TWI765908B - Benzimidazole compounds as kinase inhibitors, and preparation methods and applications thereof - Google Patents

Abstract

The present invention relates to benzimidazole compounds as kinase inhibitors, and preparation methods and applications thereof. In particular, the present invention relates to benzimidazole compounds represented by general formula(I), their preparation methods and pharmaceutical compositions, and their applications as kinase inhibitors in the preparation of drugs. The drugs can prevent and / or treat diseases related to cancer or tumor, especially bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female genital tract cancer, testicular cancer, gastrointestinal stromal tumors, and are expected to develop into a new generation of benzimidazole compounds as kinase inhibitor drugs. Each substituent in the general formula (I) is defined as that in the specification.

Description

Benzimidazole compound kinase inhibitor and preparation method and application thereof

The invention belongs to the field of drug development, and in particular relates to a benzimidazole compound kinase inhibitor and a preparation method and application thereof.

Cyclin-dependent kinases (CDKs) are a class of serine (Ser)/threonine (Thr) kinases. This family contains 13 members, cyclin is divided into A-L. Different CDKs and cyclins form CDK-cyclin complexes. Through CDK kinase activity, they catalyze phosphorylation of different substrates, initiate DNA synthesis, and realize the advancement and transformation of different phases of the cell cycle; regulate gene transcription, Involved in cell growth, proliferation, dormancy or entering apoptosis. Therefore, CDKs have important functions in the regulation of proliferation and death of all cells, including tumor cells and normal cells. Among them, CDK4/6-Cyclin D complex plays an important role in the transition of cells from G1 phase to S phase. In G1 phase, CDK4/6 phosphorylates a series of substrates including retinoblastoma protein (Rb) after binding to cyclin D. After Rb phosphorylation, the proteins bound to and inhibited by it are released, mainly transcription factors such as E2F, etc. E2F initiates and transcribes some genes necessary for entering the S phase, and promotes the transformation of cell G1/S. The study found that the specific activation of CDK4/6 is closely related to the proliferation of some tumors, and the abnormality of the cyclinD-CDK4/6-INK4-Rb pathway is common. It is manifested as: (1) p16INK4a gene deletion, point mutation, or DNA methylation leading to inactivation of p16INK4a; (2) CDK4 gene amplification or point mutation (R24C), loss of binding ability to p16INK4a; (3) cyclinD1 due to gene overloading Overexpressed due to excretion or gene amplification. Alteration of this pathway accelerates the G1 phase process, allowing tumor cells to proliferate faster and gain a survival advantage. Therefore, its intervention has become a therapeutic strategy, and CDK4/6 has thus become one of the anti-tumor targets.

Pfizer's Palbociclib (PD0332991) is the first FDA-approved CDK4/6 small molecule inhibitor for the treatment of breast cancer. Next, Novartis ribociclib (LEE011) was approved in March 2017 in combination with aromatase inhibitors. Some compounds, including Eli Lilly Abemaciclib (LY2835219), are in clinical research, and they all show good therapeutic effects. In addition to breast cancer, studies have shown that selective CDK4/6 inhibitors are very effective in ovarian cancer, non-small cell lung cancer, B cell lymphoma, liver cancer, glioma, colon cancer, multiple myeloma and other tumors. antitumor activity. Therefore, the development of new small-molecule inhibitors of CDK4/6 has become a new and effective method for the treatment of these tumors, inspiring generations of scientists to make continuous efforts.

Published patent applications for inhibitors that selectively inhibit CDK4/6 include WO2004065378, WO2012101013, WO2016192630, WO2016015604, and WO2016015604, among others.

CDK4/6 inhibitors have good application prospects as drugs in cancer or tumor treatment. The present invention will provide a novel structure of highly selective CDK4/6 inhibitors, and it is found that compounds with such structures show excellent effects and effect.

The object of the present invention is to provide a compound shown in the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound structure shown in the general formula (I) is as follows:

Wherein: L is a bond, -C(O)- or -C(O)NH-; Ring A is a heterocyclic group, wherein the heterocyclic group is selected from monocyclic heterocyclic group, spirocyclic heterocyclic group, fused ring heterocyclic group Ring group and bridged heterocyclic group; R is selected from hydrogen atom, deuterium atom or halogen; R ₁ is selected from deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, alkoxy group, haloalkoxy group, halogen, amine group , nitro, hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₃ , -(CH ₂ ) _n SR ₃ , -(CH ₂ ) _n C( O)R ₃ , -(CH ₂ ) _n C(O)OR ₃ , -(CH ₂ ) _n S(O) _m R ₃ , -(CH ₂ ) _n NR ₄ R ₅ , -(CH ₂ ) _n C (O)NR ₄ R ₅ , -(CH ₂ ) _n C(O)NHR ₄ , -(CH ₂ ) _n NR ₄ C(O)R ₅ and -(CH ₂ ) _n NR ₄ S(O) _m R ₅ , wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from deuterium atoms, alkyl, haloalkyl, halogen, amine, nitro, cyano radical, hydroxyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₆ , -SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C(O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ is substituted with one or more substituents; R ₂ is the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuteroalkyl group, a haloalkyl group, an alkoxy group, an aminoalkane Oxy, haloalkoxy, halogen, amine, pendant oxy, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₃ , - (CH ₂ ) _n SR ₃ , -(CH ₂ ) _n C(O)R ₃ , -(CH ₂ ) _n C(O)OR ₃ , -(CH ₂ ) _n S(O) _m R ₃ , -( CH ₂ ) _n NR ₄ R ₅ , -(CH ₂ ) _n C(O)NR ₄ R ₅ , -(CH ₂ ) _n C(O)NHR ₄ , -(CH ₂ ) _n NR ₄ C(O)R ₅ and -(CH ₂ ) _n NR ₄ S(O) _m R ₅ , wherein the alkyl, deuteroalkyl, haloalkyl, aminoalkoxy, cycloalkyl, heterocyclyl, aryl and heterocyclyl Aryl optionally further selected from deuterium atoms, alkyl groups, haloalkyl groups, halogens, amine groups, nitro groups, cyano groups, hydroxyl groups, alkenyl groups, alkynyl groups, alkoxy groups, haloalkoxy groups, hydroxyalkyl groups, cycloalkyl groups , heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C (O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ substituted by one or more substituents; _R is selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, deuteroalkyl group, haloalkyl group, hydroxyl group, amino group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from deuterium atoms, alkyl groups, halogens, amine groups, nitro groups, cyano groups, hydroxyl groups, hydroxyalkane groups radical, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C(O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O) Of NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ substituted by one or more substituents; R ₄ and R ₅ are the same or different, and are independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuteroalkyl groups, haloalkyl groups, hydroxyl groups, amino groups, cycloalkyl groups, Heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C( O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ , wherein the alkyl, cycloalkyl, heterocycle aryl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, halogen, hydroxy, amine, nitro, cyano, alkoxy, hydroxyalkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C(O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ R ₈ , - One or more substituents of (CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ Substituted; R ₆ is selected from hydrogen atom, deuterium atom, alkyl, deuteroalkyl, haloalkyl, hydroxyl, amino, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from deuterium atoms, alkyl, halogen, amine, nitro, cyano, hydroxyl, substituted by one or more substituents of hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ₇ and R ₈ are the same or different, and are each independently selected from hydrogen atoms, Deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyl group, amine group, ester group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, Aryl and heteroaryl groups are optionally further selected from deuterium atoms, alkyl groups, halogens, hydroxyl groups, amine groups, nitro groups, cyano groups, ester groups, alkoxy groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, substituted with one or more substituents in aryl and heteroaryl; x is an integer of 0, 1, 2, 3, 4, or 5; m is an integer of 0, 1, or 2; and n is 0, 1, An integer of 2, 3, 4 or 5.

In a preferred embodiment of the present invention, the compound represented by the general formula (I) is a compound represented by the general formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof:

Wherein: B is selected from 3-8-membered monocyclic heterocyclyl, 6-12-membered spirocyclic heterocyclyl, 6-12-membered fused ring heterocyclyl or 6-12-membered bridged heterocyclyl; preferably 3- 8-membered monocyclic heterocyclyl; L is a bond or -C(O)-; R, R ₁ , R ₂ and x are as described in claim (II).

In a preferred embodiment of the present invention, the compound shown in the general formula (II) is a compound shown in the general formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein: ring B, R, R ₁ , R ₂ and x are as described in general formula (II).

In a preferred embodiment of the present invention, the compound represented by the general formula (II) is a compound represented by the general formula (IV), a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein: ring B, R, R ₁ , R ₂ and x are as described in general formula (II).

In a preferred embodiment of the present invention, it is a compound represented by the general formula (V), a stereoisomer or a pharmaceutically acceptable salt thereof:

Wherein: M is CR ₂ R ₂ , NR ₂ or O; R is a hydrogen atom or a halogen, wherein the halogen is preferably a fluorine atom; R ₁ is an alkyl group or a halogen, wherein the alkyl group is a C _1-6 alkyl group, Preferably C _1-3 alkyl; R ₂ is the same or different, and each is independently selected from hydrogen atom, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{1 -6} aminoalkoxy, C _1-6 haloalkoxy, halogen, amino, side oxy, nitro, hydroxyl, cyano, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH ₂ ) _n OR ₃ and -(CH ₂ ) _n NR ₄ R ₅ , wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 aminoalkoxy, C _{3- 8} -cycloalkyl and 3-8 membered heterocyclyl are optionally further selected from C _1-6 alkyl, C _1-6 haloalkyl, halogen, amino, cyano, hydroxyl, alkenyl, alkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH ₂ ) _n -, -(CH ₂ ) _n OR ₆ and -(CH ₂ ) _n NR ₇ R ₈ are substituted with one or more substituents; or two R ₂ are connected to each other to form a 3-10 membered cycloalkyl or heterocyclic group, Wherein the 3-8 membered cycloalkyl or heterocyclyl group is optionally further substituted by one or more C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 amine Substituents of alkoxy, C _1-6 haloalkoxy, halogen, amino, pendant oxy, hydroxyl, cyano and C _3-8 cycloalkyl; preferably form 5-8 membered cycloalkane and y is an integer of 0, 1, 2 or 3; R ₃ ˜R ₈ , n and x are as described in the general formula (I).

In a preferred embodiment of the present invention, it is a compound represented by general formula (V), a stereoisomer or a pharmaceutically acceptable salt thereof: wherein: M is selected from CHR ₂ or NR ₂ ; R ₂ Selected from hydrogen atom, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 aminoalkoxy, C _1-6 haloalkoxy, halogen, amine group, pendant oxy, hydroxyl, cyano, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH ₂ ) _n OR ₃ and -(CH ₂ ) _n NR ₄ R ₅ , wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 aminoalkoxy, C _3-8 cycloalkyl and 3-8 membered heterocyclyl are further selected from C _1-6 alkyl as required base, C _1-6 haloalkyl, halogen, amine, cyano, hydroxyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy , C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH ₂ ) _n -, -(CH ₂ ) _n OR ₆ and -(CH ₂ ) _n NR ₇ One or more substituents in R ₈ are substituted; R, R ₁ , R ₃ to R ₈ , x, n and y are as described in general formula (V).

In a preferred embodiment of the present invention, it is a compound represented by general formula (VI), a stereoisomer or a pharmaceutically acceptable salt thereof:

wherein: R ₄ and R ₅ are each independently selected from hydrogen atom, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n C(O)R ₆ , wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl are optionally further selected from C _1-6 alkyl, halogen, hydroxy , amine group, cyano group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group and C _1-6 cycloalkyl group are substituted with one or more substituents; or R ₄ and R ₅ form a 3 -8-membered heterocyclyl, wherein the 3-8 membered heterocyclyl is optionally further selected from C _1-6 alkyl, -(CH ₂ )n-, halogen, hydroxyl, amino, cyano, C Substituted by one or more substituents in _1-6 alkoxy, C _1-6 hydroxyalkyl and C _1-6 cycloalkyl; preferably, the heterocyclic group formed by R ₄ and R ₅ is 4-6 member; R, R ₁ and n are as described in general formula (V).

In a preferred embodiment of the present invention, each of the shown general formulas, their stereoisomers or their pharmaceutically acceptable salts is characterized in that R is selected from hydrogen atoms and halogens; halogens are preferably fluorine.

In a preferred embodiment of the present invention, each of the shown general formulas, their stereoisomers or their pharmaceutically acceptable salts is characterized in that R ₁ is selected from C _1-8 alkyl and halogen, wherein The C _1-8 alkyl group is preferably a C _1-6 alkyl group, more preferably a C _1-3 alkyl group; the most preferred is a methyl group, wherein the halogen is preferably fluorine.

In a preferred embodiment of the present invention, the general formulas shown, their stereoisomers or their pharmaceutically acceptable salts are characterized in that R ₂ is selected from a hydrogen atom, a C _1-8 alkyl group, C _1-8 haloalkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, C _2-6 alkenyl, halogen, pendant oxy, -(CH ₂ ) _n NR ₄ R ₅ and 3- 10 heterocyclic groups, wherein the C _1-8 alkyl group, C _1-8 haloalkyl group, C _1-8 alkoxy group, C _3-8 cycloalkyl group and 3-10 membered heterocyclic group are further selected as required Substituted from one or more substituents of halogen, hydroxyl, cyano, C _1-8 alkyl, -(CH ₂ ) _n OR ₆ and C _1-8 alkoxy; preferably C _1-6 alkoxy group, C _1-6 haloalkyl, pendant oxy, -(CH ₂ ) _n NR ₄ R ₅ and 3-6 heterocyclyl, wherein the C _1-6 alkyl is optionally further selected from halogen, hydroxyl and One or more substituents in the cyano group are substituted; the C _1-6 alkyl group is more preferably a C _1-3 alkyl group.

In a preferred embodiment of the present invention, each of the shown general formulas, their stereoisomers or their pharmaceutically acceptable salts is characterized in that R ₄ and R ₅ are the same or different, and are independently selected from each other. From hydrogen atom, C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl, -(CH ₂ ) _n C(O)R ₆ and C _1-8 alkoxy, wherein the C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl and C _1-8 alkoxy are optionally further selected from halogen, hydroxyl, cyano, C _1-8 alkyl, Substituted with one or more substituents in C _3-8 cycloalkyl, -(CH ₂ ) _n OR ₆ and C _1-8 alkoxy; preferably C _1-6 alkyl and C _3-6 ring alkyl, wherein the C _1-6 alkyl and C _3-6 cycloalkyl groups are optionally further selected from halogen, hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl and -(CH ₂ ) substituted by one or more substituents in _n OR ₆ ; wherein the C _1-6 alkyl group is more preferably a C _1-3 alkyl group; R ₆ is selected from hydrogen atom, C _1-6 alkyl group and C _{1 -6} alkoxy; preferably C _1-3 alkyl and C _1-3 alkoxy.

In a preferred embodiment of the present invention, the preparation method of any shown compound of general formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprises the following steps:

The compound of general formula (VA) and the compound of general formula (VB) are coupled to obtain the compound of general formula (I), the compound of general formula (I) can be further reacted as needed, or further deprotected to obtain different compounds of general formula (I) , wherein the catalytic reagent in the coupling reaction is preferably Pd ₂ (dba) ₃ and _Xantphos reagent; wherein: X is halogen; preferably chlorine _; I) described.

The present invention also relates to a method for treating, preventing and/or treating and preventing a disease characterized by CDK4/6-mediated pathology, comprising administering to a patient a therapeutically effective dose of a compound represented by general formula (I), a stereoisomer thereof or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The present invention further relates to the compound represented by the general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition in the preparation for the treatment and/or prophylaxis of CDK kinase 4 and/or 6 Medication of cancer or tumor-related diseases in drug applications.

The present invention further relates to the compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, or the application of its pharmaceutical composition in the preparation of a drug related to the treatment of cancer or tumor, wherein the cancer or tumor The relevant disease is selected from the group consisting of brain tumor, lung cancer, liver cancer, gastric cancer, oral cancer, head and neck cancer, colon or rectal cancer, colon cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, squamous cell carcinoma, thyroid cancer, Bone cancer, skin cancer, non-small cell lung cancer, carcinoma in situ, lymphoma, neurofibroma, neuroblastoma, mast cell tumor, multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glioblastoma cancer, bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female reproductive tract cancer, testicular cancer, gastrointestinal stromal tumor or prostate tumor; Preferably selected from bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female reproductive tract cancer, testicular cancer, gastrointestinal stromal tumor or prostate tumor .

The present invention further relates to a compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a method for the treatment of cancer or tumor-related diseases, which comprises administering the treatment to a patient Effective dose of the compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt, or its pharmaceutical composition, wherein the cancer or tumor-related disease is selected from brain tumor, lung cancer, liver cancer, gastric cancer, Oral cancer, head and neck cancer, bowel or rectal cancer, colon cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, squamous cell carcinoma, thyroid cancer, bone cancer, skin cancer, non-small cell lung cancer, in situ Carcinoma, lymphoma, neurofibromatosis, neuroblastoma, mast cell tumor, multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glioblastoma, bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer , breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female reproductive tract cancer, testicular cancer, gastrointestinal stromal tumor or prostate tumor; preferably selected from bladder cancer, ovarian cancer, peritoneal cancer, Pancreatic, breast, uterine, cervical, endometrial, prostate, female reproductive tract, testicular, gastrointestinal stromal tumors, or prostate tumors.

As a further preferred method for preparing and treating breast cancer-related diseases, the breast cancer includes: estrogen receptor-positive and/or human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer in postmenopausal women.

The present invention further relates to a compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a therapeutically effective dose of any of the compounds represented by the general formula (I) , a stereoisomer thereof or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms An alkyl group of 1 to 3 carbon atoms, more preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl , 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl- 2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1 ,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl , 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyhexyl Methylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl , 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4 -Ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -Ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof, etc. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Dibutyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methyl Butyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2 -Dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl, butyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4 - methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably the substituents are one or more of the following groups independently selected from the group consisting of Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, Cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate, the present invention is preferably methyl, ethyl, isopropyl, third Butyl, haloalkyl, deuteroalkyl, alkoxy substituted alkyl and hydroxy substituted alkyl.

The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example: "methylene" means _-CH2- , "ethylene" means -( _CH2 ) _2- , "propylene" Refers to -(CH ₂ ) ₃ -, "butylene" refers to -(CH ₂ ) ₄ - and the like. The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3 -Butenyl, etc. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably containing 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

也包含單螺環烷基與雜環烷基共用螺原子的螺環烷基，非限制性實例包括：

The term "spirocycloalkyl" refers to a 5- to 20-membered monocyclic polycyclic group sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings are fully conjugated π electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spirocycloalkyl, double-spirocycloalkyl or poly-spirocycloalkyl, preferably mono-spirocycloalkyl and double-spirocycloalkane base. More preferably it is a 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-/6-member monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

Also included are spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, non-limiting examples include:

The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more Multiple double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl . Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two non-directly connected carbon atoms, which may contain one or more double bonds, but none of the rings has complete Conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring linked to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl, etc. Cycloalkyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

。多環雜環基包括螺環、稠環和 橋環的雜環基。術語“螺雜環基”指5至20員的單環之間共用一個原子(稱螺原子)的多環雜環基團，其中一個或多個環原子為選自氮、氧或S(O)_m(其中m是整數0至2)的雜原子，其餘環原子為碳。其可以含有一個或多個雙鍵，但沒有一個環具有完全共軛的π電子系統。較佳為為6至14員，更佳為為6至10員。根據環與環之間共用螺原子的數目將螺雜環基分為單螺雜環基、雙螺雜環基或多螺雜環基，較佳為為單螺雜環基和雙螺雜環基。更佳為為3員/6員、4員/4員、4員/5員、4員/6員、5員/5員或5員/6員單螺雜環基。螺雜環基的非限制性實例包括：

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) _m (where m is an integer from 0 to 2) heteroatoms, excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 10 ring atoms; more preferably contains 3 to 8 ring atoms; most preferably contains 6 to 10 ring atoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably piperidinyl and

. Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls. The term "spiroheterocyclyl" refers to a 5- to 20-membered monocyclic polycyclic heterocyclic group sharing one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. Preferably it is 6 to 14 members, more preferably 6 to 10 members. According to the number of spiro atoms shared between the rings, the spiro heterocyclyl groups are classified into mono-spiroheterocyclyl, bis-spiro-heterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiroheterocyclyl and double-spiro-heterocyclyl base. More preferably it is 3-member/6-member, 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-/6-membered monospiroheterocyclyl. Non-limiting examples of spiroheterocyclyl include:

The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds, but none of the rings have a fully conjugated pi-electron system, where one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2), the remaining rings Atom is carbon. Preferably it is 6 to 14 members, more preferably 6 to 10 members. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups ring base. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group of any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but none of the rings has a complete common A pi-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 6 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

和

等。 The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

and

Wait.

Heterocyclyl can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, pendant oxy, carboxyl or carboxylate.

The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, For example phenyl and naphthyl. More preferred is phenyl. The aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is an aryl ring, non-limiting examples of which include:

Aryl may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkylamine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, carboxyl or carboxylate.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, Tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, Pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring linked to the parent structure is a heteroaryl ring, non-limiting examples of which include:

Heteroaryl groups can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, carboxyl or carboxylate.

The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy , alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring Alkylthio, heterocycloalkylthio, carboxyl or carboxylate.

"Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

"Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

"Hydroxyalkyl" refers to an alkyl group substituted with hydroxy, wherein alkyl is as defined above.

"Hydroxy" refers to the -OH group.

"Halogen" refers to fluorine, chlorine, bromine or iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Carboxyl" refers to -C(O)OH.

，例如側氧哌啶基，

。 "Pendant Oxygen" means

, such as pendant piperidinyl,

.

"THF" refers to tetrahydrofuran.

"EtOAc" refers to ethyl acetate.

"MeOH" refers to methanol.

"DMF" refers to N,N-dimethylformamide.

"DIPHA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

"MeCN" means acetonitrile.

"DMA" refers to N,N-dimethylacetamide.

" _Et2O " refers to diethyl ether.

"DCE" refers to 1,2 dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodobutadiimide.

"Cbz-Cl" refers to benzyl chloroformate.

"Pd2(dba _{)3 "} refers to tris(dibenzylideneacetone)dipalladium.

"Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene.

"HATU" refers to 2-(7-oxybenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate.

"KHMDS" means potassium hexamethyldisilazide.

"LiHMDS" refers to lithium bistrimethylsilylamide.

"MeLi" refers to methyl lithium.

"n-BuLi" refers to n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triacetoxyborohydride.

"X is selected from A, B, or C", "X is selected from A, B and C", "X is A, B or C", "X is A, B and C" etc. all express the same Meaning, that means X can be any one or more of A, B, and C.

"Stereoisomerism" includes geometric isomerism (cis-trans isomerism), optical isomerism and conformational isomerism.

The hydrogen atom in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by deuterium atom.

"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not. For example, "heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .

"Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amine groups or hydroxyl groups with free hydrogens may be unstable when bound to carbon atoms with unsaturated (eg, olefinic) bonds.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients. The purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.

"Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals, and possess the desired biological activity.

The present invention is further described below in conjunction with the examples, but these examples do not limit the scope of the present invention.

Example

The structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterium dimethylsulfoxide (DMSO- d ₆ ), deuterium methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ), and the internal standard was tetramethyl Silane (TMS).

An Agilent 1200 Infinity Series mass spectrometer was used for LC-MS measurements. The determination of HPLC used an Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18 150×4.6mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm column).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specifications used for TLC are 0.15mm~0.20mm, and the specifications used for TLC separation and purification products are 0.4mm~0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.

The starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.

Unless otherwise specified, all the reactions of the present invention are carried out under continuous magnetic stirring, in a dry nitrogen or argon atmosphere, and the solvent is a dry solvent, and the reaction temperature is in degrees Celsius.

Example 1 (1,4-Diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole) Preparation of -6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

The first step: the preparation of 3rd-butyl 4-(6-chloro-2-methylnicotine)-1,4-diazepine-1-carboxylate

6-Chloro-2-methylnicotinic acid (0.7 g, 4.1 mmol), 3-butyl 1,4-diazepine-1-carboxylate (1.0 g, 4.9 mmol), TEA (1.2 g, 12.2 mmol) was dissolved in CH ₂ Cl ₂ (15 mL), HATU (1.87 g, 4.9 mmol) was added, and the reaction was stirred at room temperature for two hours. The reaction solution was diluted with CH ₂ Cl ₂ (30 mL), washed with NaHCO ₃ solution (30 mL), saturated brine (30 mL), dried over anhydrous sodium sulfate, concentrated and subjected to column chromatography [eluent: CH ₂ Cl ₂ ~CH ₂ Cl ₂ /MeOH (10:1)] to give the product 3-butyl 4-(6-chloro-2-methylnicotine)-1,4-azepane-1-carboxylate (1.4 g , the yield is 96%).

MS m/z (ESI): 354.1 [M+H] ⁺ .

The second step: preparation of 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine

4-Fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-benzene [d]imidazole (2.0 g, 6.3 mmol), 4-chloro-5-fluoropyrimidin-2-amine (0.93 g, 6.3 mmol), Pd(dppf)Cl ₂ (0.4 g, 0.6 mmol), potassium carbonate ( 2.61 g, 18.9 mmol) was refluxed in a mixed solution of dioxane/H ₂ O (4/1, 50 mL) under nitrogen protection for 5 h, cooled to room temperature and concentrated to remove the organic solvent, diluted with water, CH ₂ Cl ₂ (30 mL* 3) Extraction, the organic phases were combined and dried with anhydrous sodium sulfate. After concentration, the product was obtained by column chromatography to obtain 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]) Imidazol-6-yl)pyrimidin-2-amine (1.8 g, 94.4% yield).

MS m/z (ESI): 304.1 [M+H] ⁺ .

The third step: 4-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2- Preparation of tertiary butyl)-amino)-2-methylnicotine)-1,4-diazepan-1-carboxylate

Compound 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (1.2 g, 4.0 mmol) and compound Tertiary-butyl 4-(6-chloro-2-methylnicotine)-1,4-diazepine-1-carboxylate (1.7 g, 4.8 mmol) was dissolved in dioxane (40 mL) , and then sequentially added cesium carbonate (3.9g, 11.9mmol), Pd ₂ (dba) ₃ (0.2g, 0.22mmol), Xantphos (0.24g, 0.44mmol), replaced nitrogen three times, stirred and refluxed overnight. Cool and filter, concentrate, and separate by column chromatography [DCM~DCM/MeOH (10:1)] to obtain compound 4-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2- Methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylnicotine)-1,4-diazepine-1-carboxylic acid third -Butyl ester (2 g, 81% yield).

MS m/z (ESI): 621.3 [M+H] ⁺ .

The fourth step: 1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[ d] Preparation of imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

-4-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amine (yl)-2-methylnicotine)-1,4-diazepine-1-carboxylate 3-butyl ester (2 g, 3.2 mmol) was dissolved in CH ₂ Cl ₂ (30 mL) and cooled to 0 °C , trifluoroacetic acid (10 mL) was added dropwise, and after the addition was completed, the mixture was stirred at room temperature for 2 h, and the concentrated crude product (1,4-diazoheptan-1-yl)(6-((5-fluoro-4- (4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methyl The trifluoroacetate salt of the ketone (4 g, 99% yield), the crude product was used in the next reaction without further purification.

¹ H NMR (400MHz, MeOD)δ: 8.98(d, J =3.2Hz, 1H), 8.61(s, 1H), 8.36(d, J =9.0Hz, 1H), 8.24(d, J =11.1Hz, 1H), 7.61(d, J =8.8Hz, 1H), 5.18(dt, J =13.8, 7.1Hz, 1H), 4.07-3.84(m, 2H), 3.62-3.52(m, 3H), 3.43(m ,3H),3.00(s,3H),2.78(s,3H),2.21(d, J =43.5Hz,2H),1.84(d, J =6.9Hz,6H).

¹⁹ F NMR (376 MHz, MeOD) δ: -129.2, -143.0.

MS m/z(ESI): 521.2[M+H] ⁺ .

Example 2 1-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino )-2-methylpyridin-3-yl)-4-(methylamino)piperidin-2-one preparation

The first step: preparation of tertiary butyl (1-(6-chloro-2-methylpyridin-3-yl)-2-oxo-piperidin-4-yl)carbamate

3-Bromo-6-chloro-2-methylpyridine (200 mg, 0.969 mmol), tert-butyl (2-oxypiperidin-4-yl)carbamate (249 mg, 1.162 mmol), Pd ₂ ( dba) ₃ (89 mg, 0.0972 mmol), Xantphos (112 mg, 0.194 mmol), cesium carbonate (947 mg, 2.907 mmol) in dioxane (10 mL) were stirred overnight at 100°C under nitrogen protection, cooled, and concentrated after column chromatography The product was obtained (31 mg, 9.4% yield).

MS m/z (ESI): 340.1, 342.1 [M+H] ⁺ .

The second step: (1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 -yl)amino)-2-methylpyridin-3-yl)-2-carbonylpiperidin-4-yl)carbamate preparation of tert-butyl ester

5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (28 mg, 0.0923 mmol), (1- (6-Chloro-2-methylpyridin-3-yl)-2-oxypiperidin-4-yl)carbamic acid tert-butyl ester (31 mg, 0.0912 mmol), Pd ₂ (dba) ₃ (8.4 mg, 0.00917 mmol), Xantphos (10.6 mg, 0.0183 mmol), cesium carbonate (89 mg, 0.273 mmol) were stirred in dioxane (10 mL) at 100° C. under nitrogen protection for 5 h, cooled, and concentrated, and the product was obtained by column chromatography ( 19.6 mg, yield 35.0%).

MS m/z (ESI): 607.2 [M+H] ⁺ .

The third step: (1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 -yl)amino)-2-methylpyridin-3-yl)-2-carbonylpiperidin-4-yl) preparation of tert-butyl (methyl)carbamate

(1-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amine (19.6 mg, 0.0323 mmol), 60% NaH (1.6 mg, 0.0400 mmol) in Stir in THF (2 mL), add iodomethane (9 mg, 0.0634 mmol), stir at room temperature overnight, and then concentrate and column chromatography to obtain the product (12 mg, yield 59.8%).

MS m/z (ESI): 621.3 [M+H] ⁺ .

Step 4: 1-(6-((5-Fluoro-4-(4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2- Preparation of (methyl)amino)-2-methylpyridin-3-yl)-4-(methylamino)piperidin-2-one

The product of the previous step (12 mg, 0.0193 mmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added, stirred at room temperature for 3 h, concentrated to dryness, and separated by column chromatography to obtain the product (9.1 mg, yield 90.4%) ).

¹ H NMR (400MHz, CD3OD)δ: 8.93(s,1H), 8.53(d, J =33.8Hz,2H), 8.21(s,1H), 7.91(s,1H), 5.19(s,1H), 4.01(s, 4H), 3.73(s, 2H), 3.02(s, 3H), 2.77(s, 1H), 2.68(s, 3H), 2.38(d, J = 87.2Hz, 3H), 1.84(s ,6H).

MS m/z (ESI): 521.2 [M+H] ⁺ .

Example 3 (4-(Cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Preparation of yl- 1H -benzo[ d ]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

The first step: the preparation of 1-(6-chloro-2-methylnicotinyl)piperidin-4-one

6-Chloro-2-methylnicotinic acid (1.0 g, 5.8 mmol), piperidin-4-one (866 mg, 8.7 mmol), HATU (2.2 g, 17.5 mmol), DIEA (2 mL) were sequentially added to dichloromethane (50mL). The reaction was stirred at room temperature for 4 hours. LCMS showed that the reaction was complete. The reaction solution was added with dichloromethane (50 mL) and water (50 mL) for separation. The organic phase was washed with saturated sodium bicarbonate (3×20 mL), and the organic phase was separated with anhydrous Dry over sodium sulfate, filter and concentrate. The remaining crude product was purified by flash silica gel column (CH ₂ Cl ₂ :MeOH=20:1) to give the product 1-(6-chloro-2-methylnicotinoid)piperidin-4-one (1.2 g, 81%) ).

Second step: preparation of 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- 1H -benzo[ d ]imidazol-6-yl)pyrimidin-2-amine

4-Chloro-5-fluoropyrimidine-2-amine (4.5 g, 31.3 mmol), 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl) -1,3,2- Dioxaborolane -2-yl)-1H-benzo[ d ]imidazole (10.0 g, 31.3 mmol), Pd(dppf)Cl ₂ (200 mg), potassium carbonate (8.6 g) , 62.6 mmol) was added sequentially to dioxane (50 mL) and water (5 mL). The reaction was stirred under nitrogen protection at 100° C. for 3 hours. After the reaction was completed, the reaction solution was concentrated, and dichloromethane (50 mL) and water (50 mL) were added to the residue. The layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The remaining crude product was purified by flash silica column to give the product 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- 1H -benzo[ d ]imidazol-6-yl)pyrimidine- 2-amine (5.0 g, 52%).

MS m/z(ESI): 304.1[M+H] ⁺

The third step: 1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- 1H -benzo[ d ]imidazol-6-yl)pyrimidine-2 Preparation of -yl)amino)-2-methylnicotinyl)piperidin-4-one

5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl- 1H -benzo[ d ]imidazol-6-yl)pyrimidin-2-amine (200 mg, 0.66 mmol), 1 -(6-Chloro-2-methylnicotinyl)piperidin-4-one (167 mg, 0.66 mmol), Pd ₂ (dba) ₃ (50 mg), Xan-phos (70 mg), cesium carbonate (430 mg, 1.32 mmol) was sequentially added to anhydrous dioxane (5 mL). The reaction was stirred under nitrogen protection at 110° C. for 4 hours. After the reaction was completed, the reaction solution was concentrated, and dichloromethane (10 mL) and water (10 mL) were added to the residue. The layers were separated, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The remaining crude product was purified by flash silica column to give the product 1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- 1H -benzo[ d ]imidazole -6-yl)pyrimidin-2-yl)amino)-2-methylnicotinyl)piperidin-4-one (100 mg, 30%).

MS m/z(ESI): 520.2[M+H] ⁺

The fourth step: (4-(cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- 1H) - Preparation of benzo[ d ]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

1-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl- 1H -benzo[ d ]imidazol-6-yl)pyrimidin-2-yl) Amino)-2-methylnicotinyl)piperidin-4-one (100 mg, 0.19 mmol), cyclopropylamine (0.3 mL) was dissolved in dichloromethane (5 mL) and the reaction was stirred at room temperature for 20 minutes , sodium borohydride acetate (200mg, 0.95mmol) was added to the reaction solution, the reaction was stirred at room temperature for 1 hour, LCMS showed that the reaction was complete, the reaction solution was directly spin-dried, the residue was purified with a fast silica gel column, and then preparative HPLC Purification gave the product (4-(cyclopropylamino)piperidin-1-yl)6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- 1H -benzene) [ d ]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone (24.0 mg, 22%).

¹ H NMR (400MHz, MeOD)δ: 8.95(d, J =3.1Hz, 1H), 8.58(s, 1H), 8.20(d, J =10.7Hz, 2H), 7.65(d, J =8.8Hz, 1H), 5.24-5.09(m, 2H), 3.77(s, 1H), 3.63(s, 1H), 3.02(d, J =13.7Hz, 1H), 2.97(s, 3H), 2.84(d, J =4.2Hz, 1H), 2.73(s, 3H), 2.35(s, 1H), 2.31-2.13(m, 2H), 2.06(s, 1H), 1.83(d, J =6.9Hz, 6H), 1.73 (s, 2H), 1.33(d, J =18.5Hz, 2H), 1.04-0.89(m, 2H).

MS m/z(ESI): 561.2[M+H] ⁺

Example 4 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(9-methyl-3,9-diazabicyclo[4.2.1]nonan-3-yl)methanone

The first step: preparation of 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylic acid 9-benzyl ester 3-(tert-butyl) ester

3,9-Diazabicyclo[4.2.1]nonane-3-carboxylate 3-butyl ester (130 mg, 0.57 mmol) and triethylamine (0.3 mL) were dissolved in dichloromethane (10 mL), Benzyl chloroformate (0.16 mL, 1.14 mmol) was added dropwise under an ice bath. Stir overnight at room temperature. Then it was diluted with dichloromethane (30 mL), washed with water (20 mL) and saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, concentrated and then subjected to column chromatography [eluent: PE~PE/EtOAc (1:1) )] to give compound 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylic acid 9-benzyl ester 3-(tert-butyl) ester (170 mg, yield 82 %).

MS m/z (ESI): 305.0 [M-55] ⁺ .

Step 2: Preparation of 3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid benzyl ester

Compound 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylic acid 9-benzyl ester 3-(tert-butyl) ester (170 mg, 0.47 mmol) was dissolved in di Chloromethane (3 mL) was added dropwise with trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 2 h. Concentrated for use.

MS m/z (ESI): 261.1 [M+H] ⁺ .

The third step: the preparation of 3-(6-chloro-2-methylnicotinoyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid benzyl ester

Compound 6-chloro-2-methylnicotinic acid (85 mg, 0.5 mmol) and compound 3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid benzyl ester were dissolved in DMF (5 mL) , add DIEA (0.3 mL) and HATU (380 mg, 1 mmol), and stir at room temperature for 2 h. After concentration, it was purified by column chromatography [eluent: DCM~DCM/MeOH (10:1)] to obtain compound 3-(6-chloro-2-methylnicotine)-3,9-diazabicyclo[ 4.2.1] Nonane-9-carboxylic acid benzyl ester (180 mg, 94% yield).

MS m/z (ESI): 414.1 [M+H] ⁺ .

Step 4: 3-(6-((5-Fluoro-4-(4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2- Preparation of benzyl)amino)-2-methylnicotinoyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid benzyl ester

Compound 3-(6-Chloro-2-methylnicotinoidyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid benzyl ester (100 mg, 0.24 mmol) and compound 5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (75 mg, 0.25 mmol) in dioxane alkane (15 mL), then cesium carbonate (324 mg, 1 mmol), Pd ₂ (dba) ₃ (23 mg, 0.025 mmol) and Xant-phos (30 mg, 0.05 mmol) were added successively, nitrogen was replaced three times, and the mixture was refluxed overnight. After cooling, filtration, concentration and purification by column chromatography [DCM~DCM/MeOH(10:1)], the compound 3-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2- Methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylnicotinoyl)-3,9-diazabicyclo[4.2.1]nona Alkane-9-carboxylic acid benzyl ester (120 mg, 73% yield).

MS m/z (ESI): 681.2 [M+H] ⁺ .

The fifth step: (3,9-diazabicyclo[4.2.1]nonan-3-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2- Preparation of methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

Compound 3-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amine (120 mg, 0.17 mmol) in methanol (10 mL), Palladium hydroxide (30 mg) was added under nitrogen protection, then hydrogen was replaced three times, and the mixture was stirred at room temperature overnight. Filtration, concentrated to obtain crude product (90mg, yield 93%)

MS m/z (ESI): 547.2 [M+H] ⁺ .

The sixth step: (6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) Preparation of amino)-2-methylpyridin-3-yl)(9-methyl-3,9-diazabicyclo[4.2.1]nonan-3-yl)methanone

Compound (3,9-diazabicyclo[4.2.1]nonan-3-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- 1H-Benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone (90 mg, 0.16 mmol) and formaldehyde solution (0.1 mL) were dissolved in Dichloromethane (5 mL) was stirred at room temperature for 30 min, then sodium triacetoxyborohydride (100 mg) was added, and stirring was continued for 3 h. The reaction solution was concentrated and purified by reverse-phase column chromatography to obtain the compound (6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole- 6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)(9-methyl-3,9-diazabicyclo[4.2.1]nonan-3-yl ) ketone (56 mg, 50% yield).

¹ H NMR (400MHz, MeOD)δ: 9.00(s,1H), 8.64(s,1H), 8.50(s,1H), 8.26(d, J =10.6Hz,1H), 7.63(s,1H), 5.21(m, 1H), 4.20(m, 4H), 3.76(m, 2H), 3.02(m, 6H), 2.80(d, J =12.8Hz, 3H), 2.65(m, 2H), 2.43-2.20 (m, 2H), 2.19-1.95(m, 2H), 1.85(d, J =6.0Hz, 6H).

¹⁹ F NMR (376MHz, MeOD) δ -128.9, -142.6

MS m/z (ESI): 561.2 [M+H] ⁺ .

Example 5 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2--Methylpyridin-3-yl)(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation method of 2-methylpyridin-3-yl)(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methanone.

¹ H NMR (400MHz, MeOD))): δ: 9.00 (s, 1H), 8.63 (s, 1H), 8.38-8.22 (m, 2H), 7.58 (d, J = 8.4Hz, 1H), 5.25- 5.15(m, 1H), 4.30-4.10(m, 1H), 4.05-3.90(m, 1H), 3.75-3.35(m, 5H), 3.02(s, 3H), 2.78(s, 3H), 2.75- 2.55(m,1H),2.35-1.90(m,4H),1.85(d, J =6.7Hz,6H).

¹⁹ F NMR (400 MHz, MeOD): δ: -129.16 (s), -142.76 (d, J = 12.8 Hz).

MS m/z (ESI): 547.2 [M+H] ⁺ .

Example 6 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-fluoropyridin-3-yl)(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation method of 2-fluoropyridin-3-yl)(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methanone.

¹ H NMR (400MHz, MeOD)): δ: 8.72(d, J =3.4Hz, 1H), 8.60(s, 1H), 8.37(d, J =8.1Hz, 1H), 8.00-7.90(s, 1H) ), 5.20-5.10(m, 1H), 4.30-4.17(m, 1H), 4.02-3.93(m, 1H), 3.79-3.38(m, 5H), 2.99(s, 3H), 2.75-2.45(m ,1H),2.35-1.87(m,4H),1.82(d, J =8Hz,6H).

¹⁹ F NMR (400MHz, MeOD): δ: -129.68(d, J =4.4Hz), -148.65(s).

MS m/z (ESI): 551.2 [M+H] ⁺ .

Example 7 Diazepan-1-yl)(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole- Preparation of 6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone

(1,4-Diazepan-1-yl)(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] For the preparation method of imidazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone, refer to Example 1.

¹ H NMR (400 MHz, MeOD) δ: 8.59 (dd, J =9.5, 3.3 Hz, 1H), 8.49 (s, 1H), 8.25 (d, J =8.2 Hz, 1H), 8.07 (d, J =11.3 Hz, 1H), 7.92(t, J =8.9Hz, 1H), 5.04(dd, J =13.7, 6.9Hz, 1H), 3.91(s, 1H), 3.77(d, J =19.3Hz, 1H), 3.58-3.45(m, 2H), 3.42-3.24(m, 4H), 2.89(s, 3H), 2.10(d, J =24.5Hz, 2H), 1.73(d, J =6.9Hz, 6H).

¹⁹ F NMR (376 MHz, MeOD) δ: -70.3, -129.5, -148.5.

MS m/z(ESI): 525.2[M+H] ⁺ .

Example 8 (2-fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) Amino)pyridin-3-yl)(4-methyl-1,4-diazepan-1- The preparation of ketone

(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) For the preparation method of amino)pyridin-3-yl)(4-methyl-1,4-diazepin-1-yl)methanone, refer to Example 1.

¹ H NMR (400MHz, MeOD)δ: 8.72(d, J =3.3Hz, 1H), 8.61(s, 1H), 8.36(d, J =8.4Hz, 1H), 8.20(d, J =11.3Hz, 1H), 8.04(t, J =8.9Hz, 1H), 5.17(dt, J =14.0, 6.9Hz, 1H), 4.40-4.31(m, 1H), 4.01-3.55(m, 5H), 3.46-3.36 (m, 2H), 2.99(d, J =10.6Hz, 6H), 2.29(m, 2H), 1.85(d, J =6.9Hz, 6H).

MS m/z(ESI): 539.2[M+H] ⁺ .

Example 9 (S)-(3,4-Dimethyl-1,4-diazepan-1-yl)(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-iso) Preparation of propyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone

(S)-(3,4-Dimethyl-1,4-diazepan-1-yl)(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-iso) Refer to Example 1 for the preparation method of propyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD) δ: 8.62 (d, J =3.4Hz, 1H), 8.50 (d, J =0.9Hz, 1H), 8.26 (dd, J =8.3, 2.0Hz, 1H), 8.09 ( d, J =11.3Hz,1H),7.92(t, J =8.8Hz,1H),5.13-4.97(m,1H),4.07(d, J =15.5Hz,1H),3.82(d, J =17.3 Hz, 5H), 2.93(s, 2H), 2.89(s, 3H), 2.79(d, J =18.3Hz, 1H), 2.14(d, J =31.4Hz, 2H), 1.74(d, J =6.9 Hz,6H),1.39(dd, J =47.3,6.8Hz,3H).

MS m/z(ESI): 472.2[M+H] ⁺ .

Example 10 (4,5-Dimethyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- Preparation of 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4,5-Dimethyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- Refer to Example 1 for the preparation method of 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

MS m/z(ESI): 472.2[M+H] ⁺ .

Example 11 (4-ethyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl) Preparation of -2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-Ethyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzene Refer to Example 1 for the preparation method of [d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD) δ: 8.87(s, 1H), 8.50(s, 1H), 8.30(m, 1H), 8.13(d, J =10.9Hz, 1H), 7.49(d, J =8.2 Hz, 1H), 5.13-5.01(m, 1H), 4.23(d, J =11.8Hz, 1H), 3.85-3.40(m, 5H), 3.235-3.25(m, 4H), 2.89(s, 3H) , 2.70(m, 3H), 2.25-2.10(m, 2H), 1.73(d, J =6.7Hz, 6H), 1.32(m, 3H). ¹⁹ F NMR(376MHz, MeOD)δ:-129.1,- 142.8.

MS m/z(ESI): 549.2[M+H] ⁺ .

Example 12 (2-fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) Preparation of amino)pyridin-3-yl)(6-methyl-3,6-diazabicyclo[3.2.1]octan-3-yl)methanone

(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) For the preparation method of amino)pyridin-3-yl)(6-methyl-3,6-diazabicyclo[3.2.1]octan-3-yl)methanone, refer to Example 1.

¹ H NMR (400MHz, MeOD): δ: 8.62-8.54 (m, 1H), 8.46 (s, 1H), 8.22 (d, J = 8.2Hz, 1H), 8.05 (d, J = 11.2Hz, 1H) ,7.94-7.78(m,1H),5.05(dt, J =13.6,6.8Hz,1H),4.68-4.39(m,1H),4.05-3.90(m,1H),3.91-3.40(m,2H) ,3.35-3.05(m,2H),2.95-2.80(m,6H),2.75-2.57(m,1H),2.45-2.30(m,1H),2.23-1.98(m,2H),1.73(d, J =6.8Hz,6H). ^19F NMR (400MHz, MeOD): δ: -69.67(d, J =282.4Hz), -129.43(d, J =8.9Hz), -148.33(s).

MS m/z (ESI): 551.2 [M+H] ⁺ .

Example 13 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(1-methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation method of 2-methylpyridin-3-yl)(1-methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methanone.

¹ H NMR (400MHz, MeOD): δ: 8.88 (s, 1H), 8.51 (s, 1H), 8.25-8.10 (m, 2H), 7.52-7.44 (m, 1H), 5.20-4.96 (m, 1H) ), 4.70-4.50(m, 1H), 4.04-3.46(m, 5H), 3.40-3.30(m, 1H), 3.20-3.01(m, 1H), 2.96-2.80(m, 5H), 2.78-2.48 (m, 4H), 2.35-1.9 (dd, m, 3H), 1.92-1.51 (m, 7H).

¹⁹ F NMR (400 MHz, MeOD): δ: -129.11 (s), -142.77 (d, J = 26.3 Hz).

MS m/z (ESI): 561.2 [M+H]+.

Example 14 (3,4-Dimethyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- Preparation of 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(3,4-Dimethyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl- Refer to Example 1 for the preparation method of 1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 9.00(s, 1H), 8.63(s, 1H), 8.42(s, 1H), 8.26(s, 1H), 7.60(s, 1H), 5.20(s, 1H) ), 4.34-3.77(m, 3H), 3.63(s, 3H), 3.02(s, 5H), 2.92(s, 1H), 2.82(s, 3H), 2.32(d, J = 55.7Hz, 3H) ,1.85(s,6H),1.60(s,2H),1.31(s,3H).

MS m/z(ESI): 472.2[M+H] ⁺ .

Example 15 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(1-methylpiperidin-4-yl)-1,4-diazepan-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation method of 2-methylpyridin-3-yl)(4-(1-methylpiperidin-4-yl)-1,4-diazepan-1-yl)methanone.

¹ H NMR (400MHz, MeOD) δ: 8.99(s, 1H), 8.63(s, 1H), 8.60-8.46(m, 1H), 8.25(d, J =10.8Hz, 1H), 7.60(d, J =7.9Hz,1H),5.20(m,1H),4.31-3.93(m,2H),3.84(m,2H),3.74(m,4H),3.57(m,3H),3.23(m,2H) ,3.01(s,3H),2.93(s,3H),2.80(s,3H),2.57(m,3H),2.28(m,3H),1.85(d, J =6.4Hz,6H).

¹⁹ F NMR (376MHz, MeOD) δ: -129.0, -142.7.

MS m/z(ESI): 518.3[M+H] ⁺ .

Example 16 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(5-methyl-1,4-diazepan-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation method of 2-methylpyridin-3-yl)(5-methyl-1,4-diazepan-1-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.87(d, J =3.0Hz, 1H), 8.51(s, 1H), 8.29(d, J =8.9Hz, 1H), 8.13(d, J =11.1Hz, 1H), 7.50(dd, J =8.6, 4.8Hz, 1H), 5.07(dt, J =13.7, 6.8Hz, 1H), 4.05(m, 1H), 3.85(m, 1H), 3.65-3.39(m ,4H),3.32(m,1H),2.90(s,3H),2.67(s,3H),2.11-1.89(m,2H),1.73(d, J =6.9Hz,6H),1.35(dd, J =13.7,6.5Hz,3H).

¹⁹ F NMR (376 MHz, MeOD) δ: -129.1, -142.8.

MS m/z(ESI): 535.2[M+H] ⁺ .

Example 17 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-methyl-1,4-diazepan-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation method of 2-methylpyridin-3-yl)(4-methyl-1,4-diazepan-1-yl)methanone.

¹ H NMR (400 MHz, MeOD) δ: 9.00 (d, J =3.1 Hz, 1H), 8.63 (s, 1H), 8.42 (dd, J =15.8, 8.9 Hz, 1H), 8.26 (d, J =11.0 Hz, 1H), 7.59(d, J =8.9Hz, 1H), 5.20(dt, J =13.8, 6.7Hz, 1H), 4.36(d, J =11.3Hz, 1H), 3.94-3.54(m, 5H ),3.50-3.40(m,2H),3.01(t, J =7.9Hz,6H),2.80(d, J =9.7Hz,3H),2.29(m,2H),1.85(d, J =6.9Hz ,6H).

¹⁹ F NMR (376MHz, MeOD) δ: -129.3, -142.9.

MS m/z(ESI): 535.2[M+H] ⁺ .

Example 18 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(2-methoxyethyl)-1,4-diazepan-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- 2-Methylpyridin-3-yl)(4-(2-methoxyethyl)-1,4-diazepan-1-yl)methanone was prepared as follows.

(1,4-Diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole) -6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone (200 mg, 0.38 mmol) was dissolved in DMF (6 mL), potassium carbonate (150 mg) and 1- bromo-2-methoxyethane (0.5 mL) and stirred at 60 °C for 3 h. Cool, filter, and concentrate by column chromatography [eluent: CH ₂ Cl ₂ ~CH ₂ Cl ₂ /MeO-H (10:1)] to obtain a white solid product (150 mg, yield 68%).

¹ H NMR (400MHz, MeOD) δ: 9.00 (d, J =3.2Hz, 1H), 8.68-8.60 (m, 1H), 8.40 (dd, J =13.2, 8.9Hz, 1H), 8.26 (d, J =11.1Hz,1H),7.59(d, J =8.9Hz,1H),5.20(m,1H),4.37(m,1H),3.95-3.66(m,6H),3.59-3.39(m,8H) , 3.01(s, 3H), 2.79(s, 3H), 2.41-2.16(m, 2H), 1.85(d, J =6.9Hz, 6H). ¹⁹ F NMR(376MHz, MeOD)δ:-129.3,- 142.9.

MS m/z(ESI): 579.3[M+H] ⁺ .

Example 19 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation method of 2-methylpyridin-3-yl)(4-(2,2,2-trifluoroethyl)-1,4-diazepan-1-yl)methanone.

MS m/z(ESI): 603.2[M+H] ⁺ .

Example 20 3-(4-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl )amino)-2-methylnicotine)-1,4-diazepan-1-yl)propionitrile preparation

3-(4-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl ) amino)-2-methylnicotine)-1,4-diazepan-1-yl)propionitrile The preparation method of propionitrile refers to Example 18.

¹ H NMR (400MHz, MeOD): δ: 8.99(d, J =3.3Hz, 1H), 8.63(s, 1H), 8.49(d, J =9.0Hz, 1H), 8.25(d, J =11.1Hz ,1H),7.60(d, J =8.9Hz,1H),5.18(dq, J =14.1,7.0Hz,1H),4.10-3.85(m,1H),3.80-3.45(m,8H),3.26- 3.18(m, 2H), 3.02(s, 3H), 2.80(s, 3H), 2.43-2.18(m, 2H), 1.85(d, J = 6.9Hz, 6H).

¹⁹ F NMR (400 MHz, MeOD): δ: -129.12 (s), -142.84 (d, J = 10.2 Hz).

MS m/z (ESI): 574.2 [M+H] ⁺ .

Example 21 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(2-hydroxypropyl)-1,4-diazepin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 18 for the preparation method of 2-methylpyridin-3-yl)(4-(2-hydroxypropyl)-1,4-diazepin-1-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.56(d, J =3.3Hz, 1H), 8.31(m, 2H), 7.77(d, J =11.8Hz, 1H), 7.63(d, J =8.4Hz, 1H), 4.93(m, 1H), 4.03-3.72(m, 3H), 3.57-3.41(m, 2H), 3.04(s, 1H), 2.84(d, J = 27.2Hz, 3H), 2.73-2.57 (m, 4H), 2.49(m, 4H), 2.01(s, 1H), 1.87(s, 1H), 1.73(d, J = 6.7Hz, 6H), 1.17(m, 3H).

¹⁹ F NMR (400 MHz, MeOD): δ: -130.5, -149.5.

MS m/z(ESI): 579.3[M+H] ⁺ .

Example 22 (6-((5-Fluoro-4-(1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methyl Preparation of pyridin-3-yl)(4-methyl-1,4-diazepan-1-yl)methanone

(6-((5-Fluoro-4-(1-isopropyl-2-methyl-1H-benzo[d1imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridine For the preparation method of -3-yl)(4-methyl-1,4-diazepan-1-yl)methanone, refer to Example 1.

¹ H NMR (400 MHz, MeOD) δ: 8.97 (d, J =3.3 Hz, 1H), 8.79 (s, 1H), 8.42 (dd, J =15.2, 8.9 Hz, 2H), 8.04 (d, J =8.7 Hz,1H),7.59(d, J =8.9Hz,1H),5.19(dt, J =13.8,6.9Hz,1H),4.45-4.29(m,1H),3.98-3.52(m,5H),3.49 -3.38(m, 2H), 3.01(t, J =7.9Hz, 6H), 2.81(t, J =15.9Hz, 3H), 2.40-2.14(m, 2H), 1.84(t, J =10.5Hz, 6H).

MS m/z(ESI): 517.3[M+H] ⁺ .

Example 23 6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2 - Preparation of methyl-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)nicotinamide

6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2 -The preparation method of methyl-N-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)nicotinamide refers to Example 1.

MS m/z(ESI): 561.3[M+H] ⁺ .

Example 24 (4-Cyclopropyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H- Benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridine Preparation of pyridin-3-yl)methanone

(4-Cyclopropyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H- Refer to Example 18 for the preparation method of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.47(d, J =3.8Hz, 1H), 8.22(d, J =8.7Hz, 2H), 7.71(d, J =12.0Hz, 1H), 7.54(d, J = 8.5Hz, 1H), 5.04(m, 1H), 3.63(s, 2H), 3.50-3.29(m, 2H), 2.93(m, 1H), 2.83(s, 1H), 2.63(m, 8H) ), 2.35(s, 3H), 1.90(s, 1H), 1.76(s, 1H), 1.62(d, J = 6.9Hz, 6H), 1.19(s, 2H). ¹⁹ F NMR (376MHz, MeOD) δ: -130.7, -149.8.

MS m/z(ESI): 561.2[M+H] ⁺ .

Example 25 (4-(2,2-Difluoroethyl)-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl- Preparation of 2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(2,2-Difluoroethyl)-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl- Refer to Example 1 for the preparation method of 2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

MS m/z(ESI): 585.3[M+H] ⁺ .

Example 26 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 18 for the preparation method of 2-methylpyridin-3-yl)(4-(2-hydroxyethyl)-1,4-diazepan-1-yl)methanone.

MS m/z(ESI): 565.3[M+H] ⁺ .

Example 27 4-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino )-2-methylpyridin-3-yl)-1,7-dimethyl-1,4-diazepin-5-one preparation

4-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino )-2-methylpyridin-3-yl)-1,7-dimethyl-1,4-diazoheptan-5-one was prepared by referring to Example 2.

MS m/z(ESI): 535.3[M+H] ⁺ .

Example 28 3-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino )-2-methylpyridin-3-yl)-1,3-oxazidinecyclo-2-one preparation

3-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino )-2-methylpyridin-3-yl)-1,3-oxazidinecyclo-2-one was prepared with reference to Example 2.

MS m/z(ESI): 494.2[M+H] ⁺ .

Example 29 4-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino )-2-methylpyridin-3-yl)-1-methyl-1,4-diazepin-5-one preparation

4-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino )-2-methylpyridin-3-yl)-1-methyl-1,4-diazepin-5-one was prepared by referring to Example 2.

MS m/z(ESI): 521.2[M+H] ⁺ .

Example 30 1-Ethyl-4-(6-((5-Fluoro-4-(4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 Preparation of -yl)amino)-2-methylpyridin-3-yl)-1,4-diazepin-5-one

1-Ethyl-4-(6-((5-Fluoro-4-(4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 The preparation method of -yl)amino)-2-methylpyridin-3-yl)-1,4-diazepan-5-one- is referred to in Example 2.

MS m/z(ESI): 535.3[M+H] ⁺ .

Example 31 1-Ethyl-4-(6-((5-Fluoro-4-(4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 Preparation of -yl)amino)-2-methylpyridin-3-yl)-7-methyl-1,4-diazepin-5-one

1-Ethyl-4-(6-((5-Fluoro-4-(4-Fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2 -yl)amino)-2-methylpyridin-3-yl)-7-methyl-1,4-diazepin-5-one For the preparation method of the example 2.

MS m/z(ESI): 549.3[M+H] ⁺ .

Example 32 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-((2-(2-methoxyethoxy)ethyl)amino)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-((2-(2-methoxyethoxy)ethyl)amino)piperidin-1-yl)methanone.

MS m/z(ESI): 623.3[M+H] ⁺ .

Example 33 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(hexylamino)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-(hexylamino)piperidin-1-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.97(s, 1H), 8.64(d, J =7.4Hz, 2H), 8.44(d, J =8.0Hz, 1H), 8.24(d, J =11.0Hz, 1H), 7.73(d, J =8.3Hz, 1H), 5.19(s, 1H), 3.51(s, 1H), 3.09(d, J =6.8Hz, 3H), 3.03(s, 3H), 2.25( s, 2H), 1.86(d, J =6.4Hz, 6H), 1.76(s, 4H), 1.46(s, 2H), 1.43-1.30(m, 5H), 0.96(t, J =6.5Hz, 3H ).

MS m/z(ESI): 605.3[M+H] ⁺ .

Example 34 (4-((2,2-Difluoroethyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Preparation of -1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-((2,2-Difluoroethyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Refer to Example 3 for the preparation method of -1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD)): δ: 8.97 (d, J = 3.1 Hz, 1H), 8.60 (s, 1H), 8.35-8.15 (m, 2H), 7.80-7.54 (m, 1H), 6.39 (t, J =53.7Hz, 2H), 5.30-5.05(m, 1H), 3.90-3.55(m, 4H), 3.15 -3.05(m, 1H), 2.99(s, 3H), 2.77(s, 3H) ),3.40-2.10(m,2H),1.90-1.65(m,8H).

¹⁹ F NMR (400MHz, MeOD): δ: -124.27(s), -129.21(s), -143.14(s).

MS m/z (ESI): 585.2 [M+H] ⁺ .

Example 35 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-((2,2,2-trifluoroethyl)amino)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-((2,2,2-trifluoroethyl)amino)piperidin-1-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.95(d, J =2.8Hz, 1H), 8.63(m, 2H), 8.42(d, J =8.7Hz, 1H), 8.23(d, J =11.1Hz, 1H), 7.73(d, J = 8.9Hz, 1H), 5.25-5.10(m, 1H), 4.17(q, J =9.0Hz, 2H), 3.67(s, 1H), 3.37(m, 4H), 3.00(s, 3H), 2.39-2.19(m, 2H), 1.83(m, J = 11.6Hz, 8H).

¹⁹ F NMR (376MHz, MeOD) δ: -69.8, -129.2, -142.6.

MS m/z(ESI): 603.2[M+H] ⁺ .

Example 36 (4-((Cyclopropylmethyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H- Preparation of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-((Cyclopropylmethyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H- Refer to Example 3 for the preparation method of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.99(d, J =3.1Hz, 1H), 8.63(s, 1H), 8.27(t, J =8.1Hz, 2H), 7.59(d, J =8.9Hz, 1H), 5.19(dt, J =13.8, 6.8Hz, 1H), 3.79(d, J =13.6Hz, 1H), 3.52(s, 1H), 3.01(d, J =7.0Hz, 6H), 2.78( s, 3H), 2.30(d, J =11.0Hz, 1H), 2.17(d, J =10.2Hz, 1H), 1.85(d, J =6.9Hz, 6H), 1.74(s, 2H), 1.15( td, J =7.8,3.9Hz,1H),0.76(q, J =5.8Hz,2H),0.47(q, J =4.8Hz,2H).

MS m/z(ESI): 573.5[M+H] ⁺ .

Example 37 (4-(Cyclobutylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d ] Preparation of imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(Cyclobutylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d ] The preparation method of imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone refers to Example 3.

¹ H NMR (400MHz, MeOD)δ: 8.88(s, 1H), 8.57-8.45(m, 1H), 8.14(d, J =11.0Hz, 2H), 7.49(d, J =7.9Hz, 1H), 5.20-5.04(m, 1H), 4.66(d, J =11.9Hz, 1H), 3.86(d, J =7.1Hz, 1H), 3.65(s, 1H), 3.35(s, 1H), 2.90(d , J =7.7Hz,4H),2.66(s,3H),2.31-2.18(m,3H),2.17-1.97(m,2H),1.88(d, J =16.2Hz,2H),1.72(t, J =8.8Hz,6H),1.61(s,2H).

MS m/z(ESI): 573.3[M+H] ⁺ .

Example 38 (4-((2,2-Difluorocyclopropyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Preparation of yl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-((2,2-Difluorocyclopropyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Refer to Example 3 for the preparation method of yl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

MS m/z(ESI): 597.3[M+H] ⁺ .

Example 39 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-((2-fluorocyclopropyl)amino)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-((2-fluorocyclopropyl)amino)piperidin-1-yl)methanone.

MS m/z(ESI): 579.3[M+H] ⁺ .

Example 40 (4-(Cyclopentylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d ] Preparation of imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(Cyclopentylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d ] The preparation method of imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone refers to Example 3.

MS m/z(ESI): 589.3[M+H] ⁺ .

Example 41 (4-((4,4-Difluorocyclohexyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Preparation of -1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-((4,4-Difluorocyclohexyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Refer to Example 3 for the preparation method of -1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.56(d, J =3.8Hz, 1H), 8.32(d, J =10.1Hz, 2H), 7.79(d, J =11.9Hz, 1H), 7.61(s, 1H), 7.31(s, 1H), 4.69(d, J = 12.7Hz, 1H), 3.60(s, 1H), 3.19(t, J = 12.7Hz, 1H), 2.97(s, 2H), 2.86( s, 1H), 2.70(s, 3H), 2.46(s, 3H), 1.93(ddd, J =30.6, 29.7, 16.7Hz, 7H), 1.73(d, J =6.9Hz, 6H), 1.49(d , J =9.9Hz,2H),1.30(s,3H).

MS m/z(ESI): 639.2[M+H] ⁺ .

Example 42 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- 2-Methylpyridin-3-yl)(4-((2-hydroxyethyl)amino) Preparation of piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-((2-hydroxyethyl)amino)piperidin-1-yl)methanone.

MS m/z(ESI): 565.3[M+H] ⁺ .

Example 43 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-((2-methoxyethyl)amino)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-((2-methoxyethyl)amino)piperidin-1-yl)methanone.

MS m/z(ESI): 579.3[M+H] ⁺ .

Example 44 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)) Preparation of pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)(4-(N-morpholinyl)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-(N-morpholinyl)piperidin-1-yl)methanone.

¹ H NMR (400MHz, MeOD) δ: 8.56(d, J =3.8Hz, 1H), 8.31(m, 2H), 7.77(d, J =11.9Hz, 1H), 7.61(s, 1H), 4.91( m, 1H), 4.73(d, J =12.1Hz, 1H), 3.82-3.69(m, 4H), 3.65(d, J =13.0Hz, 1H), 3.17(t, J =12.3Hz, 1H), 2.92(dd, J =27.2,15.4Hz,1H),2.78-2.53(m,8H),2.45(s,3H),2.10(d, J =10.2Hz,1H),1.94(d, J =12.0Hz ,1H),1.73(d, J =6.9Hz,6H),1.49(m,2H).

¹⁹ F NMR (376 MHz, MeOD) δ: -130.5, -149.5.

MS m/z(ESI): 591.3[M+H] ⁺ .

Example 45 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(3,3,4-trimethylpiperazin-1-yl)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-(3,3,4-trimethylpiperazin-1-yl)piperidin-1-yl)methanone.

MS m/z(ESI): 632.4[M+H] ⁺ .

Example 46 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- The preparation method of 2-methylpyridin-3-yl)(4-(4-methyl-4,7-diazaspiro[2.5]octan-7-yl)piperidin-1-yl)methanone is referred to Example 3.

MS m/z(ESI): 630.3[M+H] ⁺ .

Example 47 (4-((3,3-Difluorocyclobutyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) yl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methyl Preparation of pyridin-3-yl)methanone

(4-((3,3-Difluorocyclobutyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Refer to Example 3 for the preparation method of yl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

MS m/z(ESI): 611.3[M+H] ⁺ .

¹ H NMR (400MHz, MeOD)δ: 9.00(d, J =3.1Hz,1H), 8.63(s,1H), 8.28(t, J =11.1Hz,2H), 7.59(d, J =8.9Hz, 1H), 5.29-5.11(m, 1H), 4.80(d, J =13.5Hz, 1H), 3.97(dd, J =12.9, 7.2Hz, 1H), 3.79(d, J =12.4Hz, 1H), 3.56(s, 1H), 3.22-2.91(m, 8H), 2.78(s, 3H), 2.21(dd, J =54.2, 9.7Hz, 2H), 1.85(d, J =6.9Hz, 6H), 1.78 (d, J = 12.2Hz, 2H).

Example 48

(S)-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) Preparation of amino)-2-methylpyridin-3-yl)(4-(morpholin-2-ylmethyl)-1,4-diazepan-1-yl)methanone

(S)-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) Amino)-2-methylpyridin-3-yl)(4-(morpholin-2-ylmethyl)-1,4-diazepan-1-yl)methanone preparation method with reference to examples 18.

MS m/z(ESI): 620.3[M+H] ⁺ .

Example 49 (R)-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) Preparation of amino)-2-methylpyridin-3-yl)(4-(morpholin-2-ylmethyl)-1,4-diazepan-1-yl)methanone

(R)-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) Amino)-2-methylpyridin-3-yl)(4-(morpholin-2-ylmethyl)-1,4-diazepan-1-yl)methanone preparation method with reference to examples 18.

MS m/z(ESI): 620.3[M+H] ⁺ .

Example 50 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(6-methyl-3,6-diazabicyclo[3.2.1]octan-3-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation method of 2-methylpyridin-3-yl)(6-methyl-3,6-diazabicyclo[3.2.1]octan-3-yl)methanone.

¹ H NMR (400MHz, MeOD) δ: 8.58 (d, J =3.8Hz, 1H), 8.39-8.31 (m, 2H), 7.82 (d, J =11.9Hz, 1H), 7.68-7.59 (m, 1H) ),4.98-4.92(m,1H),3.65-3.50(m,1H),3.48-3.40(m,2H),3.27-2.96(m,2H),2.84-2.68(m,4H),2.65(s ,3H),2.57-2.36(m,5H),2.22-2.00(m,1H),2.00-1.80(m,1H),1.74(d, J =6.9Hz,6H).

MS m/z(ESI): 5847.2[M+H] ⁺ .

Example 51 (4-(Cyclopropyl(methyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H- Preparation of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(Cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d ]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone (200 mg, 0.357 mmol), 30% aqueous formaldehyde (2 ml) in methanol (10 ml) and stirring , Sodium triacetoxyborohydride (227 mg) was added, and the mixture was stirred at room temperature for 3 h. Water was added, extracted with dichloromethane, dried, and purified to give an off-white solid (201.7 mg, 98.4% yield).

¹ H NMR (400MHz, MeOD) δ: 9.00(s, 1H), 8.63(s, 1H), 8.44-8.18(m, 2H), 7.60(d, J =7.9Hz, 1H), 5.26-5.14(m ,1H),4.87-4.82(m,1H),3.80(d, J =9.4Hz,2H),3.35(s,1H),3.02(d, J =9.3Hz,8H),2.78(s,3H) ,2.36(t, J =48.6Hz,2H),1.94(s,2H),1.85(d, J =6.5Hz,6H),1.29(d, J =8.6Hz,2H),1.05(d, J = 29.8Hz, 3H).

MS m/z(ESI): 575.3[M+H] ⁺ .

Example 52 (4-(Cyclopropyl(isopropyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H - Preparation of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(Cyclopropyl(isopropyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H - The preparation method of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone refers to Example 51.

MS m/z(ESI): 603.7[M+H] ⁺ .

Example 53 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation method of 2-methylpyridin-3-yl)(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)methanone.

MS m/z(ESI): 56].6[M+H] ⁺ .

Example 54 (4-(2-(Dimethylamino)ethyl)-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl) Preparation of yl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(2-(Dimethylamino)ethyl)-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl) Refer to Example 18 for the preparation method of yl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

MS m/z(ESI): 592.7[M+H] ⁺ .

Example 55 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-((1-methylpiperidin-4-yl)amino)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-((1-methylpiperidin-4-yl)amino)piperidin-1-yl)methanone.

MS m/z(ESI): 561.6[M+H] ⁺ .

Example 56 (4-(3,3-Dimethylpiperazin-1-yl)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-iso) Preparation of propyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(3,3-Dimethylpiperazin-1-yl)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Refer to Example 3 for the preparation method of yl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

MS m/z(ESI): 618.7[M+H] ⁺ .

Example 57 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-((1-methylcyclopropyl)amino)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-((1-methylcyclopropyl)amino)piperidin-1-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.58(d, J =3.8Hz, 1H), 8.35(s, 1H), 7.82(d, J =11.9Hz, 1H), 7.62(d, J =8.3Hz, 1H), 7.40-7.34(m, 1H), 5.00-4.92(m, 1H), 4.80-4.66(m, 1H), 3.74-3.58(m, 1H), 3.54-3.42(m, 1H), 3.30- 3.12(m,1H),3.09-2.91(m,1H),2.71(s,3H),2.60-2.38(m,4H),2.25-2.10(m,1H),2.10-1.89(m,1H), 1.74(d, J =6.9Hz,6H),1.56-1.42(m,1H),1.31(s,3H),0.83-0.67(m,2H),0.66-0.50(m,2H).

MS m/z(ESI): 575.7[M+H] ⁺ .

Example 58 1-((1-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2- Preparation of phenyl)amino)-2-methylnicotinoyl)piperidin-4-yl)amino)cyclopropane-1-carbonitrile

1-((1-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2- For the preparation method of cyclopropane-1-carbonitrile , refer to Example 3.

¹ H NMR (400MHz, MeOD) δ: 8.51(d, J =3.7Hz, 1H), 8.24(s, 1H), 8.08(d, J =8.5Hz, 1H), 7.98(s, 1H), 7.72( d, J =11.8Hz,1H),7.58(d, J =8.5Hz,1H),4.89-4.81(m,1H),4.47-4.27(m,1H),3.53-3.41(m,1H),3.19 -3.00(m,3H),2.61(s,3H),2.38(s,3H),2.06-1.92(m,1H),1.92-1.79(m,1H),1.62(d, J =6.9Hz,6H ),1.45-1.18(m,2H),1.19-0.85(m,4H).

MS m/z(ESI): 585.7[M+H] ⁺ .

Example 59

(1,4-Diazabicyclo[3.2.2]nonan-4-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H - Preparation of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(1,4-Diazabicyclo[3.2.2]nonan-4-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H - The preparation method of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone refers to Example 1.

¹ H NMR (400MHz, MeOD)δ: 8.88(d, J =3.2Hz, 1H), 8.52(s, 1H), 8.26(t, J =9.8Hz, 1H), 8.15(d, J =11.1Hz, 1H), 7.49(d, J =8.8Hz, 1H), 5.09(dt, J =13.7, 6.8Hz, 1H), 4.87(s, 1H), 4.14(s, 1H), 3.82(s, 1H), 3.52(m,6H),2.91(s,3H),2.77-2.63(m,3H),2.33(d, J =6.3Hz,2H),2.19(d, J =4.9Hz,2H),1.73(d , J =6.9Hz,6H).

¹⁹ F NMR (376 MHz, MeOD) δ: -129.1, -142.6.

MS m/z(ESI): 546.3[M+H] ⁺ .

Example 60 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(3,3,3-trifluoropropyl)-1,4-diazepan-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 1 for the preparation method of 2-methylpyridin-3-yl)(4-(3,3,3-trifluoropropyl)-1,4-diazepan-1-yl)methanone.

MS m/z(ESI): 617.6[M+H] ⁺ .

Example 61 [1,4'-Bipiperidin]-1'-yl(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole Preparation of -6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

[1,4'-Bipiperidin]-1'-yl(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole Refer to Example 1 for the preparation method of -6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 9.00(d, J =3.1Hz, 1H), 8.64(s, 1H), 8.28(t, J =13.7Hz, 2H), 7.60(d, J =8.8Hz, 1H), 5.27-5.15(m, 1H), 4.85(s, 1H), 3.83(d, J = 12.8Hz, 1H), 3.59(s, 3H), 3.37(s, 1H), 3.17-2.93(m ,6H),2.78(s,3H), 2.34(d, J =11.6Hz,1H),2.20(d, J =8.9Hz,1H),2.01(d, J =14.0Hz,2H),1.97-1.88 (m, 3H), 1.85(d, J =6.9Hz, 8H), 1.56(d, J =12.5Hz, 1H).

MS m/z(ESI): 589.3[M+H] ⁺ .

Example 62 (4-(Cyclopropylamino)piperidin-1-yl)(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H- Preparation of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone

(4-(Cyclopropylamino)piperidin-1-yl)(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H- Refer to Example 3 for the preparation method of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)pyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.71(d, J =3.4Hz, 1H), 8.58(d, J =1.0Hz, 1H), 8.38(dd, J =8.3, 1.9Hz, 1H), 8.16( d, J =11.4Hz,1H),8.02-7.87(m,1H),5.22-5.05(m,1H),3.83(s,1H),3.62(t, J =11.6Hz,1H),2.97(s ,3H),2.89-2.77(m,1H),2.25(dd, J =32.2,24.6Hz,2H),1.83(d, J =6.9Hz,6H),1.68(dd, J =12.3,4.3Hz, 2H), 1.33(d, J =19.0Hz, 2H), 1.01-0.90(m, 4H).

MS m/z(ESI): 565.6[M+H] ⁺ .

Example 63 (4-(Cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-benzo[d]imidazole-6 Preparation of -yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(Cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-benzo[d]imidazole-6 The preparation method of -yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone refers to Example 3.

¹ H NMR (400MHz, MeOD) δ: 8.96(s, 1H), 8.78(s, 1H), 8.42(d, J =8.1Hz, 1H), 8.29(s, 1H), 8.04(d, J =8.1 Hz, 1H), 7.61(d, J =7.9Hz, 1H), 5.19(s, 1H), 4.82-4.72(m, 2H), 3.72(d, J =57.5Hz, 2H), 3.04(d, J =15.4Hz, 4H), 2.80(d, J =24.0Hz, 4H), 2.46-2.16(m, 2H), 1.85(d, J =6.4Hz, 8H), 1.08-0.87(m, 4H).

MS m/z(ESI): 543.2[M+H] ⁺ .

Example 64 (S)-(3,4-Dimethyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2 Preparation of -methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(S)-(3,4-Dimethyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2 The preparation method of -methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone refers to Example 1.

¹ H NMR (400MHz, MeOD) δ: 8.54 (s, 1H), 8.32-8.04 (m, 2H), 7.72-7.48 (m, 2H), 4.86-4.73 (m, 1H), 3.95 (m, 1H) ,3.74-3.48(m,1H),3.40(m,2H),3.05(s,2H),2.93-2.68(m,1H),2.63(s,3H),2.51(s,2H),2.41(m ,4H),2.06(s,1H),1.91(s,1H),1.66(s,6H),1.26(d, J =6.6Hz,2H),0.93(d, J =6.3Hz,1H).

¹⁹ F NMR (376 MHz, MeOD) δ: -130.2, -149.0.

MS m/z(ESI): 548.3[M+H] ⁺ .

Example 65 N-(3,3-Difluorocyclobutyl)-N-(1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo Preparation of [d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylnicotinoyl)piperidin-4-yl)acetamide

(4-((3,3-Difluorocyclobutyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) yl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone (200 mg, 0.328 mmol) was dissolved in dichloromethane (10 ml) ), triethylamine (1ml) was added, acetic anhydride (1ml) was added dropwise, and the mixture was stirred at room temperature for 3h. Add water, extract with dichloromethane, dry and purify to obtain 180.3 mg of the target product with a yield of 84.3%.

¹ H NMR (400MHz, MeOD)δ: 9.00(d, J =3.2Hz, 1H), 8.63(s, 1H), 8.26(d, J =11.1Hz, 1H), 7.58(d, J =8.9Hz, 1H), 5.27-5.12(m, 1H), 4.79(s, 1H), 4.12-3.46(m, 2H), 3.35(s, 1H), 3.33(dt, J =3.3, 1.6Hz, 8H), 3.02 (s, 4H), 2.78(s, 3H), 2.65(s, 1H), 2.22(s, 3H), 1.82(t, J =18.9Hz, 9H). MS m/z(ESI): 653.2[M +H] ⁺ .

Example 66 (4-allyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H- Preparation of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-allyl-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H- Refer to Example 18 for the preparation method of benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.53(s, 1H), 8.12(d, J =17.1Hz, 2H), 7.53(d, J =7.9Hz, 2H), 6.07-5.78(m, 1H), 5.27(dt, J =48.5, 14.5Hz, 2H), 4.82(d, J =6.7Hz, 1H), 3.84(d, J =16.7Hz, 2H), 3.47(d, J =15.2Hz, 2H), 3.20(d, J =5.7Hz, 1H), 2.98(s, 1H), 2.81(s, 2H), 2.71(s, 1H), 2.60(d, J =7.4Hz, 3H), 2.41(d, J =4.9Hz,3H),2.02(s,1H),1.87(s,1H),1.64(s,6H).

¹⁹ F NMR (376 MHz, MeOD) δ: -130.0, -148.7.

MS m/z(ESI): 560.2[M+H] ⁺ .

Example 67 (4-(Cyclopropylmethyl)-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Preparation of yl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(Cyclopropylmethyl)-1,4-diazepan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl) Refer to Example 18 for the preparation method of yl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

¹ H NMR (400MHz, MeOD) δ: 8.45 (d, J =3.3Hz, 1H), 8.35-8.12 (m, 2H), 7.77-7.52 (m, 2H), 4.90-4.81 (m, 1H), 4.16 -3.63(m,3H),3.65-3.26(m,5H),3.14-2.89(m,2H),2.59(s,3H),2.36(s,3H),2.30-1.96(m,2H),1.60 (d, J =9.0Hz,6H),1.16-0.97(m,1H),0.77-0.56(m,2H),0.48-0.19(m,2H).

MS m/z(ESI): 575.2[M+H] ⁺ .

Example 68 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(N-azetidinyl)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-6- The preparation method of (4-(N-azetidinyl)piperidin-1-yl)methanone is as follows:

1-(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl- 1H -benzo[ d ]imidazol-6-yl)pyrimidin-2-yl) Amino)-2-methylnicotinyl)piperidin-4-one (350 mg, 0.67 mmol), azetidine hydrochloride (126 mg, 1.34 mmol) was dissolved in dichloromethane (5 mL) and methanol ( 15mL) in the mixed solvent, tetraethyl titanate (458mg, 2.0mmol) was added, the reaction was stirred at room temperature for 10 hours, sodium borohydride (425mg, 2.0mmol) was added to the reaction solution, and the reaction was stirred at room temperature. After 3 hours, LCMS showed that the reaction was complete, the reaction solution was added to saturated sodium bicarbonate solution (5 mL), stirred for 30 minutes, added with anhydrous sodium sulfate, filtered, and directly spin-dried. Purification by column chromatography gave the product as a light grey solid (159 mg, 42% yield).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ: 10.22 (s, 1H), 8.71 (s, 1H), 8.31 (s, 1H), 8.14 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 11.9Hz, 1H), 7.56(d, J =8.3Hz, 1H), 4.94-4.76(m, 1H), 4.08(s, 1H), 3.12(d, J =44.4Hz, 6H), 2.65( s, 3H), 2.28(d, J =47.8Hz, 4H), 1.91(s, 2H), 1.60(t, J =20.1Hz, 8H), 1.27-0.83(m, 3H).

¹⁹ F NMR (376 MHz, DMSO- d ₆ ) δ: -128.75, -148.44.

MS m/z(ESI): 561.3[M+H] ⁺

Example 69 (4-(Cyclohexyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d ] Preparation of imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(Cyclohexyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d ]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone The preparation method refers to Example 68.

¹ H NMR (400MHz, DMSO- d ₆ ) δ: 10.98(s,1H), 9.17(s,1H), 8.87(s,1H), 8.41(s,1H), 8.18-7.56(m,3H), 4.95(s, 1H), 4.58(s, 1H), 3.49(s, 1H), 3.07(s, 1H), 2.80(s, 3H), 2.48(d, J =17.7Hz, 10H), 2.06(t , J =27.0Hz,3H),1.83-1.57(m,8H),1.43-1.06(m,5H).

¹⁹ F NMR (376MHz, DMSO) δ -127.75, -127.75.

MS m/z(ESI): 603.3[M+H] ⁺ .

Example 70 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-((3,3,3-trifluoropropyl)amino)piperidin-]-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-((3,3,3-trifluoropropyl)amino)piperidin-1-yl)methanone.

¹ H NMR (400MHz, MeOD)δ: 8.57(d, J =3.8Hz, 1H), 8.33(d, J =6.9Hz, 2H), 7.80(d, J =11.8Hz, 1H), 7.62(d, J =8.5Hz,1H),4.74(d, J =12.6Hz,1H),3.67(d, J =12.2Hz,1H),3.37(s,1H),3.23(t, J =13.5Hz,1H) ,3.17-3.06(m,3H),3.00(t, J =12.5Hz,1H),2.71(s,3H),2.55(dt, J =15.7,9.2Hz,2H),2.46(s,3H), 2.20(dd, J =17.7, 10.0Hz, 1H), 2.01(d, J =10.2Hz, 1H), 1.73(d, J =6.9Hz, 6H), 1.46(dd, J =45.8, 11.0Hz, 1H) ),1.33(d, J =19.4Hz,1H).

MS m/z(ESI): 617.2[M+H] ⁺ .

Example 71 (4-(T-butylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo Preparation of [d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(T-butylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo [d] For the preparation method of imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone, refer to Example 3.

MS m/z(ESI): 577.2[M+H] ⁺ .

Example 72 (6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Preparation of 2-methylpyridin-3-yl)(4-(isopropylamino)piperidin-1-yl)methanone

(6-((5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- Refer to Example 3 for the preparation method of 2-methylpyridin-3-yl)(4-(isopropylamino)piperidin-1-yl)methanone.

¹ H NMR (400 MHz, MeOD) δ: 8.52 (d, J =3.8 Hz, 1H), 8.33-8.18 (m, 2H), 7.76 (d, J =11.9 Hz, 1H), 7.56 (d, J =8.6 Hz, 1H), 4.87(m, 1H), 4.78(m, 1H), 3.65(s, 1H), 3.52(dd, J = 12.8, 6.5Hz, 2H), 3.22(m, 1H), 2.90(d , J =13.0Hz,1H),2.64(s,3H),2.40(s,3H),2.17(s,1H),2.00(s,1H),1.68(t, J =11.1Hz,6H),1.47 (d, J =43.5Hz,2H),1.30(d, J =6.5Hz,6H).

¹⁹ F NMR (376 MHz, MeOD) δ: -130.6, -149.5.

MS m/z(ESI): 562..3[M+H] ⁺ .

Example 73 (4-((4,4-Difluorocyclohexyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-benzene) Preparation of [d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-((4,4-Difluorocyclohexyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-benzene) Refer to Example 3 for the preparation method of [d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

MS m/z(ESI): 621.2[M+H] ⁺ .

Example 74 (4-(Cyclobutylamino)piperidin-1-yl)(6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-benzo[d]imidazole-6 Preparation of -yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(Cyclobutylamino)piperidin-1-yl)(6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-benzo[d]imidazole-6 The preparation method of -yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone refers to Example 3.

MS m/z(ESI): 557.2[M+H] ⁺ .

Biological Test Evaluation

The present invention is further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

1. Analysis and detection method for the enzymatic activity of the compounds of the present invention:

In this experiment, the LANCE (Lanthanide chelate excite) kinase assay technology was used to detect and analyze the enzymatic inhibitory activity of the test compounds on CDK4/6. The method is briefly described as follows: 1) Add different concentrations of compounds to the 384-well experimental plate (Greiner, Cat. No. 784076), and set double wells for each concentration, and then add CDK4 (Carna, Cat. No. 04-105), Or CDK6 kinase CDK6 (Carna, Cat. No. 04-107), after mixing evenly; 2) Add the mixture of substrate Ulight-MBP peptide (PerkinElmer, Cat. No. TRF0109-D) and ATP; 3) Chamber After 60 minutes of warm reaction, EDTA was added to terminate the reaction, and the antibody Europium-anti-phospho-Myelin BasicProtein (MBP) (PerkinElmer, Cat.No.TRF0109-D) was added after 5 minutes of incubation; 4) After 60 minutes of incubation at room temperature, test on the machine (λ ex=330nm, λ em=620nm and λ em=665nm) 5) Collect and calculate data according to the following formula: signal value=OD665/OD620*10000; inhibition rate (%)=100-(signal value-min)/ (max-min)*100.

And use Graphpad 5.0 software for data analysis and fitting calculation IC50, the list of obtained data is as follows:

It can be seen from the above experimental results that the compounds of the examples of the present invention have strong inhibitory activity on CDK kinase activity, especially on CDK 4 and/or 6 kinase activity, and have good inhibitory activity and selectivity.

2. Determination of the proliferative activity of the compounds of the present invention on colon cancer tumor cell colo205

The compounds were tested for the proliferation activity of colon cancer tumor cell colo205 by the following method.

This method is used to determine the inhibitory effect of the compounds of the present invention on the proliferation activity of colon cancer tumor cells colo205.

Experimental steps:

In this experiment, the method of CellTiter-Glo was used to test the inhibitory effect of the compound on the proliferation of colo205 cells, and the median inhibitory concentration IC ₅₀ of the compound's inhibitory activity on cell proliferation was obtained.

1. Inoculate 50~100μL of colo205 cell suspension in a 96-well cell culture plate at a density of 1~5*10 ⁴ cells/ml, and incubate the culture plate in an incubator for 16~24 hours (37°C, 5% CO _{2 )} . ).

2. Add the solution of the compound to be tested at different concentrations diluted by gradient to the cells in the culture plate, and incubate the culture plate in an incubator for 6 days (37° C., 5% CO ₂ ).

3. Add 50~100μL of CellTiter-Glo reagent to each well, shake for 10 minutes, and stand at room temperature for 10 minutes.

4. Measure the chemiluminescence signal value of each plate with a microplate reader.

5. Calculate the inhibition rate from the chemiluminescence signal value.

6. According to the inhibition rate of different concentrations, the IC ₅₀ of the compound is obtained by curve fitting.

The compounds of the present invention were tested for the proliferation activity of colon cancer tumor cell colo205, and the IC ₅₀ values measured are shown in Table 2.

It can be seen from the above experimental results that the compounds of the examples of the present invention have a strong inhibitory effect on the proliferation activity of colon cancer tumor cells colo205.

3. Determination of Pharmacokinetics in Rats

1. Research purposes:

SD rats were used as test animals to study the pharmacokinetic behavior of compound 3, compound 34 and compound 63 in rat body (plasma) after oral administration.

2. Experimental protocol

2.1 Test drug:

Compound 3, compound 34 and compound 63 in the examples of the present invention were prepared by self-preparation.

2.2 Experimental animals:

3 SD rats, male, Shanghai Jisijie Laboratory Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 No.311620400001794).

2.3 Drug preparation:

Weigh 10 g of hydroxyethyl cellulose (HEC), dissolve it in 1000 mL of purified water, and add 2.5 mL of Tween80 and 0.5 mL of anti-foaming agent. Mix well into a clear solution. Weigh 6.1 mg of Example Compound 3, 6.9 mg of Example Compound 34, and 5.8 mg of Example Compound 63, respectively, dissolved in the solution, shaken well, and sonicated for 15 minutes to obtain a colorless and clear solution with a concentration of 0.5 mg/mL.

2.4 Administration:

Three SD rats, male, were fasted overnight and PO respectively, the dose was 5 mg/kg, and the administration volume was 10 mL/kg.

2.5 Sample collection:

Before administration and at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24.0 h after administration, 0.2 mL of blood was collected from the jugular vein, placed in an EDTA-2K test tube, centrifuged at 6000 rpm at 4°C for 6 min to separate plasma, and stored at -80°C; Food was taken 4 hours after administration.

2.5 Determination results: The final determination results were obtained by applying the LCMS/MS method, see Table 3

Experimental conclusion: The data in the table shows that when the oral dose is 5 mg/kg, the three compounds of the present invention, Example 3, Example 34 and Example 63, all achieve high exposure in rat plasma. The maximum plasma concentration and duration of action were significantly different, but the AUC was less different. Effective concentration can be guaranteed.

4. Determination of Pharmacokinetics in Tumor-bearing Mice

1. Research purposes:

Colo205 tumor-bearing mice were used as test animals to study the pharmacokinetic behaviors of Compound Example Compound 3, Compound 34 and Compound 63 in mice (plasma and tumor tissue) administered orally at a dose of 50 mg/kg.

2. Experimental protocol

2.1 Test drug:

Compound 3, compound 34 and compound 63 in the examples of the present invention were self-made.

2.2 Experimental animals:

Nude mouse 3, male, Shanghai Jisijie Laboratory Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

2.3 Drug preparation:

Weigh 10 g of hydroxyethyl cellulose (HEC), dissolve it in 1000 mL of purified water, and add 2.5 mL of Tween80 and 0.5 mL of anti-foaming agent. Mix well into a clear solution. Weigh 36.6 mg of Example Compound 3, 22.6 mg of Example Compound 34, and 35.2 mg of Example Compound 63, respectively, dissolved in the solution, shake well, and sonicated for 15 minutes to obtain a colorless clear solution with a concentration of 5.0 mg/mL.

2.4 Administration:

3 Colo205 tumor-bearing mice, male; p.o. after overnight fasting, the dose is 50 mg/kg, and the administration volume is 10 mL/kg.

2.5 Sample collection:

Before and after administration, the mice were sacrificed by _CO2 , 0.2 ml of blood was collected from the heart, placed in an EDTA-2K test tube, centrifuged at 6000 rpm at 4°C for 6 min to separate the plasma, and stored at -80°C; after weighing the tumor tissue, it was placed in 2 mL in a centrifuge tube and stored at -80°C.

2.5 Measurement results: The LCMS/MS method was used to obtain the final measurement results, as shown in Table 4.

Experimental conclusion: As shown in the data in the table, under the dose of 50mg/kg, the exposure of Example 3, Example 34 and Example 63 in mouse plasma and tumor reached a very high level, Example 3 and Example 63 The exposure in the tumor is significantly higher than that in the blood, and it can be seen from the Tmax and MRT that the concentration in the tumor is a gradual increase process, and the metabolism is slower, indicating that the compound will gradually accumulate in the tumor, and has been in the tumor. A higher concentration is maintained in the tumor, thereby ensuring a better tumor inhibition effect.

5. Tumor inhibition experiment on Colo205 xenograft model

5.1 The purpose of the experiment:

BALB/c nude mice were used as the test animals, and the human colorectal cancer cell Colo205 xenograft (CDX) model was used to conduct in vivo drug efficacy experiments to evaluate the antitumor effects of the test compounds.

5.2 Experimental instruments and reagents:

5.2.1 Instruments:

Ultra-clean workbench (BSC-1300II A2, Shanghai Boxun Industrial Co., Ltd. Medical Equipment Factory)

_CO2 incubator (Thermo)

Centrifuge (Centrifuge 5720R, Eppendorf)

Automated cell counter (Countess II, Life Technologies)

Pipette (10-20 μL, Eppendorf)

Microscope (TS100, Nikon)

Vernier caliper (500-196, Mitutoyo, Japan)

Cell culture flask (T25/T75/T225, Corning)

5.2.2 Reagents:

RPMI Medium 1640 (11875-093, Gibco)

Fetal Bovine Serum (FBS) (10099-141, Gibco)

0.25% trypsin (25200-056, Gibco)

Penicillin-streptomycin double antibody (SV30010, GE)

Phosphate Buffered Saline (PBS) (10010-023, Gibco)

5.3 Experimental operation:

Take out a Colo205 cell from the cell bank, recover the cells with 1640 medium (1640+10%FBS+1%Glu+1%SP), and place the recovered cells in a cell culture flask (mark the cell type and date on the bottle wall). , name of the cultivator, etc.) were cultured in a _CO2 incubator (incubator temperature was 37 °C, _CO2 concentration was 5%). The cells were subcultured after the cells covered 80-90% of the bottom of the culture flask. After subculture, the cells continued to be cultured in a _CO2 incubator. This process is repeated until the number of cells meets the in vivo efficacy requirements. The cultured cells were collected, counted with an automatic cell counter, and the cells were resuspended in PBS according to the counting results to prepare a cell suspension (density 4×10 ⁷ /ml). Store in ice box for later use.

BALB/c nude mice, female, 6-8 weeks old, weighing approximately 18-22 grams. Mice were maintained in a special pathogen-free environment and in single ventilated cages, 5 mice per cage. All cages, litter and water were disinfected prior to use. All animals had free access to standard certified commercial laboratory diets. Before inoculation, nude mice were marked with disposable ear tags for rats and mice, and the skin of the inoculation site was disinfected with 75% medical alcohol. Each mouse was seeded with Colo205 tumor cells subcutaneously in the right flank at a density of ⁴ x 106 cells per 0.1 ml for tumor growth. Dosing was initiated when the mean tumor volume reached 100-200 mm3. The test compounds were administered orally by gavage daily at a dose of 50 mg/kg. Tumor volume was measured with vernier calipers twice a week. Volume is measured in cubic millimeters. Calculated by the following formula: V=0.5*D*d*d, where D and d are the long and short diameters of the tumor, respectively. Antitumor efficacy was determined by dividing the mean tumor increase volume in compound-treated animals by the mean tumor increase volume in untreated animals. Tumor inhibition rate=1-[(Vt-V0) administration group/(Vt-V0) solvent control group]*100%. The animals were euthanized after the experiment.

Experimental conclusion: It can be seen from the data in the table that at the dose of 50 mg/kg, the compounds of the present invention Example 3, Example 34 and Example 63 significantly inhibit the growth of Colo205 nude mice transplanted tumor.

In the case where the tumor in the placebo group grew to 1763 cubic millimeters, the tumors in the animal group administered in Example 34 increased to 430 cubic millimeters, showing an excellent effect of inhibiting tumor growth. The tumor growth in the animal group was slower and the effect was more significant.

6. hERG potassium channel inhibitory activity test

6.1 Cell Culture

6.1.1 The cells used in this experiment were CHO cell lines (provided by Sophion Bioscience, Denmark) transfected with hERG, cDNA and stably expressing hERG channels, and the cell passages were P14 to P16. Cells were grown in medium containing) Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 μg/ml hygromycin B, 100 μg/ml Geneticin.

6.1.2 CHO hERG cells were grown in petri dishes containing the above culture medium and cultured at 37°C in an incubator containing 5% CO ₂ . 24 to 48 hours before electrophysiological experiments, CHO hERG cells were transferred to circular glass slides placed in petri dishes and grown in the same medium and culture conditions as above. The density of CHO hERG cells on each circular slide It is necessary to meet the requirement that the vast majority of cells are independent and single.

6.2 Experimental solution

The following solutions (recommended by Sophion) were used for electrophysiological recordings.

6.3 Electrophysiological recording system

In this experiment, a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) was used for whole-cell current recording. The circular slides with CHO hERG cells grown on the surface were placed in the electrophysiological recording chamber under an inverted microscope. The recording tank was continuously perfused with extracellular fluid (approximately 1 ml per minute). The experimental procedure used conventional whole-cell patch-clamp current recording technology. Unless otherwise specified, the experiments were carried out at normal room temperature (~25°C). Cells were clamped at -80mV. The cell clamp voltage was depolarized to +20 mV to activate the hERG potassium channel, and then clamped to -50 mV for 5 s to abolish inactivation and generate tail currents. The peak tail current was used as a numerical value for the magnitude of hERG current. After the hERG potassium current recorded in the above steps reaches a stable state under the continuous extracellular fluid perfusion in the recording tank, the drug to be tested can be superimposed and perfused until the inhibitory effect of the drug on the hERG current reaches a stable state. Generally, the most recent coincidence of three consecutive current recording lines is used as the criterion for judging whether it is in a stable state. After reaching a steady state, the cells were perfused with extracellular fluid until the hERG current returned to its pre-drug level. One or more drugs can be tested on a cell, or multiple concentrations of the same drug, but need to be flushed with extracellular fluid between drugs. Cisapride (cisapride, purchased from Sigma) was used in the experiments as a positive control to ensure that the cells used were of normal quality.

6.4 Compound Handling and Dilution

In order to obtain the _IC50 of the compounds, we selected the following concentrations (30, 10, 3, 1, 0.3 and 0.1, 3 (30, 10, 3, 1, 0.3 and 0.1 μM) for testing. DMSO was serially diluted to 10, 3, 1, 0.3, and 0.1 mM stock solutions, and then diluted 1000-fold with extracellular fluid to the final μM test concentration, except for the 30 μM test concentration, the final concentration of DMSO was 0.3%, The final concentration of DMSO in the other compound solutions was 0.1%. The positive control Cisapride (cisapride) was tested at a concentration of 0.1 μM. All compound solutions were routinely sonicated and shaken for 5 to 10 minutes to ensure complete dissolution of the compounds. .

6.5 Data Analysis

The experimental data were analyzed by data analysis software provided by HEKA Patchmaster (V2x73.2), Microsoft Excel and Graphpad Prism 5.0.

6.6 Quality Control

The test data in the report need to meet the following criteria:

Record parameters:

Membrane resistance Rm>500MΩ

Access resistance (Ra)<5MΩ

Tail current amplitude>300pA

Current rundown (spontaneous decrease) <2% per minute

Leakage current <200pA or 10% of peak hERG current (within 90% of recording time)

Pharmacological parameters:

Cisapride (C4740-10 mg, Sigma) at 0.1 μM blocked hERG currents by more than 50% as a positive control.

6.7 Experimental Results

The inhibition results of the embodiment on hERG current at multiple concentrations are shown in the following table:

Inhibition of cardiac hERG potassium channel by drugs is the main reason for drug-induced QT prolongation syndrome. It can be seen from the experimental results that Example Compound 3, Compound 34 and Compound 63 have basically no inhibitory effect on the cardiac hERG potassium ion channel.

In conclusion, the present invention provides a series of highly active and highly selective CDK4/6 kinase inhibitors with novel structures, with stronger enzymatic and cellular activities and better selectivity to kinases. It showed better pharmacokinetic properties and better efficacy in both rats and mice. Cardiotoxicity was significantly reduced. There is great potential to be developed into drugs for diseases of abnormal cell cycle proliferation. Especially for HR+/Her- breast cancer drugs.

Claims (31)

A compound represented by general formula (I), its stereoisomer or its pharmaceutically acceptable salt:

Wherein: L is -C(O)-; Ring A is heterocyclyl, wherein the heterocyclyl is selected from monocyclic heterocyclyl, spirocyclic heterocyclyl, fused ring heterocyclyl and bridged ring heterocyclyl; R is selected from hydrogen atom, deuterium atom or halogen; R ₁ is selected from deuterium atom, alkyl group, deuteroalkyl group, haloalkyl group, halogen, wherein the alkyl group and haloalkyl group are further selected from deuterium atom, alkyl group, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₆ , -SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C(O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -( CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ are substituted with one or more substituents; R ₂ are the same or different, and each is independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterium atom Alkyl, haloalkyl, alkoxy, aminoalkoxy, haloalkoxy, halogen, amino, pendant oxy, nitro, hydroxyl, cyano, cycloalkyl, heterocyclyl, aryl, Heteroaryl, -(CH ₂ ) _n OR ₃ , -(CH ₂ ) _n SR ₃ , -(CH ₂ ) _n C(O)R ₃ , -(CH ₂ ) _n C(O)OR ₃ , -( CH ₂ ) _n S(O) _m R ₃ , -(CH ₂ ) _n NR ₄ R ₅ , -(CH ₂ ) _n C(O)NR ₄ R ₅ , -(CH ₂ ) _n C(O)NHR ₄ , -(CH ₂ ) _n NR ₄ C(O)R ₅ and -(CH ₂ ) _n NR ₄ S(O) _m R ₅ , wherein the alkyl, deuteroalkyl, haloalkyl, aminoalkoxy , cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium, alkyl, haloalkyl, halogen, amine, nitro, cyano, hydroxy, alkenyl, alkynyl, Alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C(O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S( O) _m R ₈ is substituted by one or more substituents; R ₃ is selected from hydrogen atom, deuterium atom, alkyl group, deuteroalkyl group, haloalkyl group, hydroxyl group, amino group, alkoxy group, haloalkoxy group, cycloalkane wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from deuterium atoms, alkyl groups, halogens, Amine, nitro, cyano, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C(O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ is substituted by one or more substituents; R ₄ and R ₅ are the same or different, and are independently selected from hydrogen atoms, deuterium atoms, alkyl groups, deuteroalkyl groups, Haloalkyl, hydroxyl, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C( O)R ₆ , -(CH ₂ ) _n C(O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C (O)NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ , wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from the group consisting of deuterium atoms, alkyl, halogen, hydroxyl, amine, nitro, cyano, alkoxy, Hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C(O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ One of R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ or Substituted by multiple substituents; R ₆ is selected from hydrogen atom, deuterium atom, alkyl group, deuterated alkyl group, haloalkyl group, hydroxyl group, amino group, alkoxy group, haloalkoxy group , cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl , halogen, amine, nitro, cyano, hydroxyl, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and one or more substituents of heteroaryl; R ₇ and R ₈ are the same or different, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuteroalkyl group, a haloalkyl group, a hydroxyl group, an amine group, an ester group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group , wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from deuterium atoms, alkyl, halogen, hydroxyl, amine, nitro, cyano, ester, alkoxy substituted with one or more of the substituents in the group consisting of radical, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; x is an integer of 0, 1, 2, 3, 4 or 5; m is 0 and n is an integer of 0, 1, 2, 3, 4, or 5. The compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as described in the first item of the patent application scope, is a compound represented by the general formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

Wherein: ring B is selected from 3-8-membered monocyclic heterocyclic group, 6-10-membered spirocyclic heterocyclic group, 6-10-membered fused ring heterocyclic group or 6-10-membered bridged ring heterocyclic group; L is -C (O)-; R, R ₁ , R ₂ and x are as described in item 1 of the claimed scope. The compound represented by the general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to item 2 of the scope of the application, wherein ring B is a 3- to 8-membered monocyclic heterocyclic group. A compound represented by general formula (V), its stereoisomer or its pharmaceutically acceptable salt:

Wherein: M is CR ₂ R ₂ , NR ₂ or O; R is hydrogen atom or halogen; R ₁ is alkyl or halogen, wherein the alkyl is C _1-6 alkyl; R ₂ is the same or different, and each is independent is selected from hydrogen atom, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 aminoalkoxy, C _1-6 haloalkoxy, halogen, Amine, pendant oxy, nitro, hydroxyl, cyano, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH ₂ ) _n OR ₃ and -(CH ₂ ) _n NR ₄ R ₅ , wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 aminoalkoxy, C _3-8 cycloalkyl and 3-8 membered heterocyclic groups are further selected from C _1-6 alkyl, C _1-6 haloalkyl, halogen, amine, cyano, hydroxyl, alkenyl, alkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1- Substituted by one or more substituents among ₆ -hydroxyalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH ₂ ) _n OR ₆ and -(CH ₂ ) _n NR ₇ R ₈ ; Or two R ₂ are connected to each other to form a 3-10 membered cycloalkyl or heterocyclyl, wherein the 3-8 membered cycloalkyl or heterocyclyl is further modified by one or more C _1-6 as needed Alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 aminoalkoxy, C _1-6 haloalkoxy, halogen, amino, pendant oxy, hydroxyl, cyano and R ₃ is selected from hydrogen atom, deuterium atom, alkyl, _deuteroalkyl , haloalkyl, hydroxyl, amino, alkoxy, haloalkoxy, Cycloalkyl, heterocyclyl, aryl and heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, halogen, amine, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C(O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -( CH ₂ ) _n NR ₇ S(O) _m R ₈ is substituted with one or more substituents; R ₄ and R ₅ are the same or different, and are each independently selected from hydrogen atom, deuterium atom, alkyl group, deuterium atom group, haloalkyl, hydroxyl, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -( CH ₂ ) _n C(O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ , wherein the alkyl, Cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, halogen, hydroxy, amine, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl , heterocyclyl, aryl and heteroaryl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n SR ₆ , -(CH ₂ ) _n C(O)R ₆ , -(CH ₂ ) _n C (O)OR ₆ , -(CH ₂ ) _n S(O) _m R ₆ , -(CH ₂ ) _n NR ₇ R ₈ , -(CH ₂ ) _n C(O)NR ₇ R ₈ , -(CH ₂ ) _n C(O)NHR ₇ , -(CH ₂ ) _n NR ₇ C(O)R ₈ and -(CH ₂ ) _n NR ₇ S(O) _m R ₈ substituted by one or more substituents; R is selected from the group consisting of hydrogen atom, deuterium atom, alkyl group, _deuteroalkyl group, haloalkyl group, hydroxyl group, amino group, alkoxy group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from deuterium atoms, alkyl groups, halogens, amine groups, nitro groups, cyano groups, hydroxyl groups, hydroxyalkane groups substituted by one or more substituents of radical, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ₇ and R ₈ are the same or different, and are independently selected from hydrogen atoms, deuterium atoms , alkyl, deuteroalkyl, haloalkyl, hydroxyl, amine, ester, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from deuterium atoms, alkyl, halogen, hydroxy, amine, nitro, cyano, ester, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and one or more substituents in heteroaryl; x is an integer of 0, 1, 2, 3, 4 or 5; m is an integer of 0, 1 or 2; n is 0, 1, 2, 3 and y is an integer of 0, 1, 2, or 3. The compound represented by the general formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to the claim 4, wherein R is a fluorine atom. The compound represented by the general formula (V), a stereoisomer or a pharmaceutically acceptable salt thereof according to item 4 of the patent application scope, wherein R ₁ is a C _1-3 alkyl group. The compound represented by the general formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof as described in item 4 of the patent application scope, wherein two R ₂ are connected to each other to form a 5-8 membered cycloalkyl group or heterocyclyl. The compound represented by the general formula (V), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as described in item 4 of the patent application scope: wherein: M is selected from CHR ₂ or NR ₂ ; R ₂ is selected from hydrogen atom , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 aminoalkoxy, C _1-6 haloalkoxy, halogen, amino, side oxygen group, hydroxyl, cyano, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH ₂ ) _n OR ₃ and -(CH ₂ ) _n NR ₄ R ₅ , wherein the C _1-6 alkane group, C _1-6 haloalkyl, C _1-6 aminoalkoxy, C _3-8 cycloalkyl and 3-8 membered heterocyclyl are further selected from C _1-6 alkyl, C _{1 -6} haloalkyl, halogen, amino, cyano, hydroxyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1- Substituted by one or more substituents among ₆ -hydroxyalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, -(CH ₂ ) _n OR ₆ and -(CH ₂ ) _n NR ₇ R ₈ ; R, R ₁ , R ₃ ~R ₈ , x, n and y are as described in item 4 of the scope of the application. A compound represented by general formula (VI), its stereoisomer or its pharmaceutically acceptable salt:

Wherein: R is hydrogen atom or halogen; R ₁ is alkyl or halogen, wherein the alkyl is C _1-6 alkyl; R ₄ and R ₅ are each independently selected from hydrogen atom, C _1-6 alkyl, C _1-6 haloalkyl, C _3-8 cycloalkyl, -(CH ₂ ) _n OR ₆ , -(CH ₂ ) _n C(O)R ₆ , wherein the C _1-6 alkyl, C _1-6 Haloalkyl, C _3-8 cycloalkyl are optionally further selected from C _1-6 alkyl, halogen, hydroxy, amino, cyano, C _1-6 alkoxy, C _1-6 hydroxyalkyl and substituted by one or more substituents in C _1-6 cycloalkyl; or R ₄ and R ₅ form a 3-8 membered heterocyclic group, wherein the 3-8 membered heterocyclic group is further selected as required from C _1-6 alkyl, -(CH ₂ )n-, halogen, hydroxy, amine, cyano, C _1-6 alkoxy, C _1-6 hydroxyalkyl and C _1-6 cycloalkyl is substituted with one or more substituents of ; n is an integer of 0, 1, 2, 3, 4 or 5. In the compound represented by the general formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof as described in item 9 of the patent application scope, the heterocyclic group formed by R ₄ and R ₅ is 4-6 members. The compound represented by general formula (I), general formula (V) or general formula (VI) as described in any one of items 1 to 9 of the scope of the application, its stereoisomer or its A pharmaceutically acceptable salt, wherein R is selected from hydrogen atoms and halogens. The compound represented by the general formula (I), the general formula (V) or the general formula (VI), its stereoisomer or a pharmaceutically acceptable salt thereof as described in item 11 of the scope of the application, wherein R is fluorine. The compound represented by the general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of items 1 to 3 of the scope of the application, wherein R ₁ is selected from C _1-8 Alkyl and halogen, wherein the halogen is fluorine. The compound represented by general formula (I), general formula (V) or general formula (VI), its stereoisomer or its pharmaceutically acceptable compound according to any one of items 1 to 9 of the scope of application salt, wherein R ₁ is C _1-6 alkyl. The compound represented by the general formula (I), the general formula (V) or the general formula (VI), its stereoisomer or a pharmaceutically acceptable salt thereof as described in item 14 of the scope of the application, wherein R ₁ For C _1-3 alkyl. The compound represented by the general formula (I), the general formula (V) or the general formula (VI), its stereoisomer or a pharmaceutically acceptable salt thereof as described in item 15 of the scope of the application, wherein R ₁ is methyl. The compound represented by the general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of items 1 to 3 of the scope of the application, wherein R ₂ is selected from hydrogen atom, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkoxy, C _3-8 cycloalkyl, halogen, pendant oxy, -(CH ₂ ) _n NR ₄ R ₅ and 3-10 Heterocyclyl, wherein the C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl and 3-10 membered heterocyclyl are optionally further selected from halogen, hydroxy, cyano, C Substituted with one or more substituents in _1-8 alkyl, -(CH ₂ ) _n OR ₆ and C _1-8 alkoxy. The compound represented by general formula (I) or general formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof as described in any one of items 1 to 6 and 8 of the scope of application, wherein , R ₂ is selected from C _1-6 alkyl, C _1-6 haloalkyl, pendant oxy, -(CH ₂ ) _n NR ₄ R ₅ and 3-6 heterocyclyl, wherein the C _1-6 alkyl It is optionally further substituted with one or more substituents selected from halogen, hydroxy and cyano. The compound represented by the general formula (I) or the general formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof as described in item 18 of the claimed scope, wherein the C _1-6 alkyl group For C _1-3 alkyl. The compound represented by general formula (I) or general formula (V), its stereoisomer or a pharmaceutically acceptable salt thereof according to any one of items 1 to 8 of the scope of the application, wherein R ₄ and R ₅ are each independently selected from hydrogen atoms, C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl, -(CH ₂ ) _n C(O)R ₆ and C _{1- 8} alkoxy, wherein the C _1-8 alkyl, C _1-8 haloalkyl, C _3-8 cycloalkyl and C _1-8 alkoxy are further selected from halogen, hydroxyl, cyano, substituted by one or more substituents in C _1-8 alkyl, C _3-8 cycloalkyl, -(CH ₂ ) _n OR ₆ and C _1-8 alkoxy; R ₆ is selected from hydrogen atom, C _1-6 alkyl and C _1-6 alkoxy. The compound represented by general formula (I), general formula (V) or general formula (VI), its stereoisomer or its pharmaceutically acceptable compound according to any one of items 1 to 9 of the scope of application salts, wherein R ₄ and R ₅ are each independently selected from C _1-6 alkyl and C _3-6 cycloalkyl, wherein the C _1-6 alkyl and C _3-6 cycloalkyl are further selected as required Substituted from one or more substituents of halogen, hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl and -(CH ₂ ) _n OR ₆ . The compound represented by the general formula (I), the general formula (V) or the general formula (VI), its stereoisomer or a pharmaceutically acceptable salt thereof as described in item 21 of the scope of the application, wherein the C _1-6 alkyl is C _1-3 alkyl. The compound represented by the general formula (I), the general formula (V) or the general formula (VI), its stereoisomer or a pharmaceutically acceptable salt thereof according to the 21st item of the patent application scope, wherein, R ₆ Selected from C _1-3 alkyl and C _1-3 alkoxy. The compound of general formula (I), general formula (V) or general formula (VI), its stereoisomer or a pharmaceutically acceptable salt thereof as described in any one of items 1, 4 and 9 of the claimed scope , wherein, is selected from the following compounds:

A preparation method of the compound of general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof described in any one of items 1 to 3 of the scope of application, comprising the following steps:

Compound of general formula (VA) and compound of general formula (VB) are coupled to obtain compound of general formula (I), which compound of general formula (I) can be further reacted as required, or further deprotected to obtain different compounds of general formula (I) , wherein the catalytic reagents in the coupling reaction are Pd ₂ (dba) ₃ and Xantphos reagent; wherein: X is halogen; rings A, L, R, R ₁ , R ₂ and x are as described in item 1 of the patent application scope. The preparation method according to claim 25, wherein X is chlorine. A pharmaceutical composition comprising a compound of general formula (I), general formula (V) or general formula (VI) described in any one of items 1 to 24 of the scope of application for a therapeutically effective dose, its three-dimensional Isomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients. A compound represented by general formula (I), general formula (V) or general formula (VI) described in any one of items 1 to 24 of the scope of the application, a stereoisomer thereof or a pharmaceutically acceptable compound thereof The salt, or the use of the pharmaceutical composition described in item 27 of the scope of the patent application, which is used in the preparation of a medicament for the treatment and/or prevention of cancer or tumor-related diseases mediated by CDK kinase 4 and/or 6. The use according to item 28 of the claimed scope, wherein the cancer or tumor-related disease is selected from brain tumor, lung cancer, liver cancer, stomach cancer, oral cancer, head and neck cancer, bowel cancer, kidney cancer, esophageal adenocarcinoma, and esophageal squamous cell carcinoma cell carcinoma, squamous cell carcinoma, thyroid cancer, bone cancer, skin cancer, carcinoma in situ, lymphoma, neurofibromatosis, neuroblastoma, mast cell tumor, Multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glioblastoma, bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer , female reproductive tract cancer, testicular cancer, gastrointestinal stromal tumor or prostate tumor. The use as described in claim 29, wherein the cancer or tumor-related disease is selected from bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer cancer, female reproductive tract cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, rectal cancer, colon cancer or non-small cell lung cancer. The use according to claim 30, wherein the breast cancer comprises: locally advanced or metastatic breast cancer in postmenopausal women with estrogen receptor positive and/or human epidermal growth factor receptor 2 negative.