydrous acetonitrile, and N, N-diisopropylethylamine (434 μL, 2.5 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (350 mg, 2.38 mmol) were added. After reacting at room temperature overnight, acetonitrile was removed by rotary evaporator, and the residual solid was washed with ether three times. After vacuum drying, 1-((1R, 2R)-2-hydroxycyclohexyl)guanidine (light yellow oily liquid) was obtained, which was directly used in the next step reaction.

[0344] MS(ESI):[M+H] + =158.

[0345] Step 6-2:

[0346]

[0347] Compound 2-4 (100 mg, 0.23 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (200 μL, 2.3 mmol) was added, and the mixture was refluxed at 90 ° C for 1 h. After the reaction of the raw material was completed by TLC monitoring, it was cooled to room temperature, and 1-((1R, 2R)-2-hydroxycyclohexyl)guanidine (2.5 mmol) and sodium methoxide (126 mg, 2.5 mmol) were added. After reflux at 90 ° C for 16 hours, the reaction was completed by mass spectrometry monitoring, the solvent was removed by rotary evaporator, water (10 mL) was added, and it was extracted with ethyl acetate (10 mL×3), the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain compound 6-2 (80 mg, light yellow oily liquid, yield 62.4%). MS (ESI): [M+H] + =557.

[0348] Step 6-3:

[0349]

[0350] Compound 6-2 (80 mg, 0.144 mmol), palladium acetate (10 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (51 mg, 0.09 mmol) and potassium phosphate (93 mg, 0.44 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (34 mg, 0.44 mmol) in N,N-dimethylformamide (1.7 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and then spun dry. The residue was then filtered through a short silica gel column to obtain a light yellow solid (2-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound 6-3) (75.8 mg, 0.137 mmol, yield 95%). MS (ESI): [M+H] + =555.

[0351] Step 6-4:

[0352]

[0353] A dioxane hydrochloride solution (4 mol / L, 2 mL) was added to compound 6-3 (65 mg), and the mixture was heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to obtain the target compound (2-(((1R, 2R)-2-hydroxycyclohexyl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A206)).

[0354] 1 H NMR (400MHz, CD3OD) δ8.97(s,1H),7.78(s,1H),7.48(dd,J=13.3,7.4Hz,1H),7.34(td,J=7.8,2.2Hz,1H),4.25-3.99(m,1H),3.35-3.2 7(m,3H),2.74(t,J=5.3Hz,2H),2.17-2.07(m,2H),2.06-1.99(m,2H),1.93(s,3H),1.89(s,3H),1.84-1.77(m,2H),1.47-1.40(m,4H).

[0355] MS(ESI):[M+H] + =425.

[0356] Example 7: Preparation of (R)-(2-((2-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A207)

[0357]

[0358] (R)-2-aminopropane-1-ol (77.8 mg, 1.05 mmol) was dissolved in anhydrous acetonitrile (5 mL), and N,N-diisopropylethylamine (185 μL, 1.05 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (146.5 mg, 1 mmol) were added. After reacting at room temperature overnight, acetonitrile was removed by rotary evaporator, and the residual solid was washed with ether three times. After vacuum drying, (R)-1-(1-hydroxypropan-2-yl)guanidine (light yellow oily liquid) was obtained and used directly in the next step.

[0359] MS(ESI):[M+H] + =158.

[0360] Step 7-2:

[0361]

[0362] Compound 2-4 (91 mg, 0.21 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (182 μL, 2.1 mmol) was added, and the mixture was refluxed at 90°C for 1 h. After the reaction of the raw material was completed by TLC monitoring, the mixture was cooled to room temperature, and (R)-1-(1-hydroxypropyl-2-yl)guanidine (1.05 mmol) and sodium methoxide (56.7 mg, 1.05 mmol) were added. The mixture was refluxed at 90°C for 16 hours. After the reaction was completed by mass spectrometry monitoring, the solvent was removed by rotary evaporator, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 2:1) to obtain compound 7-2 (80 mg, 0.155 mmol, light yellow solid, yield 73.8%). MS (ESI): [M+H] + =517.

[0363] Step 7-3:

[0364]

[0365] Compound 7-2 (80 mg, 0.155 mmol), palladium acetate (11 mg, 0.047 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (54 mg, 0.093 mmol) and potassium phosphate (98 mg, 0.465 mmol) were added to a microwave tube. After replacing argon three times, a solution of deoxygenated dimethylphosphine (36 mg, 0.465 mmol) in N,N-dimethylformamide (1.8 mL) was added. The reaction was carried out at 145 ° C. under microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried with anhydrous sodium sulfate, and then the residue was filtered through a short silica gel column to obtain compound 7-3 (64 mg, 0.125 mmol, light yellow solid, yield 80.3%). MS(ESI):[M+H] + =515.

[0366] Step 7-4:

[0367]

[0368] Add dioxane hydrochloride solution (4 mol / L, 2 mL) to compound 7-3 (64 mg, 0.125 mmol), heat to 60°C for 10 minutes, until the reaction is complete as monitored by mass spectrometry. Remove the solvent using a rotary evaporator, and purify the residue by preparative HPLC to obtain the target compound (R)-(2-((2-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A207). ＝

[0369] 1 H NMR (400MHz, Methanol-d4) δ8.91(s,1H),7.82(s,1H),7.48(dd,J=13.2,7.3Hz,1H),7.35(td,J=7.7,2.6Hz,1H),4.13-4.05(m,1H), 3.60-3.41(m,2H),3.35(t,J=6.4Hz,2H),2.77(t,J=5.4Hz,2H),2.10-2.01(m,2H),1.92(s,3H),1.89(s,3H),1.29(d,J=6.3Hz,3H).

[0370] MS(ESI):[M+H] + =385.

[0371] Example 8: Preparation of (S)-(2-((2-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A208)

[0372]

[0373] Step 8-1:

[0374]

[0375] (S)-2-aminopropane-1-ol (77.8 mg, 1.05 mmol) was dissolved in anhydrous acetonitrile (5 mL), and N,N-diisopropylethylamine (185 μL, 1.05 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (146.5 mg, 1 mmol) were added. After reacting at room temperature overnight, acetonitrile was removed by rotary evaporator, and the residual solid was washed with ether three times. After vacuum drying, (S)-1-(1-hydroxypropan-2-yl)guanidine (light yellow oily liquid) was obtained and used directly in the next step. MS (ESI): [M+H] + =158.

[0376] Step 8-2:

[0377]

[0378] (Z)-4-bromo-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (91 mg, 0.21 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (182 μL, 2.1 mmol) was added, and the mixture was refluxed at 90°C for 1 h. After the reaction of the raw material was completed by TLC monitoring, the mixture was cooled to room temperature, and (S)-1-(1-hydroxypropan-2-yl)guanidine (1.05 mmol) and sodium methoxide (56.7 mg, 1.05 mmol) were added. Reflux at 90°C for 16 hours. After the reaction is complete as monitored by mass spectrometry, the solvent is removed by a rotary evaporator, water (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL×3). The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The residue is then purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V)=2:1) ​​to give (S)-1-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)propan-2-ol (72 mg, 0.14 mmol, light yellow solid, yield 66.4%). MS (ESI): [M+H] + =517.

[0379] Step 8-3:

[0380]

[0381] (S)-1-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)propan-2-ol (80 mg, 0.155 mmol), palladium acetate (11 mg, 0.047 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (54 mg, 0.093 mmol) and potassium phosphate (98 mg, 0.465 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (36 mg, 0.465 mmol) in N,N-dimethylformamide (1.8 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and spin-dried. The residue was then filtered through a short silica gel column to obtain a light yellow solid (S)-(2-((2-hydroxypropyl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (64 mg, yield 80.3%). MS (ESI): [M+H] + =515.

[0382] Step 8-4:

[0383]

[0384] To (S)-(2-((2-hydroxypropyl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (64 mg, 0.125 mmol) was added dioxane hydrochloride solution (4 mol / L, 2 mL) and heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator and the residue was purified by preparative HPLC to give (S)-(2-((2-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A208).

[0385] 1H NMR (400MHz, Methanol-d4) δ8.90(s,1H),7.81(s,1H),7.49(dd,J=13.2,7.3Hz,1H),7.36(dd,J=7.8,2.6Hz,1H),4.15-4.06(m,1H),3.6 2-3.42(m,2H),3.35(t,J=6.4Hz,2H),2.79-2.73(m,2H),2.05(t,J=13.4,10.0Hz,2H),1.93(s,3H),1.90(s,3H),1.29(d,J=6.3Hz,3H).

[0386] MS(ESI):[M+H] + =385.

[0387] Example 9: Preparation of (S)-(2-((2-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A209)

[0388]

[0389] Step 9-1:

[0390]

[0391] Dissolve (1S,2S)-2-aminocyclohexanol (120.8 mg, 1.05 mmol) in anhydrous acetonitrile, add N,N-diisopropylethylamine (185 μL, 1.05 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (146.5 mg, 1 mmol). After reacting at room temperature overnight, use a rotary evaporator to remove acetonitrile, wash the residual solid with ether three times, and vacuum dry to obtain 1-((1S,2S)-2-hydroxycyclohexyl)guanidine (light yellow oily liquid), which is directly used in the next reaction. MS (ESI): [M+H] + =158.

[0392] Step 9-2:

[0393]

[0394] (Z)-4-bromo-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (91 mg, 0.21 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (182 μL, 2.1 mmol) was added, and the mixture was refluxed at 90°C for 1 h. After the reaction of the raw material was completed as monitored by TLC, the mixture was cooled to room temperature, and 1-((1S,2S)-2-hydroxycyclohexyl)guanidine (1.05 mmol) and sodium methoxide (56.7 mg, 1.05 mmol) were added. Reflux at 90°C for 16 hours. After the reaction is complete as monitored by mass spectrometry, the solvent is removed by a rotary evaporator, water (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL×3). The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The residue is then purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V)=2:1) ​​to give (1S,2S)-2-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)cyclohexan-1-ol (109 mg, 0.196 mmol, light yellow solid, yield 93.4%). MS (ESI): [M+H] + =557.

[0395] Step 9-3:

[0396]

[0397] (1S, 2S)-2-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)cyclohexan-1-ol (98.8 mg, 0.178 mmol), palladium acetate (12 mg, 0.053 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (62 mg, 0.107 mmol) and potassium phosphate (113 mg, 0.533 mmol) were added to a microwave tube, and the argon gas was replaced three times, and then a solution of deoxygenated dimethylphosphine (41.6 mg, 0.533 mmol) in N,N-dimethylformamide (2 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and then spun dry. The residue was then filtered through a short silica gel column to obtain (2-(((1S, 2S)-2-hydroxycyclohexyl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (82 mg, 0.148 mmol, light yellow solid, yield 83.2%). MS (ESI): [M+H] + =555.

[0398] Step 9-4:

[0399]

[0400] To (2-(((1S,2S)-2-hydroxycyclohexyl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (64 mg, 0.125 mmol) was added dioxane hydrochloride solution (4 mol / L, 2 mL) and heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator and the residue was purified by preparative HPLC to give (S)-(2-((2-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A209).

[0401] 1H NMR(400MHz, Methanol-d4)δ9.00(s,1H),7.79(s,1H),7.48(dd,J=13.2,7.3Hz,1H),7.35(td,J=7.7,2.4Hz,1H),4.22-3.95(m,1H),3.60 (m,1H),3.36(t,J=6.4Hz,2H),2.81-2.75(m,2H),2.19-2.03(m,4H),1.92(s,3H),1.89(s,3H),1.82(d,J=8.8Hz,2H),1.53-1.39(m,4H).

[0402] MS(ESI):[M+H] + =425.

[0403] Example 10: Preparation of (S)-(2-((2-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A210)

[0404]

[0405] Step 10-1:

[0406]

[0407] 1-Aminomethylcyclopropanemethanol (106 mg, 1.05 mmol) was dissolved in anhydrous acetonitrile, and N,N-diisopropylethylamine (185 μL, 1.05 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (146.5 mg, 1 mmol) were added. After reacting at room temperature overnight, acetonitrile was removed by rotary evaporator, and the residual solid was washed with ether three times. After vacuum drying, 1-((1-(hydroxymethyl)cyclopropyl)methyl)guanidine (light yellow oily liquid) was obtained, which was directly used in the next step reaction.

[0408] MS(ESI):[M+H] + =144.

[0409] Step 10-2:

[0410]

[0411] (Z)-4-bromo-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (91 mg, 0.21 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (182 μL, 2.1 mmol) was added, and the mixture was refluxed at 90°C for 1 h. After the reaction of the raw material was completed as monitored by TLC, the mixture was cooled to room temperature, and 1-((1-(hydroxymethyl)cyclopropyl)methyl)guanidine (1.05 mmol) and sodium methoxide (56.7 mg, 1.05 mmol) were added. Reflux at 90°C for 16 hours. After the reaction is complete as monitored by mass spectrometry, the solvent is removed by a rotary evaporator, water (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL×3). The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The residue is then purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V)=2:1) ​​to give (1-(((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidin[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)methyl)cyclopropyl)methanol (92.3 mg, 0.17 mmol, light yellow solid, yield 80.9%). MS (ESI): [M+H] + =543.

[0412] Step 10-3:

[0413]

[0414] (1-(((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidin[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)methyl)cyclopropyl)methanol (92.3 mg, 0.17 mmol), palladium acetate (11.5 mg, 0.051 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (59 mg, 0.102 mmol) and potassium phosphate (108 mg, 0.51 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (40 mg, 0.51 mmol) in N,N-dimethylformamide (2 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated aqueous sodium bicarbonate solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and then spin-dried. The residue was then filtered through a short silica gel column to obtain (2-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (63 mg, light yellow solid, yield 68.5%). MS (ESI): [M+H] + =541.

[0415] Step 10-4:

[0416]

[0417] To (2-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (64 mg, 0.17 mmol) was added dioxane hydrochloride solution (4 mol / L, 2 mL) and heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator and the residue was purified by preparative HPLC to give (S)-(2-((2-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A210).

[0418] 1H NMR (400MHz, Methanol-d4) δ8.94(s,1H),7.84(s,1H),7.49(dd,J=13.2,7.3Hz,1H),7.36(td,J=7.8,2.6Hz,1H),3.88-3.61(m,2H),3. 53(s,2H),3.38(t,J=6.5Hz,2H),2.83-2.77(m,2H),2.13-2.07(m,2H),1.93(s,3H),1.89(s,3H),0.67-0.62(m,2H),0.61-0.55(m,2H).

[0419] MS(ESI):[M+H] + =411.

[0420] Example 11: Preparation of (R)-(2-((1-hydroxypropane-2-yl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A211)

[0421] Step 11-1:

[0422]

[0423] (R)-2-aminopropane-1-ol (77.8 mg, 1.05 mmol) was dissolved in anhydrous acetonitrile, and N,N-diisopropylethylamine (185 μL, 1.05 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (146.5 mg, 1 mmol) were added. After reacting at room temperature overnight, the acetonitrile was removed by rotary evaporator, and the residual solid was washed with ether three times. After vacuum drying, (R)-1-(1-hydroxypropane-2-yl)guanidine (light yellow oily liquid) was obtained and used directly in the next step reaction.

[0424] MS(ESI):[M+H] + =118.

[0425] Step 11-2:

[0426]

[0427] (Z)-4-bromo-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (91 mg, 0.21 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (182 μL, 2.1 mmol) was added, and the mixture was refluxed at 90°C for 1 h. After the reaction of the raw material was completed as monitored by TLC, the mixture was cooled to room temperature, and (R)-1-(1-hydroxypropane-2-yl)guanidine (1.05 mmol) and sodium methoxide (56.7 mg, 1.05 mmol) were added. Reflux at 90°C for 16 hours. After the reaction is complete as monitored by mass spectrometry, the solvent is removed by a rotary evaporator, water (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL×3). The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The residue is then purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=2:1) ​​to give (R)-2-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)propan-1-ol (80 mg, 0.155 mmol, light yellow solid, yield 73.8%). MS (ESI): [M+H] + =517.

[0428] Step 11-3:

[0429]

[0430] (R)-2-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)propan-1-ol (80 mg, 0.155 mmol), palladium acetate (10.4 mg, 0.046 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (53.7 mg, 0.093 mmol) and potassium phosphate (100 mg, 0.464 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (36.2 mg, 0.464 mmol) in N,N-dimethylformamide (1.5 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated aqueous sodium bicarbonate solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and then spin-dried. The residue was then filtered through a short silica gel column to obtain (R)-(2-((1-hydroxypropane-2-yl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (42 mg, 0.082 mmol, light yellow solid, yield 52.7%). MS (ESI): [M+H] + =515.

[0431] Step 11-4:

[0432]

[0433] To (R)-(2-((1-hydroxypropane-2-yl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (42 mg, 0.082 mmol) was added dioxane hydrochloride solution (4 mol / L, 2 mL) and heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator and the residue was purified by preparative HPLC to give (R)-(2-((1-hydroxypropane-2-yl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A211). MS (ESI): [M+H] + =385.

[0434] 1H NMR (400MHz, CD3OD) δ8.96(br,1H),7.84(s,1H),7.49(dd,J=13.2,7.3Hz,1H),7.37(td,J=7.7,2.2Hz,1H),3.76(dd,J=11.1,4.6Hz,1H),3.68 (dd,J=10.9,6.5Hz,1H),3.40(t,J=6.5Hz,2H),2.86-2.79(m,2H),2.11(q,J=6.7,6.0Hz,2H),1.93(s,3H),1.90(s,3H),1.36(d,J=6.7Hz,3H).

[0435] Example 12: Preparation of (S)-(2-((1-hydroxypropane-2-yl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A212)

[0436] Step 12-1:

[0437]

[0438] Dissolve (S)-2-aminopropane-1-ol (77.8 mg, 1.05 mmol) in anhydrous acetonitrile, add N,N-diisopropylethylamine (185 μL, 1.05 mmol) and 1H-pyrazole-1-carboximidamide hydrochloride (146.5 mg, 1 mmol). After reacting at room temperature overnight, use a rotary evaporator to remove acetonitrile, wash the residual solid with ether three times, and vacuum dry to obtain a light yellow oily liquid (S)-1-(1-hydroxypropane-2-yl)guanidine, which is directly used in the next step. MS (ESI): [M+H] + =118.

[0439] Step 12-2:

[0440]

[0441] (Z)-4-bromo-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (91 mg, 0.21 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (182 μL, 2.1 mmol) was added, and the mixture was refluxed at 90°C for 1 h. After the reaction of the raw material was completed as monitored by TLC, the mixture was cooled to room temperature, and (S)-1-(1-hydroxypropane-2-yl)guanidine (1.05 mmol) and sodium methoxide (56.7 mg, 1.05 mmol) were added. Reflux at 90°C for 16 hours. After the reaction is complete as monitored by mass spectrometry, the solvent is removed by a rotary evaporator, water (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL×3). The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The residue is then purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 2:1) to give a light yellow solid (S)-2-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)propan-1-ol (40 mg, 0.078 mmol, yield 36.9%). MS (ESI): [M+H] + =517.

[0442] Step 12-3:

[0443]

[0444] (S)-2-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)propan-1-ol (40 mg, 0.078 mmol), palladium acetate (5.2 mg, 0.023 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (26.8 mg, 0.047 mmol) and potassium phosphate (50 mg, 0.232 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (18.1 mg, 0.232 mmol) in N,N-dimethylformamide (0.7 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and then spin-dried. The residue was then filtered through a short silica gel column to obtain a light yellow solid (S)-(2-((1-hydroxypropane-2-yl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (20 mg, yield 49.9%). MS (ESI): [M+H] + =515.

[0445] Step 12-4:

[0446]

[0447] To (S)-(2-((1-hydroxypropane-2-yl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (42 mg, 0.082 mmol) was added dioxane hydrochloride solution (4 mol / L, 2 mL) and heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator and the residue was purified by preparative HPLC to give (S)-(2-((1-hydroxypropane-2-yl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A212). MS (ESI): [M+H] + =385.

[0448] 1H NMR (400MHz, CD3OD) δ8.95(br,1H),7.84(s,1H),7.49(dd,J=13.0,7.3Hz,1H),7.36(qd,J=8.0,2.7Hz,1H),4.46-4.16(m,1H),3.75(dd,J=11.1,4.7Hz, 1H),3.68(dd,J=11.2,6.7Hz,1H),3.39(t,J=6.4Hz,2H),2.85-2.78(m,2H), 2.11(p,J=5.8,5.3Hz,2H),1.93(s,3H),1.90(s,3H),1.36(d,J=6.6Hz,3H).

[0449] Example 13: Preparation of dimethyl (2-((3,3,3-trifluoro-2-hydroxypropyl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)phosphine oxide (Compound A213)

[0450] Step 13-1:

[0451]

[0452] 3-Amino-1,1,1-trifluoropropane-2-ol (135.5 mg, 1.05 mmol) was dissolved in anhydrous acetonitrile, and N,N-diisopropylethylamine (185 μL, 1.05 mmol) and 1H-pyrazole-1-carboxamidine hydrochloride (146.5 mg, 1 mmol) were added. After reacting at room temperature overnight, acetonitrile was removed by rotary evaporator, and the residual solid was washed three times with ether. After vacuum drying, a light yellow oily liquid 1-(3,3,3-trifluoro-2-hydroxypropyl)guanidine was obtained, which was directly used for the next step. MS (ESI): [M+H] + =172.

[0453] Step 13-2:

[0454]

[0455] (Z)-4-bromo-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (91 mg, 0.21 mmol) was dissolved in anhydrous ethanol (2 mL), morpholine (182 μL, 2.1 mmol) was added, and the mixture was refluxed at 90°C for 1 h. After the reaction of the raw material was completed by TLC monitoring, the mixture was cooled to room temperature, and 1-(3,3,3-trifluoro-2-hydroxypropyl)guanidine (1.05 mmol) and sodium methoxide (56.7 mg, 1.05 mmol) were added. Reflux at 90°C for 16 hours. After the reaction is complete as monitored by mass spectrometry, the solvent is removed by a rotary evaporator, water (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL×3). The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The residue is then purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 2:1) to give a yellow solid 3-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidin[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)-1,1,1-trifluoropropane-2-ol (114 mg, 0.2 mmol, yield 95%). MS (ESI): [M+H] + =571.

[0456] Step 13-3:

[0457]

[0458] 3-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidin[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)-1,1,1-trifluoropropane-2-ol (114 mg, 0.2 mmol), palladium acetate (13.5 mg, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70 mg, 0.12 mmol) and potassium phosphate (127 mg, 0.6 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (46.8 mg, 0.6 mmol) in N,N-dimethylformamide (2.2 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (5 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and then spin-dried. The residue was then filtered through a short silica gel column to obtain yellow solid dimethyl (2-((3,3,3-trifluoro-2-hydroxypropyl)amino)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)phosphine oxide (100 mg, 0.176 mmol, yield = 88%). MS (ESI): [M+H] + =569.

[0459] Step 13-4:

[0460]

[0461] To dimethyl (2- ((3,3,3-trifluoro-2-hydroxypropyl) amino) -8- ((2- (trimethylsilyl) ethoxy) methyl) -5,6,7,8-tetrahydropyrimido [4', 5': 3,4] cyclohepta [1,2-b] indol-9-yl) phosphine oxide (73 mg, 0.129 mmol) was added dioxane hydrochloride solution (4 mol / L, 3 mL), heated to 60 ° C for 10 minutes, until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to obtain dimethyl (2- ((3,3,3-trifluoro-2-hydroxypropyl) amino) -5,6,7,8-tetrahydropyrimido [4', 5': 3,4] cyclohepta [1,2-b] indol-9-yl) phosphine oxide (Compound A213).

[0462] 1H NMR (400MHz, Methanol-d4) δ8.93(d,J=8.0Hz,1H),7.93(s,1H),7.55-7.49(m,1H),7.34(tt,J=7.5,3.8Hz,1H),4.42-4.32(m,1H),4.12 -3.97(m,1H),3.84-3.74(m,1H),3.41(t,J=6.5Hz,2H),2.89-2.78(m,2H),2.16-2.06(m,2H),1.96(s,3H),1.92(s,3H).MS(ESI):[M+H] + =439.

[0463] Example 14: Preparation of (S)-(2-((6,6-dimethylpiperidin-3-yl)amino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A214)

[0464]

[0465] Step 14-1:

[0466]

[0467] Dissolve 4-bromo-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (4 g, 9.17 mmol) in anhydrous ethanol (100 mL), add morpholine (8 mL, 91.7 mmol), and reflux at 90°C for 1 h. After the reaction of the raw materials is completed by TLC monitoring, cool to room temperature, add guanidine hydrochloride (4.38 g, 45.85 mmol) and sodium methoxide (2.48 g, 45.85 mmol). The mixture was refluxed at 90° C. for 16 hours. After the reaction was completed as monitored by mass spectrometry, the solvent was removed by a rotary evaporator, water (60 mL) was added, and the mixture was extracted with ethyl acetate (60 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried. The residue was then purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 2:1) to give a yellow solid 9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-amine (3.66 g, 7.97 mmol, yield 87%).

[0468] 1H NMR(400MHz,Chloroform-d)δ8.67(dd,J=8.0,1.1Hz,1H),7.97(s,1H),7.42(dd,J=7.6,1.1Hz,1H),7.03(t,J=7.9Hz,1H),5.97(s,2H), 5.34(s,2H),3.62(t,J=8.1Hz,2H),3.18(t,J=6.8Hz,2H),2.60(t,J=5.2Hz,2H),2.15-2.08(m,2H),0.90(t,J=8.1Hz,2H),-0.05(s,9H).

[0469] 13 C NMR (101MHz, CDCl3) δ163.60,162.68,157.00,146.43,134.98,131.73,130.29,1 24.70,123.64,123.35,114.30,104.29,72.88,66.38,30.53,29.38,27.54,0.00.

[0470] MS(ESI):[M+H] + =459.

[0471] Step 14-2:

[0472]

[0473] 9-Bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-amine (137 mg, 0.3 mmol) was dissolved in a mixed solution of acetic acid and water (1.75 mL, AcOH:H2O (V / V) = 10:1), and an aqueous solution of sodium nitrite (83 mg, 1.2 mmol, 0.3 mL) was added dropwise. After the reaction of the raw materials was completed, mass spectrometry was monitored, and saturated sodium bicarbonate aqueous solution was added to pH>7, and extracted with ethyl acetate, the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and then spin-dried to obtain a crude product of 9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-2-ol, which was directly used in the next reaction.

[0474] Step 14-3:

[0475]

[0476] The crude 9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-2-ol obtained in step 14-2 was dissolved in anhydrous dichloromethane (3 mL), and triethylamine (200 μL, 1.5 mmol) and trifluoromethanesulfonic anhydride (151 μL, 0.9 mmol) were added. After the reaction was completed as monitored by TLC, saturated aqueous sodium bicarbonate solution and ethyl acetate were added to extract the reaction, the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and the residue was spin-dried and purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V) = 5:1) to give a yellow solid 9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl trifluoromethanesulfonate (92.8 mg, 0.157 mmol, two-step yield 52.3%).

[0477] Step 14-4:

[0478]

[0479] Dissolve (S)-(6-oxopiperidin-3-yl)carbamic acid tert-butyl ester (100 mg, 0.467 mmol) in anhydrous tetrahydrofuran (4.7 mL), add anhydrous zirconium tetrachloride (261 mg, 1.12 mmol) after cooling to -10 ° C, and add methylmagnesium bromide in ether solution (3 mmol / L, 2 mL, 6 mmol) dropwise after stirring for half an hour. After reacting at room temperature overnight, add 2M sodium hydroxide aqueous solution to quench the reaction. After filtering, add ethyl acetate to the filtrate for extraction, combine the organic phases, wash the combined organic phases with saturated sodium chloride solution, and dry them with anhydrous sodium sulfate. After spin drying, (S)-(6,6-dimethylpiperidin-3-yl)carbamic acid tert-butyl ester is obtained, which is directly used in the next step reaction.

[0480] Step 14-5:

[0481]

[0482] The (S)-(6,6-dimethylpiperidin-3-yl)carbamic acid tert-butyl ester obtained in step 14-4 was dissolved in anhydrous dichloromethane (4 mL), trifluoroacetic acid (0.4 mL) was added, and the mixture was reacted overnight and dried to obtain (S)-(6,6-dimethylpiperidin-3-yl)amine trifluoroacetate, which was directly used in the next reaction.

[0483] Step 14-6:

[0484]

[0485] 9-Bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl trifluoromethanesulfonate (50 mg), (S)-6,6-dimethylpiperidin-3-amine obtained in step 14-5, and excess diisopropylethylamine (300 μL) were dissolved in N-methylpyrrolidone (4 mL) and reacted at 90° C. overnight. After the reaction was completed as monitored by mass spectrometry, saturated aqueous ammonium chloride solution and ethyl acetate were added for extraction, the organic phases were combined, the combined organic phases were washed three times with saturated sodium chloride solution and then dried over anhydrous sodium sulfate, and the residue was spin-dried and purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 3:1 to 1:1) to obtain the aryl bromide key intermediate, and then the method for coupling with phosphine in step 13-3 of the above Example 13 was referred to and dimethyl phosphine oxide was replaced with the aryl bromide key intermediate for reaction, the obtained product was deprotected by the method of step 13-4 under the conditions of hydrochloric acid dioxane -SEM ((trimethylsilyl) ethoxymethyl), and separated and purified by preparative HPLC to obtain (S)-(2-((6,6-dimethylpiperidin-3-yl)amino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A214). 1 H NMR (400MHz, Methanol-d4) δ8.84-8.77(m,1H),7.96(s,1H),7.51(dd,J=13.1,7.3Hz,1H),7. 42(td,J=7.8,2.5Hz,1H),4.56(s,1H),3.53(dd,J=12.9,4.2Hz,1H),3.42(q,J=6.6,5.9Hz,3 H),2.87(td,J=16.3,15.8,8.9Hz,2H),2.28(d,J=9.2Hz,1H),2.24-2.14(m,1H),2.09(q,J=7 .1Hz,1H),2.01(dd,J=12.7,7.4Hz,2H),1.91(dd,J=13.5,1.8Hz,8H),1.48(d,J=2.7Hz,6H).

[0486] Example 15-Example 27:

[0487] Referring to the preparation method of Example 14, the compounds described in Examples 15 to 27 were prepared by changing different amino side chain substituents. The compounds obtained in each example were measured for structural characterization such as hydrogen spectrum and mass spectrum. The results are shown in Table 1 below.

[0488] Table 1:

[0489]

[0490]

[0491]

[0492] Example 28: Preparation of Compound A228

[0493]

[0494] Tert-butyl (S)-3-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (1 equivalent) was placed in a microwave tube, 0.6 equivalent of palladium acetate (Pd(OAc)2) and 0.5 equivalent of 1,3-bis(diphenylphosphino)propane (DPPP) were added, and then Add isopropanol (iPrOH, so that the concentration of tert-butyl (S)-3-((9-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate is 0.05 mol / L), degas for 30 minutes, and then add 3.0 equivalents of vinyl n-butyl ether and 2.5 equivalents of ultra-dry triethylamine. Heat to 115 degrees Celsius and stir for 24 hours. Monitor the reaction by mass spectrometry. After the reaction is complete, cool to room temperature. Use a sand core funnel to fill silica gel, filter the reaction solution with ethyl acetate and dichloromethane, and use a rotary evaporator to spin dry the solvent to obtain compound 28-1, which is directly used in the next step. LC-MS (ESI) m / z: 664 [M + H] + .

[0495] Compound 28-1 was added to a 4M HCl-dioxane solution at 60°C for hydrolysis, and the reaction was completed in 1-2 hours. The completion of the reaction was monitored by mass spectrometry. After the reaction was completed, the hydrochloric acid was dried and purified by preparative HPLC to obtain compound A228.

[0496] LC-MS (ESI) m / z: 376 [M+H] + .

[0497] 1H NMR (400MHz, CD3OD) δ8.82(d,J=8.0Hz,1H),7.93(d,J=7.6Hz,1H),7.89(s,1H),7.40(t,J=7.8Hz,1 H),4.52(s,1H),3.62(dd,J=12.5,3.8Hz,1H),3.36(q,J=6.8Hz,3H),3.29-3.23(m,1H),3.14(td,J =10.3,5.5Hz,1H),2.79(tt,J=15.0,7.3Hz,2H),2.69(s,3H),2.34(dq,J=14.0,4.4Hz,1H),2.14(d q,J=19.3,7.9,6.4Hz,2H),1.99(dq,J=14.0,10.4,8.6Hz,2H),1.85(ddt,J=15.4,9.9,4.8Hz,1H).

[0498] 13 C NMR(101MHz,CD3OD)δ201.31,170.10,153.80,152.61,143.02,136.01,130.21,129.97,127.56, 123.45,122.81,121.50,112.24,47.34,47.13,44.88,31.35,31.06,29.19,26.83,23.99,21.55.

[0499] Example 29-Example 56

[0500] Referring to the preparation method of Example 28, the compounds described in Examples 29 to 56 were prepared by changing different amino side chain substituents. The compounds obtained in each example were measured for structural characterization such as hydrogen spectrum and mass spectrum. The results are shown in Table 2 below.

[0501] Table 2:

[0502]

[0503]

[0504]

[0505]

[0506]

[0507] Example 57: Preparation of Compound A257

[0508]

[0509] Step 57-1:

[0510]

[0511] 2-Bromo-6-hydrazinopyridine (1 g, 5.32 mmol) and cycloheptanone (595 mg, 5.32 mmol) were dissolved in anhydrous ethanol (20 mL), and the solution was refluxed at 100° C. for 2 hours. The cooled reaction solution was concentrated in vacuo using a rotary evaporator to obtain 2-bromo-6-(2-cycloheptylidenehydrazino)pyridine (brown oily liquid).

[0512] 1 g of polyphosphoric acid was added to 2-bromo-6-(2-cycloheptylhydrazinyl)pyridine, heated to 160°C, reacted overnight, neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL × 3), the organic phases were combined and dried over anhydrous sodium sulfate. Concentrated, the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 50:1) to obtain a light yellow oily liquid 2-bromo-5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-b]pyridine (712 mg, 2.70 mmol, yield 50.7%).

[0513] 1H NMR(400MHz,Chloroform-d)δ9.73(s,1H),7.61(d,J=8.1Hz,1H),7.16(d,J=8.1Hz,1H ),2.96(t,J=5.9Hz,2H),2.75(t,J=5.9Hz,2H),1.93-1.86(m,2H),1.82-1.72(m,4H).

[0514] 13 C NMR (101MHz, CDCl3) δ146.65,139.11,132.35,127.81,120.82,118.51,112.51,31.63,29.56,28.51,27.20,24.68.

[0515] Step 57-2:

[0516]

[0517] 2-Bromo-5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-b]pyridine (81 mg, 0.307 mmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL) under argon protection, cooled to 0°C, and 60% sodium hydride (24 mg, 0.614 mmol) was slowly added. Half an hour later, 2-(trimethylsilyl)ethoxymethyl chloride (108 μL, 0.6144 mmol) was added dropwise and stirred at room temperature overnight. After TLC detection, saturated ammonium chloride solution was added dropwise at 0°C to quench the reaction. After removing tetrahydrofuran from the solution by rotary evaporator, ethyl acetate (10 mL×3) was added for extraction, and the organic phases were combined, and the combined organic phases were washed with saturated sodium chloride (10 mL×3) and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V) = 20:1) to give a light yellow oily liquid 2-bromo-10-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-b]pyridine (95.7 mg, 0.243 mmol, yield: 79.2%).

[0518] 1H NMR(400MHz,Chloroform-d)δ7.56(d,J=8.1Hz,1H),7.15(d,J=8.1Hz,1H),5.63(s,2H),3.47(t,J=8.2Hz,2H),2.93 (t,J=5.4Hz,2H),2.75(t,J=5.4Hz,2H),1.95-1.86(m,2H),1.83-1.71(m,4H),0.90(t,J=8.2Hz,2H),-0.08(s,9H).

[0519] 13 C NMR (101MHz, CDCl3) δ148.68,141.43,134.57,129.01,120.91,120.59,115.05,71.06,67.00,32.94,29.58,28.35,27.89,25.90,19.08,-0.00.

[0520] Step 57-3:

[0521]

[0522] 2-Bromo-10-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[4,5]pyrrolo[2,3-b]pyridine (77 mg, 0.195 mmol) was dissolved in a mixed solution of 1,4-dioxane and water (Dioxane:H2O (V / V) = 10:1, 2 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (88 mg, 0.391 mmol) was added and stirred overnight. After the reaction was completed as monitored by TLC, a saturated aqueous sodium bicarbonate solution was added to quench the reaction. After the dioxane in the solution was removed by a rotary evaporator, methyl tert-butyl ether (20 mL×3) was added for extraction, the organic phases were combined, and the combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate, spin-dried, and then the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V)=4:1) to obtain 2-bromo-10((2-)trimethylsilyl)ethoxy)methyl)-7,8,9,10-tetrahydrocyclohepta[4,5]pyrrolo[2,3-b]pyridine-5(6H)-one (53 mg, 0.134 mmol, yield 66.6%).

[0523] 1H NMR(400MHz,Chloroform-d)δ8.49(d,J=8.1Hz,1H),7.34(d,J=8.2Hz,1H),3.54(t,J=8.2Hz,2H),3.22(t,J= 6.1Hz,2H),2.82(t,J=6.0Hz,2H),2.12-2.05(m,2H),2.00-1.93(m,2H),0.92(t,J=8.2Hz,2H),-0.07(s,9H).

[0524] 13 C NMR (101MHz, CDCl3) δ198.11,148.70,147.93,135.56,132.81,122.55,118.27,114.69,70.09,66.49,43.90,26.78,25.03,22.13,17.64,-1.45.

[0525] Step 57-4:

[0526]

[0527] Dissolve 2-bromo-10-(2-(trimethylsilyl)ethoxy)methyl)-7,8,9,10-tetrahydrocyclohepta[4,5]pyrrolo[2,3-b]pyridin-5(6H)-one (400 mg, 1 mmol) in anhydrous toluene (8 ml), cool to 0°C, and add ethyl formate (260 μL, 3 mmol) and 1 mol / L potassium tert-butoxide in tetrahydrofuran (3 mL, 3 mmol). After the reaction was completed as monitored by TLC, a saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl methyl acetate was added for extraction. The organic phases were combined, and the combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate, and then spin-dried. The residue was then purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V) = 3:1) to obtain (Z)-2-bromo-6-(hydroxymethylene)-10-((2-(trimethylsilyl)ethoxy)methyl)-7,8,9-10-tetrahydrocyclohepta[4,5]pyrrolo[2,3-b]pyridine-5(6H)-one.

[0528] The above (Z)-2-bromo-6-(hydroxymethylene)-10-((2-(trimethylsilyl)ethoxy)methyl)-7,8,9-10-tetrahydrocyclohepta[4,5]pyrrolo[2,3-b]pyridin-5(6H)-one was dissolved in anhydrous ethanol (10 mL), morpholine (870 μL, 10 mmol) was added, and the temperature was raised to 90°C. After one hour, the reaction was cooled to room temperature, and crude (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester (5 mmol) and sodium methoxide (270 mg, 5 mmol) were added. The temperature was raised to 90°C for overnight reaction. After the reaction was complete, the ethanol was dried by mass spectrometry, and water (20 mL) and ethyl acetate (20 mL×3) were added for extraction. The organic phases were combined, dried and dried, and the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) to obtain tert-butyl (S)-3-((10-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3″,2″:4′,5′]pyrrolo[2′,3′:6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (362 mg, 0.564 mmol, yield: 56.4%). MS (ESI): [M+H] + =643.

[0529] Step 57-5:

[0530]

[0531] Tert-butyl (S)-3-((10-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3",2":4',5']pyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (100 mg, 0.156 mmol), tetrakistriphenylphosphine palladium (54 mg, 0.0467 mmol) and cuprous iodide (17.7 mg, 0.0934 mmol) were placed in a round-bottom flask, and after replacing argon three times, deoxygenated anhydrous triethylamine (1.5 mL) and trimethylsilyl acetylene (66 μL, 0.467 mmol) were added. The mixture was heated to 80°C and reacted overnight. After the reaction was completed as monitored by mass spectrometry, the solution was filtered through diatomaceous earth. After the reaction was completed as monitored by mass spectrometry, the solvent was removed by rotary evaporator, and the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 3:1 to 2:1) to give brown oily liquid tert-butyl (S)-3-((8-((2-(trimethylsilyl)ethoxy)methyl)-10-((trimethylmethylsilyl)ethynyl)-5,6,7,8-tetrahydropyrido[3″″,2″:4′,5′]pyrrolo[2′,3′:6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (83 mg, 0.126 mmol, yield: 80.8%). MS (ESI): [M+H] + =661.

[0532] The product of the previous step, tert-butyl (S)-3-((8-((2-(trimethylsilyl)ethoxy)methyl)-10-((trimethylmethylsilyl)ethynyl)-5,6,7,8-tetrahydropyrido[3"",2":4',5']pyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (83 mg, 0.126 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and a 1 mol / L tetrabutylammonium fluoride solution in tetrahydrofuran (0.188 mol, 188 μL) was added dropwise. After 15 minutes, a saturated aqueous ammonium chloride solution (5 mL) was added to quench the reaction. After removing tetrahydrofuran by rotary evaporator, ethyl acetate (5 mL×3) was added for extraction. The organic phases were combined, dried and spun to dryness. The residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) to obtain brown oily liquid tert-butyl (S)-3-((10-ethynyl-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3″,2″:4′,5′]pyrrolo[2′,3′:6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (70 mg, 0.119 mmol, yield: 94.5%). MS (ESI): [M+H] + =589.

[0533] Step 57-6:

[0534]

[0535] Tert-butyl (S)-3-((10-ethynyl-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3″,2″:4′,5′]pyrrolo[2′,3′:6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (75 mg, 0.128 mmol), copper sulfate pentahydrate (9.56 mg, 0.038 mmol) and sodium ascorbate (15.15 mg, 0.077 mmol) were placed in a round-bottom flask, and after replacing argon three times, a deoxygenated N,N-dimethylformamide and water mixed solution (1 mL, DMF:H2O (V / V) = 10:1) and trimethylsilylazide (50 μL, 0.383 mmol) were added. The mixture was heated to 90°C and reacted overnight. After the reaction was completed as monitored by mass spectrometry, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed three times with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, spin-dried, and the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 5:1 to 1:1) to obtain compound 57-6 (light yellow oily liquid, 40 mg, 0.063 mmol, yield: 49.5%), which was directly used in the next step reaction.

[0536] Compound 57-6 (40 mg, 0.063 mmol) was added with dioxane hydrochloride solution (4 mol / L, 2 mL), and the mixture was heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to obtain (S)-N-(piperidin-3-yl)-10-(1H-1,2,3-triazol-5-yl)-5,6,7,8-tetrahydropyrido[3",2"':4',5']pyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-amine (Compound A257). MS (ESI): [M+H] + =402.

[0537] Example 58: Preparation of (S)-3-(2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrido[3″,2″′:4′,5′]pyrrolo[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-10-yl)oxazolidin-2-one (Compound A258)

[0538]

[0539] Tert-butyl (S)-3-((10-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3″,2″′:4′,5′]pyrrolo[2′,3′:6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate 2-oxazolidinone (80 mg, 0.124 mmol), palladium acetate (8.2 mg, 0.0364 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (42 mg, 0.0728 mmol), cesium carbonate (78.6 mg, 325 mmol) and 2-oxazolidinone (15.8 mg, 0.182 mmol) were added to a round-bottom flask, and the argon atmosphere was replaced three times before adding deoxygenated anhydrous 1,4-dioxane (1.2 mL). The mixture was heated at 100°C overnight to react. After the reaction was complete as monitored by mass spectrometry, a saturated aqueous ammonium chloride solution (5 mL) was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (5 mL). The combined organic phase was washed with saturated brine and then dried by rotation. The residue was purified by flash column chromatography (petroleum ether: ethyl acetate (V / V) = 3:1) to obtain tert-butyl (S)-3-((10-(2-oxooxazolidin-3-yl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3",2":4',5']pyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (light yellow solid, 75 mg, 0.116 mmol, yield: 93.2%). MS (ESI): [M+H] + =650.

[0540] The product obtained in the previous step, tert-butyl (S)-3-((10-(2-oxoxazolidin-3-yl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3",2":4',5']pyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (60 mg, 0.092 mmol) was dissolved in tetrahydrofuran (4 mL). Ethylenediamine (400 μL) was added and stirred at room temperature until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporation and the residue was purified by preparative HPLC to give (S)-3-(2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrido[3",2"':4',5']pyrrolo[2',3':6,7]cyclohepta[1,2-d]pyrimidin-10-yl)oxazolidin-2-one (Compound A258). MS (ESI): [M+H] + =420.

[0541] 1H NMR (600MHz, Methanol-d4) δ8.74(d,J=8.6Hz,1H),8.06(d,J=8.7Hz,1H),7.92(s,1H),4.51(ddd,J=8.3,6 .9,1.6Hz,3H),4.31-4.27(m,2H),3.64-3.59(m,1H),3.36(dt,J=12.9,4.6Hz,1H),3.33-3.31(m,2H),3.24 (t,J=11.0Hz,1H),3.12(ddd,J=13.2,10.4,3.5Hz,1H),2.89-2.78(m,2H),2.32(dq,J=13.2,4.6Hz,1H),2. 14(tdd,J=15.2,7.8,4.0Hz,2H),2.08-2.02(m,1H),1.99-1.93(m,1H),1.83(dtd,J=13.6,9.9,3.7Hz,1H).

[0542] Example 59: Preparation of (S)-N-(piperidin-3-yl)-10-(1H-pyrazol-1-yl)-5,6,7,8-tetrahydropyrido[3',2':4',5']pyrrolo[2',3':6,7]cyclohepta[1,2-d]pyrimidin-2-amine (Compound A259)

[0543]

[0544] Tert-butyl (S)-3-((10-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3″,2″:4′,5′]pyrrolo[2′,3′:6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (100 mg, 0.155 mmol), imidazole (21 mg, 0.312 mmol), cuprous oxide (4.5 mg, 0.0312 mmol), cesium carbonate (100 mg, 0.312 mmol) and salicylaldehyde oxime (13.9 mg, 0.101 mg) were added to a round-bottom flask, and argon was replaced three times before adding deoxygenated anhydrous acetonitrile (1 mL). After the reaction was sealed for 72 hours, saturated ammonium chloride solution (5 mL) was added to quench. After extraction with ethyl acetate (5 mL × 3) for 3 times, the combined organic phase was washed with water and saturated sodium chloride solution, and then the residue was purified by flash column chromatography to give tert-butyl (S)-3-((10-(1H-pyrazol-1-yl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3",2':4',5']pyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (54 mg, 0.0857 mmol, yield 55.3%). MS (ESI): [M+H] + =631.

[0545] To tert-butyl (S)-3-((10-(1H-pyrazol-1-yl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3",2':4',5']pyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (54 mg, 0.0857 mmol) was added dioxane hydrochloride solution (4 mol / L, 3 mL), heated to 60 ° C for 10 minutes, and the solvent was removed by rotary evaporation. The residual The residue was redissolved in anhydrous tetrahydrofuran (4 mL) and ethylenediamine (400 μL) was added dropwise. The reaction was carried out at room temperature until complete conversion was monitored by mass spectrometry. The solvent was removed by rotary evaporator and the residue was purified by preparative HPLC to obtain (S)-N-(piperidin-3-yl)-10-(1H-pyrazol-1-yl)-5,6,7,8-tetrahydropyrido[3',2':4',5']pyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-amine (Compound A258). Characterization data of Compound A258:

[0546] MS(ESI):[M+H] + =401.

[0547] 1H NMR (400MHz, Methanol-d4) δ8.85(d,J=8.3Hz,1H),8.56(d,J=2.6Hz,1H),7.89(s,1H),7.81(d,J =8.5Hz,1H),7.76(d,J=1.7Hz,1H),6.54(t,J=2.2Hz,1H),4.45(s,1H),3.64(dd,J=12.6,3.8Hz,1 H),3.40-3.33(m,2H),3.33-3.31(m,1H),3.26-3.20(m,1H),3.17-3.08(m,1H),2.93-2.80(m,2H ),2.37-2.28(m,1H),2.20-2.11(m,2H),2.10-2.04(m,1H),2.02-1.93(m,1H),1.90-1.78(m,1H).

[0548] Example 60-Example 64:

[0549] Referring to the method of Example 59, the structures of the following examples were synthesized by changing different starting materials.

[0550] Table 3:

[0551]

[0552] Compound A261 of Example 61: 1H NMR (600 MHz, Methanol-d4) δ 9.65 (s, 1H), 9.20 (d, J = 8.3 Hz, 1H), 8.36 (t, J = 1.7 Hz, 1H), 8.03 (s, 1H), 7.76-7.72 (m, 2H), 4.42 (s, 1H), 3.62-3.58 (m, 1H), 3.39-3.34 (m ,3H),3.14(t,J=10.9Hz,1H),3.08(td,J=12.8,11.8,3.5Hz,1H),2.90-2.80(m,2H ),2.27(d,J=12.4Hz,1H),2.18-2.10(m,3H),2.00-1.93(m,1H),1.84-1.76(m,1H).

[0553] Example 65: Preparation of (S)-10-(3,5-dimethylisoxazol-4-yl)-N-(piperidin-3-yl)-5,6,7,8-tetrahydropyrido[3",2':4',5']pyrrolo[2',3':6,7]cycloheptyl[1,2-d]pyrimidin-2-amine (Compound A265)

[0554]

[0555] Tert-butyl (S)-3-((10-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3″,2″:4′,5′]pyrrolo[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (100 mg, 0.155 mmol), 3,5-dimethylisoxazoleboronic acid (26 mg, 0.186 mmol), Pd(dppf)C l2 DCM (6.3 mg, 0.008 mmol), NaHCO3 (26 mg, 0.31 mmol) were dissolved in 1 mL of a dioxane-water mixed solution (Dioxane: H2O (V / V) = 2:1), deoxygenated, reacted at 100°C overnight under argon protection, and monitored by LC-MS. After the reaction was completed. Filtered on diatomaceous earth, extracted with ethyl acetate, washed with saturated brine, and the organic layer was dried and concentrated to obtain compound 65-1, which was directly used in the next step. MS (ESI): [M+H] + =660.

[0556] Compound 65-1 obtained in the previous step was added to 4 mol / L hydrochloric acid dioxane solution (4 mL), heated to 60 ° C for 10 minutes, and then the solvent was removed by a rotary evaporator. The residue was redissolved in anhydrous tetrahydrofuran (4 mL) and ethylenediamine (400 μL) was added dropwise. The reaction was carried out at room temperature until the mass spectrometer monitored the complete conversion. The solvent was removed by a rotary evaporator, and the residue was purified by preparative HPLC to obtain compound A265. Characterization data of compound A265: MS (ESI): [M+H] + =439.

[0557] 1 H NMR (600MHz, Methanol-d4) δ8.89 (s, 1H), 7.96 (s, 1H), 7.39 (d, J = 8.0Hz, 1H), 4. 54(s,1H),3.66-3.61(m,1H),3.38(t,J=6.5Hz,2H),3.36-3.32(m,1H),3.26(t,J =11.3,10.2Hz,1H),3.16-3.10(m,1H),2.92-2.84(m,2H),2.60(s,3H),2.45(s, 3H),2.36-2.30(m,1H),2.20-2.06(m,3H),2.01-1.93(m,1H),1.89-1.81(m,1H).

[0558] Embodiment 66-embodiment 73:

[0559] Referring to the method of Example 65, the compounds of the following examples were prepared by changing the starting materials.

[0560] Table 4:

[0561]

[0562]

[0563] Characterization of Example 69 (Compound A269): 1H NMR (600 MHz, Methanol-d4) δ 8.60 (s, 1H), 7.93 (d, J = 2.9 Hz, 1H), 7.80 (s, 1H), 7.69 (d, J = 5.0 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.47 (dd, J = 4.9, 2.8 Hz, 1H), 4.45 (s, 1H), 3.62-3.58 (m, 1H), 3.37 (dt, J = 13.5, 4.5 Hz, 1H), 3.32 ( t,J=6.8Hz,2H),3.22(t,J=10.8Hz,1H),3.11(ddd,J=13.5,10.4,3.4Hz,1H),2.90-2.81(m,2H),2.30(dt,J=1 3.8,4.7Hz,1H),2.16-2.09(m,2H),2.07-2.01(m,1H),2.00-1.95(m,1H),1.81(ddt,J=14.2,9.8,5.0Hz,1H).

[0564] Characterization of Example 71 (Compound A271): 1H NMR (600 MHz, Methanol-d4) δ 8.83 (s, 1H), 7.94 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 6.72 (d, J = 1.9 Hz, 1H), 4.53 (s, 1H), 4.25 (s, 3H), 3.63 (d, J = 12.1 Hz, 1H), 3.40-3. 34(m,3H),3.27-3.21(m,1H),3.15-3.09(m,1H),2.93-2.82(m,2H),2.35-2.29(m,1H),2.1 5(ddt,J=19.4,13.8,5.9Hz,2H),2.11-2.06(m,1H),2.01-1.94(m,1H),1.87-1.80(m,1H).

[0565] Characterization of Example 72 (Compound A272): 1H NMR (400 MHz, Methanol-d4) δ 8.68 (d, J = 8.6 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 7.95 (s, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 6.58 (t, J = 2.1 Hz, 1H), 4.56 (s, 1H), 3.6 8-3.63(m,1H),3.43-3.39(m,1H),3.36(t,J=6.9,5.8Hz,2H),3.29-3.24(m,1H),3.18-3.11(m,1H ),2.93-2.81(m,2H),2.41-2.34(m,1H),2.23-2.09(m,3H),2.03-1.94(m,1H),1.89-1.81(m,1H).

[0566] Embodiment 74-79:

[0567]

[0568] Tert-butyl (S)-3-((10-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrido[3″,2″:4′,5′]pyrrolo[2′,3′:6,7]cycloheptyl[1,2-d]pyrimidin-2-yl)amino)piperidine-1-carboxylate (80 mg, 0.125 mmol), palladium acetate (8.4 mg, 0.037 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (43.3 mg, 0.075 mmol), cesium carbonate (81 mg, 0.25 mmol) were added to a round-bottom flask, and the argon atmosphere was replaced three times before adding a deoxygenated amine (NHR1R2) (0.187 mmol) in anhydrous 1,4-dioxane solution (1.2 mL). The reaction was sealed and reacted for 12 hours before adding a saturated ammonium chloride solution to quench. After extraction with ethyl acetate three times, the combined organic phase was washed with water and saturated sodium chloride solution in turn, and then spin-dried. The residue was then filtered through silica gel to obtain a crude product which was directly used in the next reaction.

[0569] The crude product obtained in the previous step was added to 4 mol / L hydrochloric acid dioxane solution (4 mL), heated to 60 ° C for 10 minutes, and then the solvent was removed by rotary evaporator. The residue was redissolved in anhydrous tetrahydrofuran (4 mL) and ethylenediamine (400 μL) was added dropwise. The reaction was carried out at room temperature until the mass spectrometer monitored complete conversion. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to obtain the target compound.

[0570] By changing the starting materials, the compounds of Examples 74-79 were prepared.

[0571] Table 5:

[0572]

[0573]

[0574] Characterization of Example 74 (Compound A274): 1H NMR (400MHz, Methanol-d4) δ8.67 (d, J = 8.3 Hz, 1H), 7.87 (s, 1H), 6.89 (d, J = 8. 3Hz,1H),4.43(s,1H),3.56-3.52(m,1H),3.34-3.31(m,1H),3.28-3.23(m,6H ),3.13-3.04(m,1H),2.85-2.73(m,2H),2.32-2.22(m,1H),2.09(dd,J=14.0, 7.0Hz,2H),2.03-1.96(m,1H),1.90(d,J=10.8Hz,1H),1.79(t,J=10.7Hz,1H).

[0575] Characterization of Example 75 (Compound A275): 1H NMR (600 MHz, Methanol-d4) δ 8.71 (d, J = 8.5 Hz, 1H), 7.91 (s, 1H), 6.96 (d, J = 8.5 Hz, 1H), 4.49 (s, 1H), 3.63-3.56 (m, 1H), 3.54 (q, J = 7.4 Hz, 2H), 3.35 (dt, J = 12.7, 4.6 Hz, 2H), 3.33-3.29 (m, 6H), 3.24 (d, J = 10.8 Hz, 1H), 3.12 ( ddd,J=13.3,10.3,3.5Hz,1H),2.90-2.77(m,2H),2.30(dt,J=14.1,4.7Hz,1H),2.13(dq,J=14.6,5.8Hz,2H), 2.05(qd,J=8.2,7.8,4.6Hz,1H),2.00-1.90(m,1H),1.83(ddt,J=15.9,9.9,5.0Hz,1H),1.35(t,J=7.4Hz,3H).

[0576] Characterization of Example 76 (Compound A276): 1H NMR (400 MHz, Methanol-d4) δ 8.76 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H), 7.04 (d, J = 8.5 Hz, 1H), 4.45 (s, 1H), 3.63-3.55 (m, 1H), 3.39-3.34 (m, 1H), 3.35-3.31 (m, 3H), 3.21 (t, J = 10.7 Hz, 1H), 3.12 (d, J = 9 .9Hz,1H),3.09-2.98(m,2H),2.92-2.76(m,3H),2.34-2.26(m,1H),2.19-2.09(m,2H),2.10-2.0 0(m,1H),1.93(dt,J=14.5,10.5Hz,1H),1.88-1.75(m,1H),1.24-1.18(m,2H),1.07-0.97(m,2H).

[0577] Characterization of Example 77 (Compound A277): 1H NMR (600 MHz, Methanol-d4) δ 8.81 (d, J = 8.3 Hz, 1H), 7.94 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.49 (s, 1H), 3.63-3.58 (m, 1H), 3.40 (s, 3H), 3.37 (t, J = 4.4 Hz, 1H), 3.34 (t, J = 6.5 Hz, 2H), 3.25-3.19 ( m,1H),3.13-3.10(m,1H),3.10(s,3H),2.90-2.80(m,2H),2.30(dd,J=13.4,5.2Hz,1H),2.14(q d,J=8.8,6.1Hz,2H),2.10-2.02(m,1H),1.99-1.92(m,1H),1.82(dtd,J=13.6,9.9,3.7Hz,1H).

[0578] Example 80: Preparation of Compound A280

[0579]

[0580] Step 80-1:

[0581]

[0582] 3-Bromophenylhydrazine hydrochloride (10 g, 44.84 mmol) and cycloheptanone (5 g, 44.64 mmol) were dissolved in acetic acid (80 mL), and the solution was refluxed at 145 ° C for 2 hours. The cooled reaction solution was concentrated in vacuo using a rotary evaporator, neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate (200 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether) to obtain light yellow oily liquid 1-bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole and 3-bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (9.8 g, 37.26 mmol, yield 83.1%).

[0583] Step 80-2:

[0584]

[0585] 1-Bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole and 3-bromo-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (7.66 g, 29.02 mmol) were dissolved in anhydrous tetrahydrofuran (80 mL) under argon protection, cooled to 0°C, and 60% sodium hydride (2.32 g, 58.03 mmol) was slowly added. Half an hour later, 2-(trimethylsilyl)ethoxymethyl chloride (10.2 mL, 58 mmol) was added dropwise and stirred at room temperature overnight. After TLC detection, saturated ammonium chloride solution was added dropwise at 0°C to quench the reaction. After removing tetrahydrofuran from the solution by rotary evaporator, ethyl acetate (200 mL×3) was added for extraction, and the organic phases were combined, and the combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The residue was concentrated and purified by flash column chromatography (silica gel, petroleum ether) to give a mixture of 1-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole and 3-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (10 g, 25.4 mmol, yield 87.5%) as a light yellow oil.

[0586] Step 80-3:

[0587]

[0588] The mixture of 1-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole and 3-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (8.5 g, 21.63 mmol) obtained in step 80-2 was dissolved in a mixed solution of tetrahydrofuran and water (THF:H2O (V / V) = 10:1, 88 mL). The mixture was cooled to 0°C, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (9.8 g, 43.17 mmol) was added, and the mixture was stirred for 4 hours. After the reaction was completed as monitored by TLC, a saturated aqueous sodium bicarbonate solution was added to quench the reaction. After tetrahydrofuran in the solution was removed by a rotary evaporator, methyl tert-butyl ether (200 mL×3) was added for extraction, and the organic phases were combined. The combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate, and then spin-dried. The residue was then purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to obtain a yellow liquid 3-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (2.4 g, yield 27.3%)

[0589] 1 H NMR (400MHz, Chloroform-d) δ8.28(d,J=8.5Hz,1H),7.53(d,J=1.7Hz,1H),7.36(dd,J=8.5,1.7Hz,1H),5.44(s,2H),3.52(t,J=8.3,7. 9Hz,2H),3.14(t,J=6.5,6.0Hz,2H),2.81(t,J=6.2Hz,2H),2.08-2.00(m,2H),1.97-1.92(m,2H),0.90(t,J=8.1Hz,2H),-0.04(s,9H).

[0590] 13 C NMR (101MHz, CDCl3) δ199.55,150.13,139.15,127.29,127.15,125.02,118. 13,117.80,113.64,73.59,67.82,44.86,27.33,26.28,23.32,19.20,0.00.

[0591] Step 80-4:

[0592]

[0593] 3-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (200 mg, 0.507 mmol) was dissolved in anhydrous toluene (4 mL), and ethyl formate (130 μL, 1.52 mmol) and a tetrahydrofuran solution of potassium tert-butoxide (1 mol / L, 1.52 mL, 1.52 mmol) were added at 0°C. After the reaction was completed by TLC monitoring, a saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate (10 mL×3) was added for extraction. The organic phases were combined, and the combined organic phases were washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After removing the solvent by a rotary evaporator, a crude product was obtained, which was directly used in the next step.

[0594] The crude product obtained in the previous step was dissolved in anhydrous ethanol (4 mL), and morpholine (440 μL, 5.07 mmol) was added, and refluxed at 90° C. for 1 h. After the reaction of the raw material was completed by TLC monitoring, it was cooled to room temperature, and crude (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester (2.5 mmol) and sodium methoxide (135 mg, 2.5 mmol) were added. The mixture was refluxed at 90°C for 16 hours. After the reaction was completed as monitored by mass spectrometry, the solvent was removed by a rotary evaporator, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried. The residue was then purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=5:1 to 1:1) to give a brown oily liquid tert-butyl (S)-3-((10-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (203 mg, 0.317 mmol, 2-step yield 62.5%).

[0595] MS(ESI):[M+H] + =642.

[0596] Step 80-5:

[0597]

[0598] Tert-butyl (S)-3-((10-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (680 mg, 1.06 mmol), tetrakistriphenylphosphine palladium (367 mg, 0.318 mmol) and cuprous iodide (121 mg, 0.636 mmol) were placed in a round-bottom flask, and after replacing argon three times, deoxygenated anhydrous triethylamine (10 mL) and trimethylsilyl acetylene (450 μL, 3.18 mmol) were added. The mixture was heated to 80°C and reacted overnight. After the reaction was complete as monitored by mass spectrometry, the solution was filtered through diatomaceous earth. After the reaction was complete as monitored by mass spectrometry, the solvent was removed by rotary evaporator, and the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 3:1 to 2:1) to obtain brown oily liquid tert-butyl (S)-3-((8-((2-(trimethylsilyl)ethoxy)methyl)-10-((trimethylmethylsilyl)ethynyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (520 mg, yield 74.4%). MS (ESI): [M+H] + =660.

[0599] The product of the previous step, tert-butyl (S)-3-((8-((2-(trimethylsilyl)ethoxy)methyl)-10-((trimethylmethylsilyl)ethynyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (170 mg, 0.258 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and a tetrahydrofuran solution of tetrabutylammonium fluoride (1 mol / L, 1.3 mL, 1.3 mmol) was added dropwise. After 15 minutes, a saturated aqueous ammonium chloride solution was added to quench the reaction, and the tetrahydrofuran was removed by a rotary evaporator. The mixture was extracted with ethyl acetate three times, and the organic phases were combined and washed with a saturated aqueous sodium chloride solution. After drying, the solvent was removed by a rotary evaporator. The residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=3:1) to give brown oily liquid tert-butyl (S)-3-((10-ethynyl-8-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (140 mg, 0.24 mmol, yield 92.4%).

[0600] MS(ESI):[M+H] + =588.

[0601] Step 80-6:

[0602]

[0603] Tert-butyl (S)-3-((10-ethynyl-8-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (105 mg, 0.179 mmol), copper sulfate pentahydrate (13.4 mg, 0.0537 mmol) and sodium ascorbate (21.3 mg, 0.107 mmol) were placed in a round-bottom flask, and after replacing argon three times, a deoxygenated N,N-dimethylformamide and water mixed solution (DMF:H2O (V / V) = 10:1, 1.5 mL) and trimethylsilylazide (70 μL, 0.537 mmol) were added. The mixture was heated to 90°C and reacted overnight. After the reaction was complete as monitored by mass spectrometry, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed three times with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The residue was then purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V) = 5:1 to 1:1) to obtain a light yellow oily liquid tert-butyl (S)-3-((10-(1H-1,2,3-triazol-5-yl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (57 mg, 0.09 mmol, yield 50.5%). MS (ESI): [M+H] + =631.

[0604] To the product of the previous step, tert-butyl (S)-3-((10-(1H-1,2,3-triazol-5-yl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (57 mg, 0.09 mmol), dioxane hydrochloride solution (4 mol / L, 2 mL) was added and the mixture was heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporation, and the residue was purified by preparative HPLC to give (S)-N-(piperidin-3-yl)-10-(1H-1,2,3-triazol-5-yl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-2-amine (Compound A280). MS (ESI): [M+H] + =401.

[0605] Example 81-Example 86:

[0606] Referring to the method of Example 80, the compounds of Examples 81 to 86 were prepared by changing the starting materials.

[0607] Table 6:

[0608]

[0609] Example 87: Preparation of (S)-(6,6-dimethyl-2-(piperidin-3-ylamino)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-8-yl)dimethylphosphine oxide (Compound A287)

[0610]

[0611] Step 87-1:

[0612]

[0613] 2-Methylcyclohexanone (4mL, 28.9mmol) was added dropwise to a suspension of sodium hydride (60%, 1.1g, 27.5mmol) in tetrahydrofuran (25mL) and heated to reflux. After 1 hour, the system was cooled to 0°C, iodomethane (3.6mL, 57.9mmol) was added dropwise and warmed to room temperature. Three hours later, a saturated aqueous sodium chloride solution (50mL) was added to the system and stirred for 30 minutes. The solvent was removed by rotary evaporator, methyl tert-butyl ether (30mL×3) was added for extraction, the combined organic phase was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate, and then the crude 2,2-dimethylcyclohexanone was obtained, which was directly used in the next step.

[0614] Step 87-2:

[0615]

[0616] 2-Bromophenylhydrazine hydrochloride (4.8 g, 21.52 mmol) and crude 2,2-dimethylcyclohexanone (3 g) were dissolved in acetic acid (80 mL), and the solution was refluxed at 145 ° C for 2 hours. The cooled reaction solution was concentrated in vacuo using a rotary evaporator, neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate (100 mL × 3), and the organic phases were combined and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether) to obtain a colorless oily liquid 8-bromo-1,1-dimethyl-2,3,4,9-tetrahydro-1H-carbazole (2.21 g, 7.98 mmol, yield 37%).

[0617] 1H NMR(400MHz,Chloroform-d)δ7.85(s,1H),7.40(dt,J=7.8,0.8Hz,1H),7.28(dd,J=7.7,0.9Hz,1H ),6.96(t,J=7.7Hz,1H),2.68(t,J=6.2Hz,2H),1.94-1.88(m,2H),1.77-1.73(m,2H),1.37(s,6H).

[0618] 13 C NMR (101MHz, CDCl3) δ142.59,134.28,128.96,123.42,120.31,117.34,110.18,104.28,39.21,31.61,29.26,21.51,20.15.

[0619] Step 87-3:

[0620]

[0621] 8-Bromo-1,1-dimethyl-2,3,4,9-tetrahydro-1H-carbazole (1.8 g, 6.5 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL) under argon protection, cooled to 0°C, and 60% sodium hydride (390 mg, 9.75 mmol) was slowly added. Half an hour later, 2-(trimethylsilyl)ethoxymethyl chloride (1.77 mL, 9.75 mmol) was added dropwise and stirred at room temperature overnight. After TLC detection, saturated ammonium chloride solution was added dropwise at 0°C to quench the reaction. After removing tetrahydrofuran from the solution by rotary evaporator, ethyl acetate (60 mL×3) was added for extraction, and the organic phases were combined, and the combined organic phases were washed with saturated sodium chloride (30 mL×3) and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V) = 100:3) to give a light yellow oily liquid 8-bromo-1,1-dimethyl-9-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,9-tetrahydro-1H-carbazole (2.46 g, 6.05 mmol, yield: 93%).

[0622] 1H NMR(400MHz,Chloroform-d)δ7.37-7.31(m,2H),6.91(t,J=7.7Hz,1H),5.84(s,2H),3.60(t,J=8.2Hz,2H), 2.63(t,J=6.1Hz,2H),1.89-1.81(m,2H),1.77-1.72(m,2H),1.44(s,6H),0.99-0.94(m,2H),-0.01(s,9H).

[0623] 13 C NMR (101MHz, CDCl3) δ143.95,133.75,131.55,127.60,120.81,117.41,111. 90,103.82,72.92,64.03,43.41,32.64,28.93,21.90,19.74,18.25,-1.44.

[0624] Step 87-4:

[0625]

[0626] 8-Bromo-1,1-dimethyl-9-((2-(trimethylsilyl)ethoxy)methyl)-2,3,4,9-tetrahydro-1H-carbazole (800 mg, 1.97 mmol) was dissolved in a mixed solution of tetrahydrofuran and water (THF:H2O (V / V) = 10:1, 11 mL). The mixture was cooled to 0°C, 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (892 mg, 3.93 mmol) was added, and the mixture was stirred for 3 hours. After the reaction was completed as monitored by TLC, a saturated aqueous sodium bicarbonate solution was added to quench the reaction. After tetrahydrofuran in the solution was removed by a rotary evaporator, methyl tert-butyl ether (20 mL×3) was added for extraction, the organic phases were combined, and the combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate, spin-dried, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 6:1) to obtain a light yellow oily liquid 8-bromo-1,1-dimethyl-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,9-tetrahydro-carbazole-4-one (642 mg, 1.52 mmol, yield 77.2%).

[0627] 1 H NMR (400MHz, Chloroform-d) δ8.36 (dd, J=7.8, 1.1Hz, 1H), 7.45 (dd, J=7.8, 1.1Hz, 1H), 7.08 (t, J=

[0628] 7.8Hz,1H),5.90(s,2H),3.66(t,J=8.6,8.0Hz,2H),2.62(t,J=6.9,6.2Hz,2H),2.10(t,J=7.0,6.2Hz,2H),1.58(s,6H),0.00(s,9H).

[0629] 13 C NMR (101MHz, CDCl3) δ194.73,158.84,133.90,129.82,128.45,124.17,121. 47,112.94,103.75,72.70,64.91,41.64,35.09,33.63,27.40,18.32,-1.33.

[0630] Step 87-5:

[0631]

[0632] 8-Bromo-1,1-dimethyl-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,9-tetrahydro-carbazole-4-one (100 mg, 0.237 mmol) was dissolved in anhydrous toluene (2 mL), and ethyl formate (57 μL, 0.711 mmol) and a tetrahydrofuran solution of potassium tert-butoxide (1 mol / L, 0.711 mL, 710 μmol) were added at 0°C. After the reaction was completed as monitored by TLC, a saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, and ethyl acetate (10 mL×3) was added for extraction, and the organic phases were combined, and the combined organic phases were washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After removing the solvent by rotary evaporation, (Z)-8-bromo-3-(hydroxymethylene)-1,1-dimethyl-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,9-tetrahydro-4H-carbazole-4-one was obtained, which was directly used in the next reaction.

[0633] (Z)-8-bromo-3-(hydroxymethylene)-1,1-dimethyl-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,9-tetrahydro-4H-carbazole-4-one was dissolved in anhydrous ethanol (2 mL), morpholine (200 μL, 10 mmol) was added, and the mixture was refluxed at 90° C. for 1 h. After the reaction of the raw material was completed by TLC monitoring, the mixture was cooled to room temperature, and crude (S)-tert-butyl 3-guanidinopiperidine-1-carboxylate (1.19 mmol) and sodium methoxide (64 mg, 1.19 mmol) were added. Reflux at 90°C for 16 hours. After the reaction is complete as monitored by mass spectrometry, the solvent is removed by a rotary evaporator, water (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL×3). The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The residue is then purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 3:1) to give a light yellow oily liquid tert-butyl (S)-3-((8-bromo-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-2-yl)amino)piperidine-1-carboxylate (64 mg, 0.098 mmol, 2-step yield 41.2%). MS (ESI): [M+H] + =656.

[0634] Step 87-6:

[0635]

[0636] Tert-butyl (S)-3-((8-bromo-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-2-yl)amino)piperidine-1-carboxylate (64 mg, 0.098 mmol), palladium acetate (7 mg, 0.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (34.7 mg, 0.06 mmol) and potassium phosphate (63.6 mg, 0.3 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (23 mg, 0.3 mmol) in N,N-dimethylformamide (1.2 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and then spin-dried. The residue was then filtered through a short silica gel column to obtain tert-butyl (S)-3-((8-(dimethylphosphoryl)-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-2-yl)amino)piperidine-1-carboxylate (40 mg, 0.061 mmol, yield 62.5%). MS (ESI): [M+H] + =654.

[0637] A dioxane hydrochloride solution (4 mol / L, 3 mL) was added to the tert-butyl (S)-3-((8-(dimethylphosphoryl)-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-2-yl)amino)piperidine-1-carboxylate (40 mg, 0.061 mmol) obtained in the previous step, and the mixture was heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to obtain (S)-(6,6-dimethyl-2-(piperidin-3-ylamino)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-8-yl)dimethylphosphine oxide (Compound A287).

[0638] 1H NMR (400MHz, Methanol-d4) δ8.52 (dd, J=7.5, 2.2Hz, 1H), 7.95 (s, 1H), 7.60-7.48 (m, 2H),4.63(s,1H),3.72(dd,J=12.5,4.0Hz,1H),3.41(dt,J=12.8,4.5Hz,1H),3.31-3. 23(m,1H),3.19-3.11(m,1H),2.95(s,2H),2.35-2.28(m,1H),2.21-2.13(m,1H),2.07 -2.00(m,1H),1.98(s,3H),1.94(s,3H),1.93-1.84(m,1H),1.49(s,3H),1.48(s,3H).

[0639] MS(ESI):[M+H] + =424.

[0640] Example 88: Preparation of (S)-(2-((1-hydroxypropane-2-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-8-yl)dimethylphosphine oxide (Compound A288)

[0641]

[0642] Step 88-1:

[0643]

[0644] 8-Bromo-1,1-dimethyl-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,9-tetrahydro-carbazole-4-one (100 mg, 0.237 mmol) was dissolved in anhydrous toluene (2 mL), and ethyl formate (57 μL, 0.711 mmol) and a tetrahydrofuran solution of potassium tert-butoxide (1 mol / L, 0.711 mL, 0.71 mmol) were added at 0°C. After the reaction was complete as monitored by TLC, a saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate (10 mL×3) was added for extraction. The organic phases were combined, and the combined organic phases were washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After removing the solvent by a rotary evaporator, a crude product was obtained, which was directly used in the next step.

[0645] The crude product obtained in the previous step was dissolved in anhydrous ethanol (2 mL), and morpholine (200 μL, 2.3 mmol) was added, and refluxed at 90° C. for 1 h. After the reaction of the raw material was completed by TLC monitoring, it was cooled to room temperature, and (S)-1-(1-hydroxypropyl-2-yl)guanidine crude product (2.5 mmol) and sodium methoxide (64 mg, 1.185 mmol) were added. Reflux at 90°C for 16 hours. After the reaction is complete as monitored by mass spectrometry, the solvent is removed by a rotary evaporator, water (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL×3). The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The residue is then purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate (V / V)=3:1) to give (S)-2-((8-bromo-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-2-yl)amino)propan-1-ol (70 mg, 0.132 mmol, light yellow oily liquid, 2-step yield 55.7%). MS (ESI): [M+H] + =531.

[0646] Step 88-2:

[0647]

[0648] (S)-2-((8-bromo-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-2-yl)amino)propan-1-ol (70 mg, 0.132 mmol), palladium acetate (9 mg, 0.04 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (45.85 mg, 0.08 mmol) and potassium phosphate (84 mg, 0.396 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (31 mg, 0.396 mmol) in N,N-dimethylformamide (1.5 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and then spin-dried. The residue was then filtered through a short silica gel column to obtain (S)-(2-((1-hydroxypropane-2-yl)amino)-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimidinyl[5,4-c]carbazole-8-yl)dimethylphosphine oxide (40 mg, 0.076 mmol, yield 57.4%). MS (ESI): [M+H] + =529.

[0649] To the product of the previous step (S)-(2-((1-hydroxypropane-2-yl)amino)-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimidinyl[5,4-c]carbazole-8-yl)dimethylphosphine oxide (40 mg, 0.076 mmol), a hydrochloric acid solution of dioxane (4 mol / L, 3 mL) was added and heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator and the residue was purified by preparative HPLC to obtain (S)-(2-((1-hydroxypropane-2-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-pyrimidinyl[5,4-c]carbazole-8-yl)dimethylphosphine oxide (Compound A288).

[0650] 1 H NMR(400MHz, Methanol-d4)δ8.52(d,J=7.7Hz,1H),7.84(s,1H),7.60-7.43(m,2H),4.65-4.30(m,1H), 3.78-3.66(m,2H),2.90(s,2H),1.94(s,3H),1.91(s,3H),1.45(d,J=3.0Hz,6H),1.37(d,J=6.7Hz,3H).

[0651] MS(ESI):[M+H] + =399.

[0652] Example 89: Preparation of (S)-(2-((4-hydroxybutan-2-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-8-yl)dimethylphosphine oxide (Compound A289)

[0653]

[0654] Step 89-1:

[0655]

[0656] 8-Bromo-1,1-dimethyl-9-((2-(trimethylsilyl)ethoxy)methyl)-1,2,3,9-tetrahydro-carbazole-4-one (100 mg, 0.237 mmol) was dissolved in anhydrous toluene (2 mL), and ethyl formate (57 μL, 0.711 mmol) and a tetrahydrofuran solution of potassium tert-butoxide (1 mol / L, 0.711 mL, 0.71 mmol) were added at 0°C. After the reaction was complete as monitored by TLC, a saturated aqueous ammonium chloride solution was added to quench the reaction, and ethyl acetate (10 mL×3) was added for extraction. The organic phases were combined, and the combined organic phases were washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After removing the solvent by a rotary evaporator, a crude product was obtained, which was directly used in the next step.

[0657] The crude product of the previous step was dissolved in anhydrous ethanol (2 mL), and morpholine (200 μL, 2.3 mmol) was added, and refluxed at 90°C for 1 h. After the reaction of the raw material was completed by TLC monitoring, it was cooled to room temperature, and (S)-1-(4-hydroxybutyl-2-yl)guanidine crude product (1.05 mmol) and sodium methoxide (62 mg, 1.15 mmol) were added. Reflux at 90°C for 16 hours. After the reaction is complete as monitored by mass spectrometry, the solvent is removed by a rotary evaporator, water (10 mL) is added, and the mixture is extracted with ethyl acetate (10 mL×3). The organic phases are combined, washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then spin-dried. The residue is then purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate (V / V) = 3:1) to give a light yellow oily liquid (S)-3-((8-bromo-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-2-yl)amino)butan-1-ol (34 mg, 0.063 mmol, 2-step yield 26.4%). MS (ESI): [M+H] + =545.

[0658] Step 89-2:

[0659]

[0660] (S)-3-((8-bromo-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-2-yl)amino)butan-1-ol (34 mg, 0.063 mmol), palladium acetate (4.2 mg, 0.019 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (21.7 mg, 0.038 mmol) and potassium phosphate (40 mg, 0.19 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (14.7 mg, 0.019 mmol) in N,N-dimethylformamide (700 μL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated sodium bicarbonate aqueous solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, and then spin-dried. The residue was then filtered through a short silica gel column to obtain (S)-(2-((4-hydroxybutyl-2-yl)amino)-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-8-yl)dimethylphosphine oxide (25 mg, 0.046 mmol, yield 73.2%). MS (ESI): [M+H] + =543.

[0661] The product (S)-(2-((4-hydroxybutyl-2-yl)amino)-6,6-dimethyl-7-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-8-yl)dimethylphosphine oxide (25 mg, 0.046 mmol) was added with dioxane hydrochloride solution (4 mol / L, 3 mL), and the mixture was heated to 60°C for 10 minutes until the reaction was complete as monitored by mass spectrometry. The solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC to obtain (S)-(2-((4-hydroxybutyl-2-yl)amino)-6,6-dimethyl-6,7-dihydro-5H-pyrimido[5,4-c]carbazole-8-yl)dimethylphosphine oxide (Compound A289).

[0662] 1H NMR(400MHz,)δ8.58(d,J=7.8Hz,1H),7.84(s,1H),7.56-7.49(m,1H),7.44(td,J=7.6,2.6Hz,1H),4.68(s,1 H),3.74(d,J=6.1Hz,2H),2.92(s,2H),1.94(d,J=13.5Hz,8H),1.47(d,J=1.5Hz,6H),1.42(d,J=6.7Hz,3H).

[0663] MS(ESI):[M+H] + =413.

[0664] Example 90: Preparation of Compound A290

[0665]

[0666] Cyclohept-2-en-1-one (10 mmol), 4-bromopyridin-2-amine (5 mmol), iron powder (0.5 mmol), and iodine (0.5 mmol) were added to acetic acid and reacted overnight at 110°C under an oxygen atmosphere. After the reaction was completed, the mixture was concentrated under reduced pressure, an amine methanol solution was added, stirred, concentrated, and purified by column chromatography to obtain the compound 3-bromo-6,7,8,9-tetrahydro-10H-cyclohept[4,5]imidazo[1,2-a]pyridin-10-one. MS (ESI): [M+H]+=279.

[0667] The compound 3-bromo-6,7,8,9-tetrahydro-10H-cyclohepta[4,5]imidazo[1,2-a]pyridin-10-one obtained in the previous step was synthesized with reference to the synthesis method of the pyrimidine ring and the left amino side chain in Example 1 to synthesize the target compound (S)-10-bromo-N-(piperidin-3-yl)-6,7-dihydro-5H-pyrido[1',2':1',2']imidazo[4',5':6,7]cyclohepta[1,2-d]pyrimidin-2-amine (Compound A290). MS (ESI): [M+H]+=413.

[0668] Example 91-Example 112:

[0669] According to the synthesis strategy of Example 90, the following target compound can be synthesized by changing the starting materials:

[0670] Table 7:

[0671]

[0672]

[0673]

[0674] Example 113: Preparation of Compound A313

[0675]

[0676] (S)-3-((10-bromo-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.156 mmol), imidazole (21 mg, 0.312 mmol), cuprous oxide (4.5 mg, 0.0312 mmol), cesium carbonate (100 mg, 0.312 mmol) and salicylaldehyde oxime (13.9 mg, 0.101 mg) were added to a round-bottom flask, and argon was replaced three times before adding deoxygenated anhydrous acetonitrile (1 mL). After the reaction was sealed for 72 hours, saturated ammonium chloride solution (5 mL) was added to quench. After extraction with ethyl acetate (5 mL×3) for three times, the combined organic phase was washed with water and saturated sodium chloride solution in turn and spin-dried to obtain crude tert-butyl (S)-3-((10-(1H-pyrazol-1-yl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate.

[0677] MS(ESI):[M+H] + =630.

[0678] To the crude product of (S)-tert-butyl 3-((10-(1H-pyrazol-1-yl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate, add dioxane hydrochloride solution (4 mol / L, 3 mL), heat to 60°C for 10 minutes, remove the solvent by rotary evaporator, redissolve the residue in anhydrous tetrahydrofuran (4 mL), and add ethylenediamine (400 μL) dropwise. Reaction at room temperature until complete conversion is monitored by mass spectrometry. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC to give (S)—N-(piperidin-3-yl)-10-(1H-pyrazol-1-yl)-5,6,7-8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-2-amine (Compound A313).

[0679] MS(ESI):[M+H] + =400.

[0680] 1H NMR(400MHz, Methanol-d4)δ8.68(d,J=8.6Hz,1H),8.25(d,J=2.4Hz,1H),7.95(s,1H), 7.77(d,J=1.8Hz,1H),7.73(d,J=1.8Hz,1H),7.64(d,J=8.5Hz,1H),6.58(t,J=2.1Hz,1H ),4.56(s,1H),3.68-3.63(m,1H),3.36(t,J=6.9,5.8Hz,2H),3.29-3.24(m,1H),3.18-3 .11(m,1H),2.93-2.81(m,2H),2.41-2.34(m,1H),2.23-1.96(m,5H),1.89-1.81(m,1H).

[0681] Example 114: Biological Activity Test

[0682] (1) CDK7 kinase inhibitory activity assay

[0683] Diluent: It consists of an aqueous solution containing 24 mM MES (pH 6.75), 0.012% Tween 20, 0.06 mg / mL BSA and 7.2 mM MgCl2.

[0684] Experimental method: In a 384-well reaction plate, a blank control group, a test group and a positive drug control group were set up respectively, wherein 2 μL of diluent was added to the blank control group, 2 μL of the test compound diluted with diluent was added to the test group, and 2 μL of staurosporine diluted with diluent was added to the positive control group. Then, 5 μL of CDK7 / CyclinH / MAT1 enzyme solution (Promega) was added to all groups, incubated for 30 min, 5 μL of CDK7tide / ATP substrate mixture (Beijing Zhongke Yaguang Biotechnology Co., Ltd.) was added, incubated at room temperature for 110 min, 4 μL of 150 mM ethylenediaminetetraacetic acid was added to terminate the reaction, and the plate was read on an EZreader II instrument. IC50 was calculated using GraphPad Prism 8 software.

[0685] The experimental results are shown in Table 8 below:

[0686] Table 8:

[0687] Compound CDK7 inhibition IC50 Compound CDK7 inhibition IC50 A201 A A257 A A202 A A258 A A203 A A259 A A204 A A260 A A205 A A261 A A206 A A262 A A207 B A263 A A208 A A264 A A209 A A265 A A210 A A266 A A211 A A267 A A212 A A268 A A213 B A269 A A214 A A270 A A215 A A271 A A218 A A272 A A219 B A273 A A221 B A274 A A222 B A275 A A223 B A276 A A225 A A277 A A226 A A278 A A227 A A279 A A228 A A280 A A229 A A281 A A230 C A282 A A237 B A283 A A238 A A284 A A239 B A285 A A240 C A287 A A241 C A288 B A248 A A289 A A250 A Staurosporine A

[0688] A: IC50 is not greater than 50nM; B: IC50 is greater than 50nM and not greater than 500nM; C: IC50 is greater than 500nM and not greater than 5000nM.

[0689] Conclusion: The compounds provided by the present invention have good CDK7 kinase inhibitory activity.

[0690] (2) Cell proliferation inhibitory activity

[0691] The following experiment is used to determine the inhibitory activity of the compounds of the present invention on tumor cell proliferation under in vitro conditions. The inhibitory activity of the compounds can be expressed by IC50 values.

[0692] The experimental scheme is briefly described as follows: human colorectal cancer cells HCT116 are suspended in a medium containing 10% FBS at an appropriate cell density (such as 15000-50000 cells / mL culture medium), and then inoculated on a 96-well plate and cultured overnight in a cell culture incubator at 37°C and 5% carbon dioxide. The test compound is first dissolved with DMSO, then diluted with DMEM medium without FBS to the concentration required for the experiment (generally 9 concentration points are set for each compound), added to a 96-well plate, and the blank control group is added with an equal volume of DMEM medium without the test compound, and continued to be cultured at 37°C and 5% carbon dioxide for 72 hours. Thereafter, the CCK8 method is used to determine the inhibitory activity of the compound on the proliferation of human colorectal cancer cells HCT116. The IC50 value of the compound can be calculated by the inhibitory value of the test compound on the proliferation of human colorectal cancer cells HCT116 at different concentrations, and the IC50 value is calculated using GraphPad prism 8 software.

[0693] The experimental results are shown in Table 9 below:

[0694] Table 9:

[0695]

[0696]

[0697] A: IC50 is not greater than 200nM; B: IC50 is greater than 200nM and not greater than 2000nM; C: IC50 is greater than 2μM and not greater than 10μM; D is greater than 10μM; The example compounds exhibit excellent tumor cell proliferation inhibitory activity against human colorectal cancer cells HCT116.

[0698] Conclusion: The compounds provided by the present invention have good anti-human colorectal cancer cell HCT116 activity.

[0699] Example 115: Preparation of Compound A314

[0700]

[0701] Compound 2-6 was used as a raw material, and a dioxane hydrochloride solution (4 mol / L, 3 mL) was added. After heating to 60°C for 10 minutes, the solvent was removed by a rotary evaporator, and the residue was redissolved in anhydrous tetrahydrofuran (4 mL), and ethylenediamine (400 μL) was added dropwise. The reaction was carried out at room temperature until the mass spectrometer monitored complete conversion. The solvent was removed by a rotary evaporator, and the residue was purified by preparative HPLC to obtain the target compound (S)-9-bromo-N-(piperidin-3-yl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indole-2-amine (Compound A314). [M+H] + =412. 1 H NMR (400MHz, Methanol-d4) δ8.86(d,J=8.0Hz,1H),8.00(s,1H),7.54(m,1H),7.44(td,J=7.7,2.7Hz,1H),4.55(s,1H),3.64(m,1H ),3.42(t,J=6.6Hz,2H),3.39(m,1H),3.26(m,1H),3.12(m,1H),2.84(m,2H),2.41(m,1H),2.19(m,3H),1.98(m,1H),1.820(m,1H).

[0702] Example 116: Compound A315

[0703]

[0704] The aryl bromide key intermediate was prepared according to the preparation method of Example 14, and then the target compound (S)-9-bromo-N-(6,6-dimethylpiperidin-3-yl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-amine was obtained according to the method for removing the protecting group of compound A314. [M+H] + =440. 1 H NMR (400MHz, Methanol-d4) δ8.82(m,1H),7.96(s,1H),7.51(dd,J=7.8,2.0Hz,1H),7.38(td,J=7.8,2.5Hz,1H),3.52(m,1H ),3.41(m,3H),2.87(m,2H),2.28(d,J=9.2Hz,1H),2.24-2.14(m,1H),2.12(m,1H),2.01(m,2H),1.91(m,2H),1.28(s,6H).

[0705] Example 117: Compound A316

[0706] Step 117-1:

[0707]

[0708] Dissolve 2-bromo-3-chloroaniline (4g) in concentrated hydrochloric acid (20mL), cool to 0°C, and slowly drip sodium nitrite aqueous solution (2.08g sodium nitrite, 5mL water). One hour later, slowly drip stannous chloride (9.5g) in concentrated hydrochloric acid (20mL). After TLC monitoring of the reaction is complete, slowly drip 12M sodium hydroxide aqueous solution until pH = 10. After filtration through diatomaceous earth, the filtrate is extracted with ethyl acetate (100mL×2). After combining the organic phases, the combined organic phases are washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After spin drying and concentration, a brown solid (2-bromo-3-chlorophenyl) hydrazine (3.29g) is obtained.

[0709] 1 H NMR (400MHz, Chloroform-d) δ7.18(t,J=8.1Hz,1H),7.02(d,J=1.4Hz,1H),6.90(dd,J=7.9,1.5Hz,1H),5.87(s,1H),3.65(s,2H).

[0710] 13 C NMR (101MHz, CDCl3) δ149.32,134.79,128.53,119.72,109.96,107.46.

[0711] Step 117-2:

[0712]

[0713] Dissolve (2-bromo-3-chlorophenyl)hydrazine (1.6 g) and cycloheptanone (815 mg) in acetic acid (30 mL), heat at 145 ° C and seal overnight. After cooling to room temperature, the reaction solution was concentrated in vacuo using a rotary evaporator, slowly added with saturated sodium bicarbonate solution at 0 ° C for neutralization, and extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether) to obtain 4-bromo-3-chloro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (480 mg).

[0714] 1H NMR(400MHz,Chloroform-d)δ7.88(s,1H),7.30(d,J=8.4Hz,1H),7.13(d,J=8.4Hz,1H) ,2.85(t,2H),2.75(t,2H),1.89(dddd,J=10.9,6.4,4.7,2.2Hz,2H),1.82-1.73(m,4H).

[0715] Step 117-3:

[0716]

[0717] 4-Bromo-3-chloro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (480 mg) was dissolved in anhydrous tetrahydrofuran (12 mL) under argon protection, cooled to 0°C, and 60% sodium hydride (130 mg) was slowly added. Half an hour later, 2-(trimethylsilyl)ethoxymethyl chloride (572 μL, 3.23 mmol) was added dropwise and stirred at room temperature overnight. After TLC detection, saturated ammonium chloride solution was added dropwise at 0°C to quench the reaction. After removing tetrahydrofuran from the solution by rotary evaporator, ethyl acetate (30 mL×3) was added for extraction, and the organic phases were combined and washed with saturated sodium chloride solution. The organic phase was then dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=200:1) to give 4-bromo-3-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (690 mg).

[0718] 1 H NMR(400MHz,Chloroform-d)δ7.31(d,J=8.4Hz,1H),7.21(d,J=8.3Hz,1H),5.93(s,2H),3.54-3.48(m,2H),2.92- 2.88(m,2H),2.78-2.72(m,2H),1.93-1.88(m,2H),1.82-1.74(m,4H),0.90-0.86(m,2H),-0.05(d,J=1.4Hz,9H). 13 C NMR (101MHz, CDCl3) δ142.05,133.65,130.06,128.43,121.48,117.35,115. 90,104.21,71.30,64.60,31.23,27.80,26.69,26.44,23.82,18.09,-1.44.

[0719] Step 117-4:

[0720]

[0721] 4-Bromo-3-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (690 mg) was dissolved in a mixed solution of 1,4-dioxane and water (Dioxane:H2O (V / V) = 10:1, 15 mL), and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (734 mg) was added, and the mixture was stirred overnight. After the reaction was completed as monitored by TLC, a saturated aqueous sodium bicarbonate solution was added to quench the reaction. The dioxane in the solution was removed by a rotary evaporator, and then ethyl acetate (20 mL×3) was added for extraction. The organic phases were combined, and the combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate, spin-dried, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to give 4-bromo-3-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (410 mg).

[0722] 1 H NMR(400MHz,Chloroform-d)δ8.37(d,J=8.5Hz,1H),7.36(d,J=8.5Hz,1H),6.02(s,2H),3.63-3.57(m,2H),3 .18-3.14(m,2H),2.83-2.79(m,2H),2.08-2.02(m,2H),1.97-1.91(m,2H),0.94-0.89(m,2H),-0.03(s,9H).

[0723] 13 C NMR (101MHz, CDCl3) δ199.44,152.33,135.90,132.45,129.77,125.98,123. 26,117.82,105.49,73.22,66.74,44.74,27.32,26.27,23.11,19.52,0.00.

[0724] Step 117-5:

[0725]

[0726] 4-Bromo-3-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (100 mg) was dissolved in anhydrous toluene (2 ml), cooled to 0°C, and ethyl formate (55 μL) and 1 mol / L potassium tert-butoxide tetrahydrofuran solution (680 μL, 0.68 mmol) were added. After TLC monitoring, saturated aqueous ammonium chloride solution () was added to quench the reaction, ethyl methyl acetate was added for extraction, the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried to obtain 4-bromo-3-chloro-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one crude product, which was directly used in the next step reaction.

[0727] The above crude 4-bromo-3-chloro-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one was dissolved in anhydrous ethanol (1 mL), morpholine (200 μL, 2.27 mmol) was added, and the temperature was raised to 90°C. After one hour, the reaction was cooled to room temperature, and crude (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester (1.14 mmol) and sodium methoxide (61.3 mg) were added. The temperature was raised to 90°C for overnight reaction. After the reaction was completed as monitored by mass spectrometry, the ethanol was dried and water (10 mL) and ethyl acetate (10 mL×3) were added for extraction. The organic phases were combined, dried and then dried. The residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=4:1) to give (S)-tert-butyl 3-((9-bromo-10-chloro-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (66 mg).

[0728] MS(ESI):[M+H] + =676.

[0729] Step 117-6:

[0730]

[0731] (S)-3-((9-bromo-10-chloro-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (44.5 mg), palladium acetate (4.4 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg) and potassium phosphate (41.8 mg) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (15.6 mg) in N,N-dimethylformamide (700 μL) was added. The reaction was carried out at 145° C. under microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and spin-dried. The residue was then filtered to obtain crude (S)-3-((10-chloro-9-(dimethylphosphoryl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidinyl[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. MS (ESI): [M+H] + =674.

[0732] Step 117-7:

[0733]

[0734] To the crude product of (S)-3-((10-chloro-9-(dimethylphosphoryl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester, add dioxane hydrochloride solution (4 mol / L, 3 mL), heat to 60°C for 20 minutes, remove the solvent by rotary evaporator, redissolve the residue in anhydrous tetrahydrofuran (4 mL), and add ethylenediamine (400 μL) dropwise. Reaction at room temperature until complete conversion is monitored by mass spectrometry. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC to give (S)-(10-chloro-2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide.

[0735] MS(ESI):[M+H] + =444;

[0736] 1H NMR(600MHz,Methanol-d4)δ8.84-8.77(m,1H),7.98(s,1H),7.40(dd,J=8.6,4.0Hz,1H),4 .47(s,1H),3.60(dd,J=12.4,3.9Hz,1H),3.36(t,J=5.9Hz,3H),3.25-3.19(m,1H),3.10(d dd,J=13.2,10.5,3.5Hz,1H),2.90-2.79(m,2H),2.34-2.28(m,1H),2.20-2.11(m,2H),2.0 9(s,3H),2.08(s,1H),2.07(s,3H),1.97-1.90(m,1H),1.82(dtd,J=13.7,10.1,3.7Hz,1H).

[0737] Example 118: Compound A317

[0738] Step 118-1:

[0739]

[0740] Dissolve 2-bromo-4-chloroaniline (4g) in concentrated hydrochloric acid (20mL), cool to 0°C, and slowly drip sodium nitrite aqueous solution (2.08g sodium nitrite, 5mL water). One hour later, slowly drip stannous chloride (9.5g) in concentrated hydrochloric acid (20mL). After TLC monitoring of the reaction is complete, slowly drip 12M sodium hydroxide aqueous solution until pH = 10. After filtration through diatomaceous earth, the filtrate is extracted with ethyl acetate (100mL×2). After combining the organic phases, the combined organic phases are washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After spin drying and concentration, a brown solid (2-bromo-4-chlorophenyl) hydrazine (3.46g) is obtained. MS (ESI): [M+H] + =221. Step 118-2:

[0741]

[0742] Dissolve (2-bromo-4-chlorophenyl)hydrazine (1.6 g) and cycloheptanone (815 mg) in acetic acid (30 mL), heat at 145 ° C and seal overnight. After cooling to room temperature, the reaction solution is concentrated in vacuo using a rotary evaporator, slowly added with saturated sodium bicarbonate solution at 0 ° C for neutralization, and extracted with ethyl acetate (50 mL × 3), and the organic phases are combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After concentration, the residue is purified by flash column chromatography (silica gel, petroleum ether) to obtain 4-bromo-2-chloro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (900 mg, light yellow solid).

[0743] 1 H NMR(400MHz,Chloroform-d)δ7.86(s,1H),7.37(d,J=1.7Hz,1H),7.22(d,J=1.7Hz,1H),2. 86(t,J=6.2Hz,2H),2.73(t,J=5.3Hz,2H),1.89(tq,J=6.4,2.0Hz,2H),1.81-1.73(m,4H).

[0744] 13 C NMR (101MHz, CDCl3) δ139.91,131.46,130.74,124.94,122.54,116.68,115.03,103.70,31.59,29.53,28.45,27.22,24.83.

[0745] Step 118-3:

[0746]

[0747] 4-Bromo-2-chloro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (900 mg) was dissolved in anhydrous tetrahydrofuran (20 mL) under argon protection, cooled to 0°C, and 60% sodium hydride (242 mg) was slowly added. After half an hour, 2-(trimethylsilyl)ethoxymethyl chloride (1.07 mL) was added dropwise and stirred at room temperature overnight. After TLC detection, saturated ammonium chloride solution was added dropwise at 0°C to quench the reaction. After removing tetrahydrofuran from the solution by rotary evaporator, ethyl acetate (30 mL×3) was added for extraction, and the organic phases were combined and washed with saturated sodium chloride solution. The organic phase was then dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=200:1) to give 4-bromo-2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (1.18 g, light yellow oily liquid).

[0748] 1 H NMR(400MHz,Chloroform-d)δ7.37(d,J=1.9Hz,1H),7.29(d,J=2.0Hz,1H),5.88(s,2H),3.51(t,J=8.2Hz,2H),2.90(t, J=5.7Hz,2H),2.73(t,J=5.7Hz,2H),1.93-1.87(m,2H),1.81-1.72(m,4H),0.87(t,J=8.3Hz,2H),-0.04--0.06(m,9H).

[0749] 13 C NMR (101MHz, CDCl3) δ144.44,133.79,132.41,127.42,126.58,118.10,118.07, 117.17,104.83,72.63,66.09,32.69,29.21,28.09,27.74,25.34,19.52,-0.00.

[0750] Step 118-4:

[0751]

[0752] 4-Bromo-2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (1.12 g) was dissolved in a mixed solution of 1,4-dioxane and water (Dioxane:H2O (V / V) = 10:1, 25 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (1.19 g) was added and stirred overnight. After the reaction was completed as monitored by TLC, saturated aqueous sodium bicarbonate solution was added to quench the reaction. After removing the dioxane in the solution by a rotary evaporator, ethyl acetate (20 mL×3) was added for extraction, the organic phases were combined, and the combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate, spin-dried, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to give 4-bromo-2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (724 mg, yellow solid).

[0753] 1 H NMR(400MHz,Chloroform-d)δ8.46(d,J=2.0Hz,1H),7.43(d,J=2.1Hz,1H),5.95(s,2H),3.61(t, 2H),3.15(t,2H),2.80(t,2H),2.07-2.02(m,2H),1.96-1.90(m,2H),0.90(t,2H),-0.04(s,9H).

[0754] 13 C NMR (101MHz, CDCl3) δ199.18,152.91,133.14,132.05,130.09,129.88,122. 44,117.59,104.57,73.11,66.83,44.62,27.12,26.18,23.07,19.52,0.00.

[0755] Step 118-5:

[0756]

[0757] 4-Bromo-2-chloro-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (100 mg) was dissolved in anhydrous toluene (2 ml), cooled to 0°C, and ethyl formate (55 μL) and 1 mol / L potassium tert-butoxide tetrahydrofuran solution (680 μL, 0.68 mmol) were added. After TLC monitoring, saturated aqueous ammonium chloride solution () was added to quench the reaction, ethyl methyl acetate was added for extraction, the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried to obtain 4-bromo-2-chloro-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one crude product, which was directly used in the next step reaction.

[0758] The crude 4-bromo-2-chloro-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one was dissolved in anhydrous ethanol (1 mL), morpholine (200 μL) was added, and the temperature was raised to 90°C. After one hour, the reaction was cooled to room temperature, and crude (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester (1.14 mmol) and sodium methoxide (61.3 mg) were added. The temperature was raised to 90°C for overnight reaction. After the reaction was completed as monitored by mass spectrometry, the ethanol was dried and water (10 mL) and ethyl acetate (10 mL×3) were added for extraction. The organic phases were combined, dried and then dried. The residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=4:1) to give (S)-tert-butyl 3-((9-bromo-11-chloro-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (45 mg).

[0759] MS(ESI):[M+H] + =676.

[0760] Step 118-6:

[0761]

[0762] (S)-3-((9-bromo-11-chloro-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (35 mg), palladium acetate (3.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (18 mg) and potassium phosphate (33 mg) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (12 mg) in N,N-dimethylformamide (500 μL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and spin-dried. The residue was then filtered to obtain crude tert-butyl ((S)-3-((11-chloro-9-(dimethylphosphoryl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidinyl[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate. MS (ESI): [M+H] + =674.

[0763] Step 118-7:

[0764]

[0765] To the crude product of (S)-3-((11-chloro-9-(dimethylphosphoryl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester, add dioxane hydrochloride solution (4 mol / L, 3 mL), heat to 60°C for 20 minutes, remove the solvent by rotary evaporator, redissolve the residue in anhydrous tetrahydrofuran (4 mL), and add ethylenediamine (400 μL) dropwise. Reaction at room temperature until complete conversion is monitored by mass spectrometry. The solvent was removed on a rotary evaporator and the residue was purified by preparative HPLC to give ((S)-(11-chloro-2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide.

[0766] MS(ESI):[M+H] + =444;

[0767] 1H NMR (600MHz, Methanol-d4) δ8.82(s,1H),7.99(s,1H),7.52(dd,J=13.2,2.0Hz,1H),4.49(s,1H),3.56(dd ,J=12.5,3.9Hz,1H),3.40-3.37(m,2H),3.36(d,J=5.9Hz,1H),3.28(d,J=5.9Hz,1H),3.12(ddd,J=13.2,1 0.1,3.6Hz,1H),2.88(dd,J=15.2,8.8Hz,1H),2.77(dd,J=15.2,9.7Hz,1H),2.36(d,J=13.5Hz,1H),2.24- 2.13(m,2H),2.09-2.00(m,2H),1.94(d,J=5.0Hz,3H),1.92(d,J=5.0Hz,3H),1.87(qd,J=9.9,5.1Hz,1H).

[0768] Example 119: Compound A318

[0769] Step 119-1:

[0770]

[0771] Dissolve 2-bromo-4-fluoroaniline (4g) in concentrated hydrochloric acid (20mL), cool to 0°C, and slowly drip sodium nitrite aqueous solution (2.08g sodium nitrite, 5mL water). One hour later, slowly drip stannous chloride (9.5g) in concentrated hydrochloric acid (20mL). After TLC monitoring of the reaction is complete, slowly drip 12M sodium hydroxide aqueous solution until pH = 10. After filtration through diatomaceous earth, the filtrate is extracted with ethyl acetate (100mL×2). After combining the organic phases, the combined organic phases are washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After spin drying and concentration, a brown solid (2-bromo-4-chlorophenyl) hydrazine (3.07g) is obtained.

[0772] 1 H NMR (400MHz, Chloroform-d) δ7.19 (ddd, J=7.8, 2.7, 0.8Hz, 1H), 7.10 (ddd, J=9.0, 5.2, 1.1Hz, 1H), 7.03-6.97 (m, 1H), 5.56 (s, 1H), 3.61 (s, 2H).

[0773] 13C NMR (101 MHz, CDCl3) δ 156.84, 154.45, 144.25, 119.45, 119.19, 115.12, 114.91, 113.00, 112.93, 107.15, 107.05. Step 119-2:

[0774]

[0775] Dissolve (2-bromo-4-fluorophenyl)hydrazine (1.5 g, 7.32 mmol) and cycloheptanone (820 mg) in acetic acid (30 mL), heat at 145 ° C and seal overnight. After cooling to room temperature, the reaction solution was concentrated in vacuo using a rotary evaporator, slowly added with saturated sodium bicarbonate solution at 0 ° C for neutralization, and extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether) to obtain 4-bromo-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (1.11 g, light yellow solid).

[0776] 1 H NMR(400MHz,Chloroform-d)δ7.81(s,1H),7.07(dd,J=9.5,2.3Hz,1H),7.03(dd,J=8.8,2.2Hz,1H),2.88-2 .83(m,2H),2.76-2.68(m,2H),1.90(dddd,J=11.0,6.2,4.8,2.3Hz,2H),1.77(ddt,J=14.1,9.2,3.3Hz,4H).

[0777] Step 119-3:

[0778]

[0779] 4-Bromo-2-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (1.11 g) was dissolved in anhydrous tetrahydrofuran (30 mL) under argon protection, cooled to 0°C, and 60% sodium hydride (315 mg) was slowly added. After half an hour, 2-(trimethylsilyl)ethoxymethyl chloride (1.4 mL) was added dropwise and stirred at room temperature overnight. After TLC detection, saturated ammonium chloride solution was added dropwise at 0°C to quench the reaction. After removing tetrahydrofuran from the solution by rotary evaporator, ethyl acetate (30 mL×3) was added for extraction, and the organic phases were combined and washed with saturated sodium chloride solution. The organic phase was then dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=400:1) to give 4-bromo-2-fluoro-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (1.59 g, light yellow oily liquid).

[0780] Step 119-4:

[0781]

[0782] 4-Bromo-2-fluoro-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (1.59 g) was dissolved in a mixed solution of 1,4-dioxane and water (Dioxane:H2O (V / V) = 10:1, 30 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (1.75 g) was added and stirred overnight. After the reaction was completed as monitored by TLC, a saturated aqueous sodium bicarbonate solution was added to quench the reaction. The dioxane in the solution was removed by a rotary evaporator, and then ethyl acetate (20 mL×3) was added for extraction. The organic phases were combined, and the combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate. The residue was then purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to give 4-bromo-2-fluoro-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (1.25 g, light yellow solid).

[0783] Step 119-5:

[0784]

[0785] 4-Bromo-2-fluoro-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (200 mg) was dissolved in anhydrous toluene (4 ml), cooled to 0°C, and ethyl formate (113 μL) and 1 mol / L potassium tert-butoxide tetrahydrofuran solution (1.41 mL, 1.41 mmol) were added. After the reaction was completed by TLC monitoring, saturated aqueous ammonium chloride solution () was added to quench the reaction, ethyl methyl acetate was added for extraction, the organic phases were combined, the combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product of 4-bromo-2-fluoro-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one, which was directly used in the next step.

[0786] The crude 4-bromo-2-fluoro-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one was dissolved in anhydrous ethanol (1 mL), morpholine (4.7 mmol) was added, and the temperature was raised to 90°C. After one hour, the reaction was cooled to room temperature, and crude (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester (2.35 mmol) and sodium methoxide (127 mg) were added. The temperature was raised to 90°C for overnight reaction. After the reaction was completed as monitored by mass spectrometry, the ethanol was dried and extracted with water (10 mL) and ethyl acetate (10 mL×3). The organic phases were combined, dried and then dried. The residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=4:1) to give (S)-tert-butyl 3-((9-bromo-11-fluoro-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate (160 mg).

[0787] MS(ESI):[M+H] + =660.

[0788] Step 119-6:

[0789]

[0790] (S)-3-((9-fluoro-11-chloro-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (73 mg), palladium acetate (7.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (38.4 mg) and potassium phosphate (70.4 mg, 0.332 mmol) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (25.8 mg) in N,N-dimethylformamide (1.1 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and spin-dried. The residue was then filtered to obtain crude tert-butyl ((S)-3-((11-fluoro-9-(dimethylphosphoryl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidinyl[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylate. MS (ESI): [M+H] + =658.

[0791] Step 119-7:

[0792]

[0793] To the crude product of (S)-3-((11-fluoro-9-(dimethylphosphoryl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester, add dioxane hydrochloride solution (4 mol / L, 3 mL), heat to 60°C for 20 minutes, remove the solvent by rotary evaporator, redissolve the residue in anhydrous tetrahydrofuran (4 mL), and add ethylenediamine (400 μL) dropwise. Reaction at room temperature until complete conversion is monitored by mass spectrometry. The solvent was removed by rotary evaporation and the residue was purified by preparative HPLC to give ((S)-(11-fluoro-2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide (Compound A318). MS (ESI): [M+H] + =428; 1H NMR (600MHz, Methanol-d4) δ8.48 (s, 1H), 7.97 (s, 1H), 7.33 (ddd, J = 13.5, 8.7, 2.5Hz, 1H), 4.50 (s, 1 H),3.63-3.60(m,1H),3.44-3.38(m,2H),3.37-3.34(m,1H),3.29-3.24(m,1H),3.14-3.08(m,1H),2 .88(dd,J=15.2,8.8Hz,1H),2.78(dd,J=15.3,9.8Hz,1H),2.41-2.36(m,1H),2.22-2.11(m,2H),2.0 8-1.98(m,2H),1.95(d,J=13.6Hz,3H),1.92(d,J=13.6Hz,3H),1.82(dtd,J=13.8,10.4,3.9Hz,1H).

[0794] Example 120: Compound A319

[0795] Step 120-1:

[0796]

[0797] Dissolve the crude product of 4-bromo-2-fluoro-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (1.41 mmol) in anhydrous ethanol (7 mL), add morpholine (14.1 mmol), and heat to 90°C. After one hour, cool the reaction to room temperature, add guanidine hydrochloride (7.05 mmol) and sodium methoxide (7.05 mmol). Heat to 90°C and react overnight. After the reaction was complete, the ethanol was dried by mass spectrometry, and water (30 mL) and ethyl acetate (30 mL × 3) were added for extraction. The organic phases were combined, dried, and then dried by spin drying. The residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) to obtain 9-bromo-11-fluoro-8-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-amine (1.05 mmol). MS (ESI): [M+H] + =477.

[0798] Step 120-2:

[0799]

[0800] After dissolving 9-bromo-11-fluoro-8-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-amine (250 mg) in 5 mL of anhydrous dichloromethane and 288 μL of anhydrous N,N-dimethylformamide, trimethylchlorosilane (267 μ), tetrabutylammonium chloride (144 mg) and tert-butyl nitrite (187 μL) were added in sequence. The temperature was then raised to 50°C until the reaction was complete as monitored by TLC. Water (10 mL) and dichloromethane (10 mL×3) were added to the solution for extraction. The organic phases were combined, dried and then spin-dried. The residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=8:1) to give a light yellow solid 9-bromo-2-chloro-11-fluoro-8-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4′,5′:3,4]cyclohepta[1,2-b]indole (72 mg).

[0801] MS(ESI):[M+H] + =496.

[0802] 1 H NMR(400MHz,Chloroform-d)δ8.57(dd,J=10.0,2.6Hz,1H),8.27(s,1H),7.28(dd,J=8.5,2.6Hz,1H),5.96(s,2H),3 .66(t,2H),3.30(t,J=6.6Hz,2H),2.84-2.78(m,2H),2.19(dt,J=10.5,6.4Hz,2H),0.98-0.92(m,2H),-0.01(s,9H). 13 C NMR (101MHz, CDCl3) δ162.74,159.16,158.68,157.72,156.77,147.55,130.62,130.55,130.30,130.19,117.5 9,117.31,112.02,111.98,108.23,107.98,102.39,102.27,71.66,65.30,29.68,29.03,24.03,18.15,-1.41.

[0803] Step 120-3:

[0804]

[0805] 9-Bromo-2-chloro-11-fluoro-8-(2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indole (70 mg) and crude (S)-6,6-dimethylpiperidin-3-amine hydrochloride (0.934 mmol) were dissolved in N-methylpyrrolidone (1 mL), and N,N-diisopropylethylamine (200 μL) was added and microwaved at 200° C. for one hour. Saturated aqueous ammonium chloride solution (10 mL) and ethyl acetate (10 mL×3) were then added for extraction, and the organic phases were combined and washed with saturated ammonium chloride solution 3 times and saturated sodium chloride solution once, respectively. The organic phase was dried and then spin-dried, and the residue was purified by flash column chromatography (silica gel, dichloromethane: methanol = 10:1) to obtain a crude product of (S)-9-bromo-N-(6,6-dimethylpiperidin-3-yl)-11-fluoro-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-2-amine. MS (ESI): [M+H] + =458.

[0806] Step 120-4:

[0807]

[0808] The above crude product of ((S)-9-bromo-N-(6,6-dimethylpiperidin-3-yl)-11-fluoro-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-2-amine (17 mg), palladium acetate (2.5 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (13 mg) and potassium phosphate (23.7 mg) were added to a microwave tube, and the argon gas was replaced three times, and then deoxygenated N,N-dimethylphosphine (8.7 mg) was added. Formamide solution (400 μL). Under microwave conditions at 145°C, react for 45 minutes until the reaction is complete as monitored by mass spectrometry. The reaction solution was filtered through diatomaceous earth, the solvent was removed by rotary evaporator, and the residue was purified by preparative HPLC. (S)-(2-((6,6-dimethylpiperidin-3-yl)amino)-11-fluoro-5,6,7,8-tetrahydropyrimido[4',5':3,4]cycloheptyl[1,2-b]indol-9-yl)dimethylphosphine oxide was obtained. MS (ESI): [M+H] + =456.

[0809] 1H NMR (600MHz, Methanol-d4) δ8.50 (s, 1H), 7.98 (s, 1H), 7.34 (ddd, J = 13.6, 8.7, 2.5 Hz,1H),4.49(s,1H),3.54-3.49(m,1H),3.39(dt,J=12.5,5.9Hz,3H),2.89(dd,J= 15.3,8.9Hz,1H),2.79(dd,J=15.3,9.7Hz,1H),2.31(s,1H),2.20(dd,J=14.8,7.9 Hz,1H),2.00(dd,J=10.8,7.0Hz,2H),1.97-1.93(m,6H),1.91(s,2H),1.49(s,6H).

[0810] Example 121: Compound 31

[0811] Step 121-1:

[0812]

[0813] Dissolve 2-bromo-3-fluoroaniline (4g) in concentrated hydrochloric acid (20mL), cool to 0°C, and slowly drip sodium nitrite aqueous solution (2.08g sodium nitrite, 5mL water). One hour later, slowly drip stannous chloride (9.5g) in concentrated hydrochloric acid (20mL). After TLC monitoring of the reaction is complete, slowly drip 12M sodium hydroxide aqueous solution until pH = 10. After filtration through diatomaceous earth, the filtrate is extracted with ethyl acetate (100mL×2). After combining the organic phases, the combined organic phases are washed with saturated sodium chloride solution and then dried over anhydrous sodium sulfate. After spin drying and concentration, a brown solid (2-bromo-3-fluorophenyl) hydrazine (1.5g) is obtained.

[0814] Step 121-2:

[0815]

[0816] Dissolve (2-bromo-3-fluorophenyl)hydrazine (1.5 g) and cycloheptanone (820 mg) in acetic acid (30 mL), heat at 145 ° C and seal overnight. After cooling to room temperature, the reaction solution was concentrated in vacuo using a rotary evaporator, slowly added with saturated sodium bicarbonate solution at 0 ° C for neutralization, and extracted with ethyl acetate (50 mL × 3), and the organic phases were combined, washed with saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 20: 1) to obtain 4-bromo-3-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (600 mg, light yellow oily liquid).

[0817] Step 121-3:

[0818]

[0819] 4-Bromo-3-fluoro-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (600 mg) was dissolved in anhydrous N,N-dimethylformamide (10 mL) under argon protection, cooled to 0°C, and 60% sodium hydride (170 mg) was slowly added. After half an hour, 2-(trimethylsilyl)ethoxymethyl chloride (753 μL) was added dropwise and stirred at room temperature overnight. After TLC detection, saturated ammonium chloride solution was added dropwise at 0°C to quench the reaction. After removing tetrahydrofuran from the solution by rotary evaporator, ethyl acetate (30 mL×3) was added for extraction. After the organic phases were combined, they were washed with water and saturated sodium chloride solution in turn. The organic phase was then dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography (silica gel, petroleum ether) to give 4-bromo-3-fluoro-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (660 mg, light yellow oily liquid).

[0820] Step 121-4:

[0821]

[0822] 4-Bromo-3-fluoro-5-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (660 mg) was dissolved in a mixed solution of 1,4-dioxane and water (Dioxane:H2O (V / V) = 10:1, 15 mL), and then 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (727 mg) was added and stirred overnight. After the reaction was completed as monitored by TLC, saturated aqueous sodium bicarbonate solution was added to quench the reaction. After removing the dioxane in the solution by a rotary evaporator, ethyl acetate (20 mL×3) was added for extraction, the organic phases were combined, and the combined organic phases were easily washed with saturated sodium chloride and dried over anhydrous sodium sulfate, spin-dried, and then the residue was purified by flash column chromatography (silica gel, petroleum ether: ethyl acetate = 12:1) to give 4-bromo-3-fluoro-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (430 mg, brown solid).

[0823] Step 121-5:

[0824]

[0825] 4-Bromo-3-fluoro-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one (200 mg, 0.47 mmol) was dissolved in anhydrous toluene (4 ml), cooled to 0°C, and ethyl formate (113 μL) and 1 mol / L potassium tert-butoxide tetrahydrofuran solution (1.41 mL, 1.41 mmol) were added. After the reaction was completed as monitored by TLC, a saturated aqueous ammonium chloride solution was added to quench the reaction, ethyl methyl acetate was added to extract, the organic phases were combined, the combined organic phases were washed with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate, and spin-dried to obtain a crude product of 4-bromo-3-fluoro-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one, which was directly used in the next step.

[0826] The above crude 4-bromo-3-fluoro-9-(hydroxymethylene)-5-((2-(trimethylsilyl)ethoxy)methyl)-6,7,8,9-tetrahydrocyclohepta[b]indol-10(5H)-one was dissolved in anhydrous ethanol (2 mL), morpholine (4.69 mmol) was added, and the temperature was raised to 90°C. After one hour, the reaction was cooled to room temperature, and crude (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester (2.35 mmol) and sodium methoxide (127 mg) were added. The temperature was raised to 90°C for overnight reaction. After the reaction was complete, the ethanol was dried by mass spectrometry, and water (10 mL) and ethyl acetate (10 mL×3) were added for extraction. The organic phases were combined, dried, and then dried by spin drying. The residue was purified by flash column chromatography (silica gel, petroleum ether:ethyl acetate=4:1) to obtain (S)-3-((9-bromo-10-fluoro-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (92 mg). MS (ESI): [M+H] + =660.

[0827] Step 121-6:

[0828]

[0829] (S)-3-((9-bromo-10-fluoro-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7-8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (66 mg), palladium acetate (6.7 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (34.7 mg) and potassium phosphate (63.6 mg) were added to a microwave tube, and after replacing argon three times, a solution of deoxygenated dimethylphosphine (23.4 mg) in N,N-dimethylformamide (1 mL) was added. The reaction was carried out at 145°C microwave conditions for 45 minutes until the reaction was complete as monitored by mass spectrometry. Saturated aqueous sodium bicarbonate solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL×3), dried over anhydrous sodium sulfate, and spin-dried. The residue was then filtered to obtain crude (S)-3-((10-fluoro-9-(dimethylphosphoryl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidinyl[4′,5′:3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester. MS (ESI): [M+H] + =658. Step 121-7:

[0830]

[0831] To the crude product of (S)-3-((10-fluoro-9-(dimethylphosphoryl)-8-((2-(trimethylsilyl)ethoxy)methyl)-5,6,7,8-tetrahydropyrimidinyl[4',5':3,4]cycloheptyl[1,2-b]indol-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester, add dioxane hydrochloride solution (4 mol / L, 3 mL), heat to 60°C for 20 minutes, remove the solvent by rotary evaporator, redissolve the residue in anhydrous tetrahydrofuran (4 mL), and add ethylenediamine (400 μL) dropwise. Reaction at room temperature until complete conversion is monitored by mass spectrometry. The solvent was removed by rotary evaporation and the residue was purified by preparative HPLC to give (S)-(10-fluoro-2-(piperidin-3-ylamino)-5,6,7,8-tetrahydropyrimido[4',5':3,4]cyclohepta[1,2-b]indol-9-yl)dimethylphosphine oxide. MS (ESI): [M+H] + =428. 1H NMR (400MHz, Methanol-d4) δ8.87 (t, J = 8.1 Hz, 1H), 8.00 (s, 1H), 7.17 (td, J = 9. 8,4.5Hz,1H),4.49(s,1H),3.65-3.59(m,1H),3.39(t,J=5.4,4.4Hz,2H),3.29 -3.20(m,2H),3.17-3.10(m,1H),2.91-2.80(m,2H),2.39-2.29(m,1H),2.14(d dq,J=20.9,13.5,7.7,6.8Hz,3H),1.99(s,3H),1.96(s,3H),1.91-1.79(m,2H).

[0832] Example 122: Compound A320

[0833]

[0834] Take 1.5g2-amino-4-bromopyridine and 1.8g cycloheptanone, 47mg reducing iron powder, 213mg elemental iodine solid, and 20mL acetic acid treated with oxygen bubbling for 30 minutes, so that the entire reaction system is in an oxygen atmosphere, stir for 10 minutes to mix the system, then heat the system to 140 degrees Celsius, reflux for 8-10 hours, and detect the reaction system by TLC and 254nm fluorescence. After the reaction is completed, the system is cooled to room temperature, and the system is a dark brown liquid with black solid suspension. Remove all acetic acid as much as possible with rotary evaporation, then add EA (ethyl acetate) and saturated sodium bicarbonate aqueous solution for extraction, extract with EA three times, wash with saturated sodium chloride solution, add anhydrous sodium sulfate drying, and finally concentrate with rotary evaporation. Purify using column chromatography, the eluent is petroleum ether: ethyl acetate with a volume ratio of 5: 1. Obtain compound b, beige solid 1.2g, yield 52%. Compound b characterization data: MS (ESI): [M+H] + =279. 1 H NMR(400MHz,Chloroform-d)δ9.56(d,J=7.4Hz,1H),7.82(dd,J=7.0,2.0Hz,1H), 7.12(t,J=7.3Hz,1H), 3.02(t,J=6.9Hz,2H), 2.80(t,J=7.0Hz,2H), 1.77(m,4H).

[0835] Take 1.0g of compound b, after anhydrous and oxygen-free treatment, add 10mL of tetrahydrofuran. After waiting for the solid to dissolve completely, place it in an ice-water bath, add 0.8g of ethyl formate to the system, then add 0.28g (7.0mmol) of sodium hydride (60% content) to the system, wait for the system to produce no bubbles, take the system out of the ice bath, warm it to 80 degrees Celsius, reflux for 1 hour, and detect the reaction system by TLC and 254nm fluorescence. After the reaction is complete, add saturated ammonium chloride solution to the system to quench, and then remove tetrahydrofuran by rotary evaporation. Extract with EA three times, wash with saturated sodium chloride solution, add anhydrous sodium sulfate to dry, and finally concentrate with rotary evaporation. This step does not use column chromatography for purification. Compound c is obtained as a creamy yellow solid of 920mg. Characterization data of compound c: MS (ESI): [M+H] + =307.

[0836] Take 150mg of compound c, add 3mL of anhydrous ethanol and 0.45mL of morpholine after anhydrous and oxygen-free operation, reflux at 100 degrees Celsius, and detect the reaction system by TLC and 254nm fluorescence. After the reaction is complete, stop heating and restore the system to room temperature, and add 135mg of sodium methoxide and 2mL of previously configured guanidine (2.5mmol) ethanol solution in sequence. Then resume heating to 100 degrees Celsius for reflux reaction for 12 hours. After the reaction is completed, remove all the ethanol by rotary evaporation, then add 10mL of water into the system, extract three times with EA (ethyl acetate), wash with saturated sodium chloride solution, add anhydrous sodium sulfate to dry, and finally concentrate with rotary evaporation. Purify by column chromatography, the eluent is petroleum ether: ethyl acetate (V / V) = 1:1, and obtain compound d. Characterization data of compound d: MS (ESI): [M+H] + =513.

[0837] Synthesis of compound e: 0.2mmol of compound d was added to a dry microwave reaction tube, followed by 0.04mmol of palladium acetate, 0.08mmol of 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (Xantphos), 0.6mmol of dimethylphosphine oxide and 0.6mmol of potassium phosphate, followed by anhydrous and oxygen-free operation, the microwave reaction tube was filled with argon, and then an appropriate amount of argon-bubbled deoxygenated N,N-dimethylformamide (DMF) was added to make the concentration of compound d about 0.1M. Then the lid of the microwave tube was covered, and the reaction temperature was set to 135 degrees Celsius with a microwave reactor, and the reaction time was 1 hour. After the microwave reaction was completed, the reaction was detected by a mass spectrometer to determine whether the reaction was complete. After the reaction was completed, a saturated sodium bicarbonate aqueous solution was added to the system, extracted three times with EA, washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate, and finally concentrated by rotary evaporation. The crude product was filtered using diatomaceous earth, eluted with ethyl acetate, and purified by column chromatography to obtain the intermediate (compound e) without removing the Boc protecting group. MS (ESI): [M+H] + =511;

[0838] The above intermediate (Compound e) was dissolved in 1 mol / L hydrochloric acid-dioxane solution, reacted at room temperature for 15 minutes, and dissolved under reduced pressure to obtain the target compound A320. Characterization data of Compound A320: MS (ESI): [M+H] + =411.

[0839] Example 123: Compound A321

[0840]

[0841] The preparation of compound A321 refers to the synthesis method of Example 87, except that (S)-3-guanidinopiperidine-1-carboxylic acid tert-butyl ester in the last step of step 87-5 is replaced with (S)-1-(6,6-dimethylpiperidin-3-yl)guanidine to obtain compound A321. Characterization data of compound A321: MS (ESI): [M+H] + =452; 1H NMR(600MHz,MeOD)δ8.50(d,J=7.8Hz,1H),7.94(s,1H),7.53(dd,J=13.0,7.4Hz,1H), 7.47(td,J=7.6,2.6Hz,1H),4.58(s,1H),3.61(dd,J=9.9,3.4Hz,1H),3.41-3.35(m,1 H),2.94(s,2H),2.28-2.21(m,1H),2.04-2.00(m,1H),2.00-1.96(m,1H),1.95(s,3H) ,1.92(s,3H),1.92-1.89(m,1H),1.51(s,3H),1.49(s,3H),1.47(s,3H),1.46(s,3H).

[0842] Example 124: Biological Activity Test

[0843] 1. CDK7 inhibition IC50 and inhibition of human colon cancer HCT116 proliferation IC50 test

[0844] The compounds in Table 10 were taken respectively, and the CDK7 inhibition IC50 and the inhibition of human colon cancer HCT116 proliferation IC50 tests were performed according to the biological activity test in Example 114. The results are shown in Table 10.

[0845] Table 10:

[0846] Compound CDK7 inhibition IC50 Inhibits proliferation of human colon cancer HCT116 IC50 (nM) Compound A314 A A Compound A315 A A Compound A316 A 15.8 Compound A317 A 109.2 Compound A318 A 10.7 Compound A319 A 8 Compound 31 A 3.2 Compound A320 B B Compound A321 A 52.7

[0847] A: IC50 is not greater than 200nM; B: IC50 is greater than 200nM, but not greater than 2000nM; C: IC50 is greater than 2μM, but not greater than 10μM; D is greater than 10μM

[0848] 2. IC50 test of compounds on CDK1, CDK2, CDK6, CDK7, CDK9

[0849] 2.1. CDK1 inhibitory activity test method:

[0850] Diluent: It consists of an aqueous solution containing 60 mM MES (pH 8.0), 0.012% Tween 20, 0.06 mg / mL BSA and 6 mM MgCl2.

[0851] Experimental method: In a 384-well reaction plate, a blank control group, a test group and a positive drug control group were set up respectively, wherein the blank control group was added with 2 μL of diluent, the test group was added with 2 μL of the test compound diluted with diluent, and the positive control group was added with 2 μL of staurosporine diluted with diluent, and then all groups were added with 5 μL of CDK1 / CyclinA2 enzyme solution (Promega Company), incubated for 30 minutes, and 5 μL of CDK7tide / ATP substrate mixture (Beijing Zhongke Yaguang Biotechnology Co., Ltd.) was added, incubated at room temperature for 110 minutes, and 4 μL of 150mM ethylenediaminetetraacetic acid was added to terminate the reaction, and the plate was read on the EZreader II instrument. IC50 was calculated by GraphPad Prism 8 software.

[0852] 2.2. CDK2 inhibitory activity test method:

[0853] Diluent: It consists of an aqueous solution containing 24 mM MES (pH 6.75), 0.012% Tween 20, 0.06 mg / mL BSA and 2.4 mM MgCl2.

[0854] Experimental method: In a 384-well reaction plate, a blank control group, a test group and a positive drug control group were set up respectively, wherein 2 μL of diluent was added to the blank control group, 2 μL of the test compound diluted with diluent was added to the test group, and 2 μL of staurosporine diluted with diluent was added to the positive control group. Then, 5 μL of CDK2 / CyclinE1 enzyme solution (Promega) was added to all groups, incubated for 30 min, 5 μL of CDK7tide / ATP substrate mixture (Beijing Zhongke Yaguang Biotechnology Co., Ltd.) was added, incubated at room temperature for 110 min, 4 μL of 150 mM ethylenediaminetetraacetic acid was added to terminate the reaction, and the plate was read on an EZreader II instrument. IC50 was calculated using GraphPad Prism 8 software.

[0855] 2.3. CDK6 inhibitory activity test method:

[0856] Diluent: It consists of an aqueous solution containing 24 mM MES (pH 6.75), 0.012% Tween 20, 0.06 mg / mL BSA and 2.4 mM MgCl2.

[0857] Experimental method: In a 384-well reaction plate, a blank control group, a test group and a positive drug control group were set up respectively, wherein 2 μL of diluent was added to the blank control group, 2 μL of the test compound diluted with diluent was added to the test group, and 2 μL of staurosporine diluted with diluent was added to the positive control group. Then, 5 μL of CDK6 / CyclinD3 enzyme solution (Promega) was added to all groups, incubated for 30 min, 5 μL of CDK7tide / ATP substrate mixture (Beijing Zhongke Yaguang Biotechnology Co., Ltd.) was added, incubated at room temperature for 110 min, 4 μL of 150 mM ethylenediaminetetraacetic acid was added to terminate the reaction, and the plate was read on an EZreader II instrument. IC50 was calculated using GraphPad Prism 8 software.

[0858] 2.4. CDK9 inhibitory activity test method:

[0859] Diluent: It consists of an aqueous solution containing 24 mM MES (pH 6.75), 0.012% Tween 20, 0.06 mg / mL BSA and 12 mM MgCl2.

[0860] Experimental method: In a 384-well reaction plate, a blank control group, a test group and a positive drug control group were set up respectively, wherein the blank control group was added with 2 μL of diluent, the test group was added with 2 μL of the test compound diluted with diluent, and the positive control group was added with 2 μL of staurosporine diluted with diluent, and then all groups were added with 5 μL of CDK9 / CyclinT1 enzyme solution (Promega Company), incubated for 30 minutes, and 5 μL of CDK9tide / ATP substrate mixture (Beijing Zhongke Yaguang Biotechnology Co., Ltd.) was added, incubated at room temperature for 110 minutes, and 4 μL of 150mM ethylenediaminetetraacetic acid was added to terminate the reaction, and the plate was read on the EZreader II instrument. IC50 was calculated by GraphPad Prism 8 software.

[0861] The activity results are shown in Table 11 below.

[0862] Table 11:

[0863]

[0864] The activity results indicate that the compounds of the present invention have significant selective inhibitory activity against CDK7.

[0865] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A compound, characterized in that The compound is selected from the compound of formula (I) or a deuterated compound thereof or a pharmaceutically acceptable salt thereof or a solvate thereof or a hydrate thereof or a prodrug thereof or an optical isomer thereof or an atropisomer thereof, in, is a single bond or a double bond; X is selected from -(CH2) n1 -、-(CH2) n1 O-, -(CH2) n2 C(R 5a )(R 5b )(CH2) n3 - or -CH=CH-; L is -NH- or -NH(CH2) n4 -; Preferably, L is -NH-; n1 is 1, 2, 3 or 4; preferably, n1 is 2; n2 is 0, 1, 2 or 3; preferably, n2 is 0, 1 or 2; n3 is 0, 1, 2 or 3; preferably, n3 is 0 or 1; n4 is 1, 2, 3, 4, 5 or 6; R 5a , R 5b are each independently selected from H, halogen, substituted or unsubstituted C 1- C6 alkyl, substituted or substituted C 2- C6 alkene, substituted or unsubstituted C 2- C6 alkynyl, or R 5a , R 5b Together with the carbon atoms adjacent to them, they form a C3-C6 cycloalkyl group; R1 is selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 4-12 membered heterocyclyl, substituted or unsubstituted 5-9 membered heterobridged cycloalkyl, substituted or unsubstituted 5-9 membered bridged cycloalkyl, substituted or unsubstituted 6-10 membered heterospirocycloalkyl, substituted or unsubstituted 6-10 membered spirocycloalkyl, substituted or unsubstituted 6-10 membered heteroparacycloalkyl, substituted or unsubstituted 6-10 membered paracycloalkyl, substituted or unsubstituted 5-10 membered heteroaryl, substituted or unsubstituted C6-C 10 Aryl; Y is selected from CH, NR6, N, O or S; R6 is selected from hydrogen, amino, -C(=O)-(C1-C6 alkyl), -C(=O)-O-(C1-C6 alkyl), C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, -C(=O)-NR 7a R 7b ; Optionally, the 3-8 membered heterocycloalkyl group containing 1, 2 or 3 heteroatoms independently selected from N, O and S in R6 contains 1-7 carbon atoms in the ring; R 7a , R 7b Each independently selected from hydrogen or C1-C6 alkyl; Z1 and Z2 are each independently selected from C or N; Z3 is selected from N or C(R8); Z4 is selected from N or C(R9); R9 is selected from H or halogen; R8, R 10 , R 10 'are each independently selected from H, F, Cl, Br, I, cyano, or substituted or unsubstituted C1-C6 alkyl, halogenated C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C1-C6 heteroalkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyloxy, halogenated C3-C6 cycloalkyl, C6-C 10 aryl, 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, 3-8 membered heterocyclyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, 3-8 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, -NR 11 -C(=O)-O-(C1-C6 alkyl), -OC(=O)-R 12 , -C(=O)-R 12 , R 11 , R 12 , R 13 , R 13 '、R 14 , R 14 '、R 15 , R 15 '、R 16 , R 16 'are independently selected from: hydrogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 heteroalkyl containing 1, 2 or 3 independently selected from N, O, S, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C1-C6 alkylamino, C3-C6 cycloalkylamino, substituted or unsubstituted 3-8 membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O, S, C6-C 10 Aryl, 5-10 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; or R 13 , R 13 'Connected to their adjacent P to form a 4-6 membered ring; or R 12 , R 16 ' are independently selected from methyl, ethyl, cyclopropyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S; or R 16 is methyl; Optionally, R8, R 10 , R 10 The 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1 to 7 carbon atoms in the ring; optionally, R8, R 10 , R 10 'The 3-8 membered heterocycloalkyl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1 to 7 carbon atoms in the ring; Optionally, R 11 , R 12 , R 13 , R 13 '、R 14 , R 14 '、R 15 , R 15 '、R 16 , R 16 The substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S contains 1-7 carbon atoms in the ring; Optionally, the substituted or unsubstituted 4-12 membered heterocyclic group in R1 contains 1-11 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 5-9 membered heterobridged cycloalkyl in R1 contains 1-8 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 6-10 membered heterospirocycloalkyl in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 6-10 membered heterocycloalkyl in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group in R1 contains 1-9 carbon atoms and 1, 2, 3 or 4 heteroatoms or hetero groups independently selected from N, O, S, S(O) or S(O)2 in the ring; Optionally, the R 5a , R 5b In each substituted or unsubstituted, one or more hydrogen atoms are substituted independently by methyl groups; preferably, R 5a , R 5b is H or methyl; and / or Optionally, the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl, hydroxyethyl, fluorine atom, chlorine atom, bromine atom, iodine atom, C1-C6 alkyl, C2-C6 alkene group, C2-C6 alkynyl group, C3-C8 cycloalkyl, trifluoromethyl, difluoromethyl, -NH-(3-6 membered cycloalkyl) or -NH-R2; or the substitution in the substituted or unsubstituted in R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, fluorine atom, chlorine atom, hydroxymethyl, hydroxyethyl, methyl, ethyl, -CH2CH2 CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, trifluoromethyl, difluoromethyl, -NH-(3-membered cycloalkyl) or -NH-R2 are substituted; preferably, the substitution in the substituted or unsubstituted R1 is that one or more hydrogen atoms are independently replaced by hydroxyl, hydroxymethyl or methyl; and / or Optionally, R2 is selected from hydrogen, substituted or unsubstituted amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, substituted or unsubstituted -C(=O)-NR 2a R 2b ; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S in R2 contains 1-7 carbon atoms in the ring; and / or Optionally, R 2a , R 2b Each is independently selected from hydrogen or C1-C6 alkyl; and / or Optionally, R8, R 10 , R 10 The substitution in the substituted or unsubstituted 'independently represents that one or more hydrogen atoms are replaced by =O or methyl; preferably, R8 is selected from F, Cl, Br, -C(=O)-R 12 , and / or Optionally, the substitution in the substituted or unsubstituted 3-8 membered heterocyclic group in R1 is that one or more H atoms are replaced by methyl or =O.

2. The compound according to claim 1, wherein Y is N or NH; Z1 and Z2 are each independently selected from C or N; Z3 is selected from N or C(R8); Z4 is selected from C(R9); R9 is selected from H or halogen; L is -NH-; X is selected from -(CH2) n1 -or-(CH2) n2 C(R 5a )(R 5b )(CH2) n3 -; Preferably, X is selected from: -CH2-, -CH2CH2-, -CH2CH2CH2-, -(CH2)4-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH2C(CH3)2CH2-, -CF2CH2-, -CH=CH-, More preferably, X is selected from: -CH2CH2-, -C(CH3)2CH2-, -CH2C(CH3)2CH2-.

3. According to the compound according to any one of claims 1 to 2, the compound of formula (I) is selected from the group consisting of a compound of formula (II), a compound of formula (III), a compound of formula (IV), a compound of formula (V), a compound of formula (VI), a compound of formula (VII), a compound of formula (III-1), a compound of formula (IV-1), a compound of formula (V-1), a compound of formula (VI-1), a compound of formula (VI-2), a compound of formula (VI-3) or a compound of formula (VII-1), The definitions of the symbols are as described in any one of claims 1 to 3.

4. The compound according to any one of claims 1 to 3, wherein R 5a , R 5b It is H or methyl.

5. The compound according to claim 4, wherein the compound of formula (I) is selected from: ① The compound of formula (I) is selected from the compound of formula (III), in, Z3 is selected from N or C(R8); R8 is H, F, Cl, -C(=O)-CH3 or R 10 , R 10 'are each independently selected from H, cyano, methyl, F, Cl, Br, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, -C(=O)-R 12 , or R 10 ' is H, methyl, Br or chlorine atom, R 10 is selected from H, cyano, methyl, F, Cl, Br, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, -C(=O)-R 12 , Other symbols as described in any one of claims 1-3; Optionally, the substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1-7 carbon atoms in the ring; or ② The compound of formula (I) is selected from the compound of formula (VI-2), Wherein n2 is 2, R8 is selected from -C(=O)-CH3 or R 10 is selected from H, cyano, methyl, F, Cl, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, -C(=O)-R 12 , Other symbols as described in any one of claims 1-3; Optionally, the substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1-7 carbon atoms in the ring; or ③ The compound of formula (I) is selected from the compound represented by formula (II), Among them, R 10 is selected from H, cyano, methyl, F, Cl, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, -C(=O)-R 12 , Other symbols as described in any one of claims 1-3; Optionally, the substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1-7 carbon atoms in the ring; or ④ The compound of formula (I) is selected from the compound represented by formula (V), Among them, R 10 , R 10 'are each independently selected from H, cyano, methyl, fluorine atom, chlorine atom, Br, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S, -C(=O)-R 12 , or R 10 ' is H, methyl, Br or chlorine atom, R 10 is selected from H, cyano, methyl, fluorine atom, chlorine atom, trifluoromethyl, halogenated C3-C6 cycloalkyl, substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, -C(=O)-R 12 , n2 is 0 or 1, n3 is 0 or 1, and n2 and n3 are not 0 at the same time; Other symbols as described in any one of claims 1-3; Optionally, the substituted or unsubstituted 3-8 membered heterocyclic group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S contains 1-7 carbon atoms in the ring.

6. A compound according to any one of claims 1 to 5, The substituted or unsubstituted C1-C6 alkyl group in R1 is selected from the following groups: or Where p1 is 0, 1, 2 or 3; p2 is 0 or 1; p3 is 1, 2 or 3; and / or The substituted or unsubstituted C3-C8 cycloalkyl group in R1 is selected from the following groups: and / or The substituted or unsubstituted 6-10 membered spirocycloalkyl group in R1 is selected from the following groups: and / or The substituted or unsubstituted 4-12 membered heterocyclic group in R1 is selected from the following groups: R3 and R4 are each independently selected from: H, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3 and R4 are linked to form a 3-6 membered cycloalkyl; and / or The substituted or unsubstituted 5-9 membered hetero-bridged cycloalkyl group in R1 is selected from the following groups: and / or The substituted or unsubstituted 5-9 membered bridged cycloalkyl group in R1 is selected from the following groups: and / or The substituted or unsubstituted 6-10 membered heterospirocycloalkyl group in R1 is selected from the following groups: and / or The substituted or unsubstituted 6-10 membered heterocycloalkyl group in R1 is selected from the following groups: and / or R2 is independently selected from the following groups: hydrogen, substituted or unsubstituted amino, substituted or unsubstituted -C(=O)-O-(C1-C6 alkyl), substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted halogenated C1-C6 alkyl, substituted or unsubstituted C1-C6 heteroalkyl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted halogenated C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted 5-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, S, substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, substituted or unsubstituted -C(=O)-NR 2a R 2b ; Optionally, the substituted or unsubstituted 5-10 membered heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O and S in R2 contains 1 to 9 carbon atoms in the ring; Optionally, the substituted or unsubstituted 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S in R2 contains 1-7 carbon atoms in the ring; and / or Optionally, R 2a , R 2b Each is independently selected from hydrogen or C1-C6 alkyl.

7. The compound according to any one of claims 1 to 6, wherein R 10 , R 10 ' are each independently selected from: H, -CN, methyl, F, Cl, Br, or R 10 ' is H, methyl, Br or chlorine atom; R 10 Selected from H, -CN, methyl, F, Cl, Br, R8 is selected from H, F, Cl, -C(=O)-CH3 or R1 is selected from the following groups: or in, R2 is H; R3 and R4 are each independently selected from: H, halogen, cyano, C1-C6 alkyl, C2-C6 alkene, C2-C6 alkynyl, or R3 and R4 are linked to form a 3-6 membered cycloalkyl; p1 is 0, 1, 2 or 3; p2 is 0 or 1; p3 is 1, 2 or 3.

8. The compound according to any one of claims 1 to 7, wherein the compound of formula (I) is selected from:

9. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 8, and a pharmaceutically acceptable auxiliary material, diluent or carrier.

10. Use of the compound according to any one of claims 1 to 8 or the pharmaceutical composition according to claim 9 in the preparation of a drug for inhibiting CDK7 kinase activity or a drug for preventing and / or treating diseases related to increased CDK7 kinase activity; Optionally, the disease associated with increased CDK7 kinase activity includes cancer, inflammation, cardiovascular disease, infectious disease, immune disease or metabolic disease; and / or The cancer comprises breast cancer, ovarian cancer, colorectal cancer, liver cancer, lung cancer, stomach cancer, brain cancer, bile duct cancer, pancreatic cancer, cervical cancer, endometrial cancer, head and neck cancer, bladder cancer, bone cancer, intestinal cancer, kidney cancer, laryngeal cancer, lymphoma, leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia, multiple myeloma, melanoma, mesothelioma, myeloma, neuroendocrine cancer, esophageal cancer, penile cancer, prostate cancer, skin cancer, soft tissue sarcoma cancer, spinal cord cancer, testicular cancer, thyroid cancer or uterine cancer; and / or The cancer includes estrogen receptor (ER)-positive breast cancer, triple-negative breast cancer, ovarian cancer, castration-resistant prostate cancer, colorectal cancer, pancreatic cancer, liver cancer, lung cancer, or acute myeloid leukemia.

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