TW201811771A - 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 particularly relates to a benzimidazole compound kinase inhibitor and a preparation method and application thereof.

Cyclin-dependent kinase (CDK) is a class of serine/threonine (Thr) kinases. This family contains 13 members, which are divided into A-L by cyclin. Different CDKs and cyclins form CDK-cyclin complexes, which catalyze the phosphorylation of different receptors by CDK kinase activity, initiate DNA synthesis, promote the promotion and transformation of different phases of the cell cycle, and regulate gene transcription. Participate in cell growth, proliferation, dormancy or apoptosis. Therefore, CDKs have important functions in the regulation of proliferation and death of all cells, including tumor cells and normal cells. Among them, the CDK4/6-Cyclin D complex plays an important role in the transformation of cells from G1 to S phase. In the G1 phase, CDK4/6 binds to cyclin D and phosphorylates a series of receptors including Retinoblastoma protein (Rb). Rb phosphorylates and releases the protein bound to and inhibited by it, mainly the transcription factor E2F, etc. E2F initiates and transcribes some genes necessary for S phase, and promotes the transformation of G1/S cells. The study found that the specific initiation of CDK4/6 is closely related to the proliferation of some tumors, and the abnormality of the cyclinD-CDK4/6-INK4-Rb pathway is widespread. The performance is as follows: (1) p16INK4a gene deletion, point mutation, or DNA methylation results in inactivation of p16INK4a; (2) CDK4 gene amplification or point mutation (R24C), loss of binding ability to p16INK4a; (3) cyclinD1 due to gene weight Excretion or gene amplification is overexpressed. The change of this pathway accelerates the G1 phase process, which accelerates the proliferation of tumor cells and gains a survival advantage. Therefore, its intervention has become a therapeutic strategy, and CDK4/6 has thus become one of the targets for anti-tumor.

Pfizer's Palbociclib (PD0332991) is the first FDA-approved CDK4/6 small molecule inhibitor for breast cancer treatment. Next, Novartis ribociclib (LEE011) was approved in March 2017 for treatment with aromatase inhibitors. Some compounds, such as Lilly Abemaciclib (LY2835219), are in clinical research and both perform well. In addition to breast cancer, studies have shown that selective CDK4/6 inhibitors are excellent in many tumors such as ovarian cancer, non-small cell lung cancer, B cell lymphoma, liver cancer, glioma, colon cancer, multiple myeloma, etc. Antitumor activity. Therefore, the development of new CDK4/6 small molecule inhibitors has become a new and effective method for treating these tumors, inspiring generations of scientists to make continuous efforts.

Inhibitors of the disclosed selective inhibition of CDK4/6 include WO2004065378, WO2012101013, WO2016192630, WO2016015604 and WO2016015604, and the like.

CDK4/6 inhibitors have good application prospects in cancer or tumor therapy, and the present invention will provide a novel structure of highly selective CDK4/6 inhibitors, and found that compounds having such structures exhibit excellent effects. And role.

An object of the present invention is to provide a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) has the following structure:

Wherein: L is a bond, -C(O)- or -C(O)NH-; ring A is a heterocyclic group, wherein the heterocyclic group is selected from the group consisting of a monocyclic heterocyclic group, a spirocyclic heterocyclic group, and a fused ring a cyclic group and a bridged ring heterocyclic group; R is selected from a hydrogen atom, a halogen atom or a halogen; and R _{1 is} selected from a halogen atom, an alkyl group, a decyl group, a haloalkyl group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amine group. , 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 group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from the group consisting of a halogen atom, an alkyl group, a halogen alkyl group, a halogen group, an amine group, a nitro group, and a cyano group. Base, 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) Substituting one or more substituents in _m R ₈ ; R _{2 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a decyl group, a haloalkyl group, an alkoxy group, an amine alkane Oxyl, 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 group, the alkyl group, the haloalkyl group, the amino alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group and the hetero The aryl group is further selected from the group consisting of a halogen atom, an alkyl group, a halogen alkyl group, a halogen group, an amine group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, and a ring. Alkyl, heterocyclic, 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 One or more 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 by a substituent; R _{3 is} selected from a hydrogen atom, a halogen atom, an alkyl group, a decyl group, a haloalkyl group, a hydroxyl group, an amine group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group. And a heteroaryl group; wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from the group consisting of a halogen atom, an alkyl group, a halogen group, an amine group, a nitro group, and a cyano group. , 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) Substituting one or more substituents in _m R ₈ ; R ₄ and R _{5 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a decyl group, a haloalkyl group, a hydroxyl group, an amine Base, cycloalkyl, heterocyclic, 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 group, The cycloalkyl, heterocyclic, aryl and heteroaryl groups are further optionally selected from the group consisting of a halogen atom, an alkyl group, a halogen, a hydroxyl group, an amine group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group. ,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 Substituting one or more substituents of _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 ; R _{6 is} selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a halogen alkyl group, a halogenated alkyl group, a hydroxyl group, an amine group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; The alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, The aryl and heteroaryl are further selected from the group consisting of a halogen atom, an alkyl group, a halogen, an amine group, a nitro group, a cyano group, a hydroxyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and Substituted by one or more substituents of a heteroaryl group; R ₇ and R _{8 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a decyl group, a haloalkyl group, a hydroxyl group, an amine group, An ester group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are further selected from a halogen atom, an alkyl group, and a halogen as needed. Substituting one or more substituents of a hydroxyl group, an amine group, a nitro group, a cyano group, an ester group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; An integer of 0, 1, 2, 3, 4 or 5; m is an integer of 0, 1 or 2; and n is an integer of 0, 1, 2, 3, 4 or 5.

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

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

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

Wherein: Rings B, R, R ₁ , R ₂ and x are as defined in the formula (II).

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

Wherein: Rings B, R, R ₁ , R ₂ and x are as defined in the formula (II).

In a preferred embodiment of the invention, it is a compound of the formula (V), a stereoisomer thereof 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, Preferred is C _1-3 alkyl; R _{2 are the} same or different and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group, C _{1 -6} aminoalkoxy, C _1-6 haloalkoxy, halogen, amine, pendant oxy, nitro, hydroxy, cyano, C _3-8 cycloalkyl, 3-8 membered heterocyclic, -(CH ₂ ) _n OR ₃ and -(CH ₂ ) _n NR ₄ R ₅ , wherein the C _1-6 alkyl group, the C _1-6 haloalkyl group, the C _1-6 amino alkoxy group, C _{3 The 8} -cycloalkyl and 3-8 membered heterocyclic groups are further selected from C _1-6 alkyl, C _1-6 haloalkyl, halogen, amine, cyano, hydroxy, alkenyl, alkynyl, C, as desired. _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, -(CH ₂ ) _n -, -(CH ₂ ) one or more substituents of _n OR ₆ and -(CH ₂ ) _n NR ₇ R ₈ are substituted; or two R ₂ are bonded to each other to form a 3-10 membered cycloalkyl or heterocyclic group, Wherein the 3-8 membered cycloalkyl or heterocyclic group is further required by one By a plurality of C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, amino C _1-6 alkoxy, C _1-6 haloalkoxy, halo, amino, Substituted with a substituent of a pendant oxy group, a hydroxy group, a cyano group and a C _3-8 cycloalkyl group; preferably a 5- to 8-membered cycloalkyl group or a heterocyclic group; and y is an integer of 0, 1, 2 or 3; R ₃ to R ₈ , n and x are as defined in the formula (I).

In a preferred embodiment embodiment of the present invention, is a compound of formula (V) shown acceptable salt thereof, or a pharmaceutically acceptable stereoisomer thereof: wherein: M is selected from CHR ₂ or NR _2; R ₂ Selected from hydrogen atom, C _1-6 alkyl group, C _1-6 haloalkyl group, C _1-6 alkoxy group, C _1-6 amino alkoxy group, C _1-6 haloalkoxy group, halogen, amine a base, a pendant oxy group, a hydroxyl group, a cyano group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, -(CH ₂ ) _n OR ₃ and -(CH ₂ ) _n NR ₄ R ₅ , wherein the C _{a 1-6} alkyl group, a C _1-6 haloalkyl group, a C _1-6 amino alkoxy group, a C _3-8 cycloalkyl group and a 3-8 membered heterocyclic group are further selected from a C _1-6 alkane as needed , C _1-6 haloalkyl, halogen, amine, cyano, hydroxy, 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 heterocyclic, -(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 the general formula (V).

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

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

In a preferred embodiment of the invention, the formula, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of a hydrogen atom and a halogen, is preferred, and the halogen is preferably fluorine.

In a preferred embodiment of the invention, the formula, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R _{1 is} selected from the group consisting of C _1-8 alkyl and halogen, wherein The C _1-8 alkyl group, preferably a C _1-6 alkyl group, more preferably a C _1-3 alkyl group; most preferably a methyl group, wherein the halogen is preferably fluorine.

In a preferred embodiment of the invention, the formula, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R _{2 is} selected from the group consisting of 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- a heterocyclic group 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 needed Substituted from one or more substituents of halogen, hydroxy, cyano, C _1-8 alkyl, -(CH ₂ ) _n OR ₆ and C _1-8 alkoxy; preferably C _1-6 alkane a C _1-6 haloalkyl group, a pendant oxy group, a —(CH ₂ ) _n NR ₄ R ₅ and a 3-6 heterocyclic group, wherein the C _1-6 alkyl group is further selected from the group consisting of halogen, hydroxy and Substituted by one or more substituents in the cyano group; the C _1-6 alkyl group is more preferably a C _1-3 alkyl group.

In a preferred embodiment of the invention, the formula, the stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein R ₄ and R _{5 are the} same or different, are each independently selected From a hydrogen atom, a C _1-8 alkyl group, a C _1-8 haloalkyl group, a C _3-8 cycloalkyl group, a —(CH ₂ ) _n C(O)R ₆ and a C _1-8 alkoxy group, wherein The C _1-8 alkyl group, the C _1-8 haloalkyl group, the C _3-8 cycloalkyl group and the C _1-8 alkoxy group are further selected from the group consisting of halogen, hydroxy, cyano, C _1-8 alkyl, as needed. Substituted by one or more substituents of C _3-8 cycloalkyl, -(CH ₂ ) _n OR ₆ and C _1-8 alkoxy; preferably C _1-6 alkyl and C _3-6 ring An alkyl group, wherein the C _1-6 alkyl group and the C _3-6 cycloalkyl group are further selected from the group consisting of halogen, hydroxy, cyano, C _1-6 alkyl, C _3-6 cycloalkyl and —(CH ₂ ) Substituting one or more substituents in _n OR ₆ ; wherein the C _1-6 alkyl group is more preferably a C _1-3 alkyl group; and R _{6 is} selected from a hydrogen atom, a 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 invention, the method for preparing a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of the present invention, comprises the steps of:

The compound of the formula (I) is coupled with the compound of the formula (VB) to give a compound of the formula (I), which is further reacted as needed, or further deprotected to give a different compound of the formula (I) Wherein the catalytic reagent in the coupling reaction is preferably Pd ₂ (dba) ₃ and Xantphos reagent; wherein: X is a halogen; preferably chlorine; the rings A, L, R, R ₁ , R ₂ and x are as defined by the formula ( I) stated.

The invention also relates to a method of treating a disease which prevents and/or treats a CDK4/6 mediated pathological feature, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

The present invention further relates to a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, which is prepared for the treatment and/or prevention by CDK kinase 4 and/or 6 Use in drugs that mediate cancer or tumor-related diseases.

The present invention further relates to a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in the preparation of a medicament for treating cancer or a tumor, wherein the cancer or tumor Related diseases are selected from brain tumor, lung cancer, liver cancer, stomach cancer, oral cancer, head and neck cancer, intestinal 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, neurofibromatosis, neuroblastoma, mast cell tumor, multiple myeloma, melanoma, glioma, sarcoma or liposarcoma, glioblastoma Tumor, bladder, ovarian, peritoneal, pancreatic, breast, uterine, cervical, endometrial, prostate, female, genital, testicular, gastrointestinal stromal or prostate; Jia is selected from bladder cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, uterine cancer, cervical cancer, endometrial cancer, prostate cancer, female genital cancer, testicular cancer, gastrointestinal interstitial Tumor or prostate tumor.

The present invention further relates to a compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a method for treating cancer or a tumor-related disease, which comprises administering a treatment to a patient An effective dose of the compound of the formula (I): a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the cancer or tumor-related 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, in situ Cancer, 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 genital 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 genital tract cancer, testicular cancer, gastrointestinal stromal tumor or prostate tumor.

As a still further preferred method of preparing a breast cancer-related disease, the breast cancer comprises: a late-stage or metastatic breast cancer that is negative for estrogen receptor-positive and/or human epidermal growth factor receptor 2 negative in postmenopausal women.

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

Unless otherwise stated, the terms used in the specification and claims are intended to have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a linear or branched group having 1 to 20 carbon atoms, preferably an alkyl group having 1 to 8 carbon atoms, more preferably 1 to 6 The alkyl group of one carbon atom is 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, t-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-di 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-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -ethylhexyl 2,2-Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Second butyl, 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, and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of Alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, a pendant oxy group, a carboxyl group or a carboxylate group, and the invention is preferably a methyl group, an ethyl group, an isopropyl group or a third group. Butyl, haloalkyl, nonylalkyl, 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" refers to -CH ₂ -, "ethylene" refers to -(CH ₂ ) ₂ -, "propylene" Refers to -(CH ₂ ) ₃ -, "butylene" means -(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 ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, sulfhydryl, hydroxy, 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 which contains from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably contains 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 The polycyclic cycloalkyl group includes a spiro ring, a fused ring, and a bridged cycloalkyl group, preferably a cyclopropyl group, a cyclobutyl group, a cyclohexyl group, a cyclopentyl group, and a cycloheptyl group.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings are fully conjugated π electronic system. It is preferably from 6 to 14 members, more preferably from 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkane, depending on the number of common spiro atoms between the ring and the ring. base. More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include: Also included are spirocycloalkyl groups in which a monospirocycloalkyl group shares a spiro atom with a heterocycloalkyl group, and non-limiting examples include:

The term "fused cycloalkyl" refers to 5 to 20 members, each ring of the system sharing an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably from 6 to 14 members, more preferably from 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member bicycloalkyl group. . 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 carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of which has a complete Conjugate π-electron system. It is preferably from 6 to 14 members, more preferably from 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthyl , benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy groups. , alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring An alkylthio group, a heterocycloalkylthio group, a pendant oxy group, a carboxyl group or a carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). A hetero atom of _m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are hetero atoms; further preferably 3 to 10 ring atoms; more preferably 3 to 8 ring atoms; most preferably 6 to 10 Ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine. a base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably piperidinyl and . Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups. The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) _m (where m is an integer 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. It is preferably from 6 to 14 members, more preferably from 6 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclyl group, a dispiroheterocyclic group or a polyspiroheterocyclic group, preferably a monospiroheterocyclic group and a double spiro heterocyclic ring, depending on the number of shared spiro atoms between the ring and the ring. base. More preferably, it is 3/6, 4/4, 4/5, 4/6, 5/5 or 5/6 single spiro heterocyclic. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to 5 to 20 members, each ring of the system sharing an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system 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 rings The atom is carbon. It is preferably from 6 to 14 members, more preferably from 6 to 10 members. According to the number of constituent rings, it may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5 members/5 members or 5 members/6 members double rings. Ring base. Non-limiting examples of fused heterocyclic groups include:

The term "bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A π-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), the remaining ring atoms being carbon. It is preferably from 6 to 14 members, more preferably from 6 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridge heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include: with Wait.

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy groups. , alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring An alkylthio group, a heterocycloalkylthio group, a pendant oxy group, a carboxyl group or a carboxylate group.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably from 6 to 10 members. For example phenyl and naphthyl. More preferably, it is a phenyl group. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkanethio Base, alkylamino, halogen, sulfhydryl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably from 5 to 10 members, more preferably 5 members or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, a tetrazolyl group, a pyridyl group, a pyrimidinyl group, a thiadiazole group, a pyrazinyl group or the like, preferably a triazolyl group, a thienyl group, an imidazolyl group, a pyrazolyl group or a pyrimidinyl group, a thiazolyl group; Pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy groups. , alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring An alkylthio group, a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

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. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy groups. , alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring An alkylthio group, a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

"Haloalkyl" means an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.

"Haloalkoxy" means an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.

"Hydroxyalkyl" means an alkyl group substituted by a hydroxy group, wherein alkyl is as defined above.

"Hydroxy" refers to an -OH group.

"Halogen" means fluoro, chloro, bromo or iodo.

"Amino" means -NH _2.

"Cyano" means -CN.

"Nitro" means -NO ₂ .

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

"Sideoxy" means , for example, oxypiperidinyl, .

"THF" refers to tetrahydrofuran.

"EtOAc" means ethyl acetate.

"MeOH" refers to methanol.

"DMF" means N,N-dimethylformamide.

"DIPHA" refers to diisopropylethylamine.

"TFA" refers to trifluoroacetic acid.

“MeCN” means 乙晴.

"DMA" means N,N-dimethylacetamide.

"Et ₂ O" means diethyl ether.

"DCE" means 1,2 dichloroethane.

"DIPEA" refers to N,N-diisopropylethylamine.

"NBS" refers to N-bromosuccinimide.

"NIS" refers to N-iodobutanediamine.

"Cbz-Cl" means benzyl chloroformate.

"Pd ₂ (dba) ₃ " refers to tris(dibenzylideneacetone) dipalladium.

"Dppf" means 1,1'-bisdiphenylphosphinoferrocene.

"HATU" means 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

"KHMDS" means potassium hexamethyldidecylamino.

"LiHMDS" refers to lithium bis-trimethyldecylamine.

"MeLi" means methyl lithium.

"n-BuLi" means n-butyllithium.

"NaBH(OAc) ₃ " refers to sodium triethoxy borohydride.

"X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" and the like are expressed in the same language. Meaning, that is, X can be any one or several of A, B, and C.

"Stereoisomerization" includes three types of geometric isomerism (cis-trans isomerization), optical isomerism, and conformational isomerism.

The hydrogen atom of the present invention may be substituted by its isotope ruthenium, and any of the hydrogen atoms in the examples of the present invention may also be substituted by a ruthenium atom.

"As needed" or "as needed" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes a case where a heterocyclic group is substituted with an alkyl group and a case where a heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amine group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

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

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.

The invention is further described in the following examples, which are not intended to limit the scope of the invention.

 Example  

The structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). The NMR chemical shift (δ) is given in parts per million (ppm). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus. The solvent was determined to be dimethyl dimethyl hydrazine (DMSO- d ₆ ), hydrazine methanol (CD ₃ OD) and deuterated chloroform (CDCl ₃ ). The internal standard was tetramethyl. Decane (TMS).

LC-MS was determined by LC-MS using an Agilent 1200 Infinity Series mass spectrometer. The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm chromatography column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm chromatography column).

The thin layer chromatography tantalum sheet uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tantalum sheet. The specification for TLC is 0.15mm~0.20mm, and the specification for thin layer chromatography separation and purification is 0.4mm~0.5mm. Pipe column chromatography generally uses Yantai Huanghai Tanji 200~300 mesh silicone as carrier.

Starting materials in the examples of the invention are known and commercially available or can be synthesized or synthesized according to methods known in the art.

Unless otherwise stated, all the reactions of the present invention are carried out under continuous magnetic stirring under 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-Diazephen-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

First step: Preparation of tert-butyl 4-(6-chloro-2-methyl nicotine oxime)-1,4-diazepine ring-1-carboxylate

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

MS m/z (ESI): 354.1 [M+H] ⁺ .

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-dioxaborolan-2-yl)-1H-benzene And [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 ( 2.61g, 18.9mmol) was refluxed under a nitrogen atmosphere for 5 h in a mixture of dioxane / H ₂ O (4 /1, 50 mL), cooled to room temperature, concentrated to remove organic solvent, diluted with water, CH ₂ Cl ₂ (30 mL* 3) Extraction, combining the organic phases and drying with anhydrous sodium sulfate, and concentrating and column chromatography to give the product 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d] Imidazolium-6-ylpyrimidin-2-amine (1.8 g, yield 94.4%).

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)pyrimidin-2- Of tert-amino)-2-methyl nicotine oxime)-1,4-diazepine-l-carboxylic acid tert-butyl ester

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 Tri-butyl 4-(6-chloro-2-methyl nicotine oxime)-1,4-diazepine ring-l-carboxylate (1.7 g, 4.8 mmol) was dissolved in dioxane (40 mL) Then, cesium carbonate (3.9 g, 11.9 mmol), Pd ₂ (dba) ₃ (0.2 g, 0.22 mmol), Xantphos (0.24 g, 0.44 mmol) were successively added, and the mixture was replaced with nitrogen three times and stirred under reflux overnight. Cooling, filtration, concentration and column chromatography [DCM~DCM/MeOH (10:1)] to give compound 4-(6-(5-fluoro-4-(4-fluoro-1-isopropyl-2-) Methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methyl nicotine oxime)-1,4-diazepine-l-carboxylic acid -butyl ester (2 g, yield 81%).

MS m/z (ESI): 621.3 [M+H] ⁺ .

The fourth step: 1,4-diazaheptan-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[ Preparation of d]imidazol-6-ylpyrimidin-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 3-methyl nicotine oxime)-1,4 diazepine-l-carboxylic acid tert-butyl ester (2 g, 3.2 mmol) dissolved in CH ₂ Cl ₂ (30 mL), cooled to 0 ° C Trifluoroacetic acid (10 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hr, and then concentrated ( 1,4-diazinoheptane-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) The trifluoroacetic acid salt of the ketone (4 g, yield 99%) was used directly in the next step 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 = 8.8 Hz, 1H), 5.18 (dt, J = 13.8, 7.1 Hz, 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 = 43.5 Hz, 2H), 1.84 (d, J = 6.9 Hz, 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) Of 2-methylpyridin-3-yl)-4-(methylamino)piperidin-2-one

First step: Preparation of (1-(6-chloro-2-methylpyridin-3-yl)-2-oxopiperidin-4-yl)carbamic acid tert-butyl ester

3-bromo-6-chloro-2-methylpyridine (200 mg, 0.969 mmol), (2-oxopiperidin-4-yl)carbamic acid tert-butyl ester (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), stirred under nitrogen at 100 ° C overnight, cooled and concentrated. The product was obtained (31 mg, yield 9.4%).

MS m/z (ESI): 340.1, 3421. [M+H] ⁺ .

The second step: (1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidine-2) Of 3-butylamino)-2-methylpyridin-3-yl)-2-carbonylpiperidin-4-yl)carbamic acid 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-oxopiperidin-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) in dioxane (10 mL). 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) Of 3-(amino)-2-methylpyridin-3-yl)-2-carbonylpiperidin-4-yl)(methyl)aminocarbamic acid tert-butyl ester

(1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amine) Tert-butyl 2-methylpyridin-3-yl)-2-carbonylpiperidin-4-yl)carbamate (19.6 mg, 0.0323 mmol), 60% NaH (1.6 mg, 0.0400 mmol) After stirring in THF (2 mL), EtOAc (EtOAc,EtOAc.

MS m/z (ESI): 621.3 [M+H] ⁺ .

The fourth step: 1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- Of amino)amino)-2-methylpyridin-3-yl)-4-(methylamino)piperidin-2-one

The product of the previous step (12 mg, 0.0193 mmol) was dissolved in methylene chloride (2 mL), trifluoroacetic acid (1 mL), and the mixture was stirred at room temperature for 3 h, then concentrated to dryness. ).

^{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 = 87.2 Hz, 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-yl) Preparation of yl-1 H -benzo[ d ]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

First step: Preparation of 1-(6-chloro-2-methylindolyl)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) (50mL). The reaction was stirred at room temperature for 4 hours. LCMS showed EtOAc EtOAc (EtOAc) (EtOAc) Dry over sodium sulfate and concentrate by filtration. The remaining crude product was purified by flash column (CH ₂ Cl ₂ :MeOH = 20:1) to give the product 1-(6-chloro-2-methylindole)piperidin-4-one (1.2 g, 81%) ).

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

4-Chloro-5-fluoropyrimidin-2-amine (4.5 g, 31.3 mmol), 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1 H -benzo[ d ]imidazole (10.0 g, 31.3 mmol), Pd(dppf)Cl ₂ (200 mg), potassium carbonate (8.6 g) , 62.6 mmol) were sequentially added to dioxane (50 mL) and water (5 mL). The reaction was stirred at 100 ° C for 3 hours under a nitrogen atmosphere. After the reaction was completed, the mixture was concentrated, and the residue was taken to dichloromethane (50mL) and water (50mL). The organic layer was dried over anhydrous sodium sulfate and filtered and evaporated. The remaining crude product was purified by flash gel column to give the product 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1 H -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-1 H -benzo[ d ]imidazolyl-6-yl)pyrimidine-2) Of -amino)amino)-2-methylindolyl)piperidin-4-one

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

MS m/z (ESI): 520.2 [M+H] ⁺

Fourth step: (4-(cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1 H) -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-1 H -benzo[ d ]imidazol-6-yl)pyrimidin-2-yl)) Amino)-2-methylindolyl)piperidin-4-one (100 mg, 0.19 mmol), cyclopropylamine (0.3 mL) was dissolved in dichloromethane (5 mL) and stirred at room temperature for 20 min. Sodium borohydride (200 mg, 0.95 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was completed, the reaction mixture was directly dried, and the residue was purified by a flashing column and preparative HPLC. Purification of the product (4-(cyclopropylamino)piperidin-1-yl)6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1 H -benzene) And [ d ]imidazol-6-ylpyrimidin-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 = 13.7 Hz, 1H), 2.97 (s, 3H), 2.84 (d, J =4.2 Hz, 1H), 2.73 (s, 3H), 2.35 (s, 1H), 2.31-2.13 (m, 2H), 2.06 (s, 1H), 1.83 (d, J = 6.9 Hz, 6H), 1.73 (s, 2H), 1.33 (d, J = 18.5 Hz, 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

First step: Preparation of 3-(tri-tert-butyl) ester of 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylic acid 9-benzyl ester

3,9-diazabicyclo[4.2.1]nonane-3-carboxylic acid tert-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 ice bath. Stir at room temperature overnight. It was then diluted with dichloromethane (30 mL), washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate The compound 3,9-diazabicyclo[4.2.1]nonane-3,9-dicarboxylic acid 9-benzyl ester 3-(tri-butyl) ester (170 mg, yield 82) %).

MS m/z (ESI): 305.0 [M - 55] ⁺ .

Second step: 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-(tri-butyl) ester (170 mg, 0.47 mmol) dissolved in two Methyl chloride (3 mL) was added dropwise trifluoroacetic acid (2 mL). Concentrated for use.

MS m/z (ESI): 261.1 [M+H] ⁺ .

Step 3: Preparation of 3-(6-chloro-2-methylnicotinyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid benzyl ester

Compound 6-Chloro-2-methylnicotonic acid (85 mg, 0.5 mmol) and the compound 3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid benzyl ester were dissolved in DMF (5 mL) DIEA (0.3 mL) and HATU (380 mg, 1 mmol) were added and stirred at room temperature for 2 h. After concentration and purification by column chromatography [eluent: DCM~DCM/MeOH (10:1)], compound 3-(6-chloro-2-methyl nicotine)-3,9-diazabicyclo[ 4.2.1] Benzene-9-carboxylic acid benzyl ester (180 mg, yield 94%).

MS m/z (ESI): 414.1 [M+H] ⁺ .

Fourth step: 3-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2- Of amino)amino)-2-methylnicotinyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid benzyl ester

Compound 3-(6-Chloro-2-methylnicotinyl)-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) dissolved in dioxins dioxane (15 mL), followed by addition of cesium carbonate _{(324mg, 1mmol), Pd 2} (dba) 3 (23mg, 0.025mmol) and Xant-phos (30mg, 0.05mmol) , replaced three times with nitrogen, refluxed overnight. Cooling and filtration, concentration and purification by column chromatography [DCM~DCM/MeOH (10:1)] to give compound 3-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-) Methyl-1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylnicotinyl)-3,9-diazabicyclo[4.2.1]壬Alkyl-9-carboxylic acid benzyl ester (120 mg, yield 73%).

MS m/z (ESI): 6821. [M+H] ⁺ .

Step 5: (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-ylpyrimidin-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 Benzyl-2-methylnicotinyl)-3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid benzyl ester (120 mg, 0.17 mmol) was dissolved in methanol (10 mL). Palladium hydroxide (30 mg) was added under nitrogen, then the hydrogen was replaced three times and stirred at room temperature overnight. Filtration and concentration to give crude product (90 mg, yield 93%)

MS m/z (ESI): 547.2 [M+H] ⁺ .

Step 6: (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-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone (90 mg, 0.16 mmol) and a solution of formaldehyde (0.1 mL) were dissolved. Dichloromethane (5 mL) was stirred at rt for 30 min then EtOAc (EtOAc &lt The reaction solution was concentrated and purified by reverse phase column chromatography to afford 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, yield 50%).

^{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 = 12.8 Hz, 3H), 2.65 (m, 2H), 2.43-2.20 (m, 2H), 2.19-1.95 (m, 2H), 1.85 (d, J = 6.0 Hz, 6H).

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

MS m/z (ESI): 5621. [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)- The preparation method of 2-methylpyridin-3-yl)(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methanone is referred to Example 1.

^{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 = 6.7 Hz, 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)- A method for producing 2-fluoropyridin-3-yl)(octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methanone is described in Example 1.

^{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 = 8 Hz, 6H).

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

MS m/z (ESI): 5521. [M+H] ⁺ .

Example 7 Diazepine-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-Diazephen-1-yl)(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo) The preparation method of [d]imidazol-6-ylpyrimidin-2-yl)amino)pyridin-3-yl)methanone is referred to Example 1.

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

(2-Fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) The preparation method of the amino)pyridin-3-yl)(4-methyl-1,4-diazepine-1-yl)methanone is as described in 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 = 8.9 Hz, 1H), 5.17 (dt, J = 14.0, 6.9 Hz, 1H), 4.40-4.31 (m, 1H), 4.01-3.55 (m, 5H), 3.46-3.36 (m, 2H), 2.99 (d, J = 10.6 Hz, 6H), 2.29 (m, 2H), 1.85 (d, J = 6.9 Hz, 6H).

MS m/z (ESI): 539.2 [M+H] ⁺ .

Example 9 (S)-(3,4-dimethyl-1,4-diazepine-1-yl)(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-) 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-diazepine-1-yl)(2-fluoro-6-((5-fluoro-4-(4-fluoro-1-) For the preparation of propyl-2-methyl-1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)pyridin-3-yl)methanone, refer to Example 1.

^{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 = 11.3 Hz, 1H), 7.92 (t, J = 8.8 Hz, 1H), 5.13-4.97 (m, 1H), 4.07 (d, J = 15.5 Hz, 1H), 3.82 (d, J =17.3) Hz, 5H), 2.93 (s, 2H), 2.89 (s, 3H), 2.79 (d, J = 18.3 Hz, 1H), 2.14 (d, J = 31.4 Hz, 2H), 1.74 (d, J = 6.9) Hz, 6H), 1.39 (dd, J = 47.3, 6.8 Hz, 3H).

MS m/z (ESI): 472.2 [M+H] ⁺ .

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

(4,5-Dimethyl-1,4-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-) A method for producing 1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is described in Example 1.

MS m/z (ESI): 472.2 [M+H] ⁺ .

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

(4-ethyl-1,4-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzene) And [d] imidazole-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is prepared by referring to Example 1.

^{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 = 11.8 Hz, 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 = 6.7 Hz, 6H), 1.32 (m, 3H). ¹⁹ F NMR (376 MHz, 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]octane-3-yl)methanone

(2-Fluoro-6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) A method for preparing amino)pyridin-3-yl)(6-methyl-3,6-diazabicyclo[3.2.1]oct-3-yl)methanone is described in 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, 6.8 Hz, 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 = 6.8 Hz, 6H). ¹⁹ F NMR (400 MHz, MeOD): δ: -69.67 (d, J = 282.4 Hz), -129.43 (d, J = 8.9 Hz), -148.33 (s).

MS m/z (ESI): 5521. [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)- A method for preparing 2-methylpyridin-3-yl)(1-methyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)methanone is referred to in Example 1.

^{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-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-) Preparation of 1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(3,4-Dimethyl-1,4-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-) A method for producing 1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is described in Example 1.

^{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 = 55.7 Hz, 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-diazepin-1-yl)methanone

(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- A method for preparing 2-methylpyridin-3-yl)(4-(1-methylpiperidin-4-yl)-1,4-diazepin-1-yl)methanone is described in Example 1.

^{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 = 7.9 Hz, 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 = 6.4 Hz, 6H).

¹⁹ F NMR (376 MHz, 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-diazaheptan-1-yl)methanone

(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- A method for producing 2-methylpyridin-3-yl)(5-methyl-1,4-diazaheptan-1-yl)methanone is referred to in Example 1.

^{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, 4.8 Hz, 1H), 5.07 (dt, J = 13.7, 6.8 Hz, 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 = 6.9 Hz, 6H), 1.35 (dd, J =13.7, 6.5 Hz, 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-diazaheptan-1-yl)methanone

(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- A method for preparing 2-methylpyridin-3-yl)(4-methyl-1,4-diazepin-1-yl)methanone is referred to in Example 1.

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

¹⁹ F NMR (376 MHz, 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-diazaheptan-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-(2-methoxyethyl)-1,4-diazepin-1-yl)methanone is as follows.

(1,4-Diazephen-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), and then potassium carbonate (150 mg) Bromo-2-methoxyethane (0.5 mL) was stirred at 60 ° C for 3 h. Cooled, filtered, and concentrated purified by column chromatography _{[eluent: CH 2 Cl 2 ~ CH 2} Cl 2 / MeO-H (10: 1)] to give the product as a white solid (150 mg of, 68% yield).

^{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 =11.1 Hz, 1H), 7.59 (d, J = 8.9 Hz, 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 = 6.9 Hz, 6H). ¹⁹ F NMR (376 MHz, 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-diazepin-1-yl)methanone

(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- A method for preparing 2-methylpyridin-3-yl)(4-(2,2,2-trifluoroethyl)-1,4-diazepin-1-yl)methanone is referred to in Example 1.

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) Preparation of Amino)-2-methylnicotinium)-1,4-Diazephen-1-yl)propanenitrile

3-(4-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl) The preparation method of amino)-2-methyl nicotine oxime)-1,4-diazepine-1-yl)propanenitrile was carried out in the same manner as in 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 = 8.9 Hz, 1H), 5.18 (dq, J = 14.1, 7.0 Hz, 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 = 6.9 Hz, 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-diazaheptan-1-yl)methanone

(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- A method for producing 2-methylpyridin-3-yl)(4-(2-hydroxypropyl)-1,4-diazepin-1-yl)methanone is described in Example 18.

^{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 = 27.2 Hz, 3H), 2.73-2.57 (m, 4H), 2.49 (m, 4H), 2.01 (s, 1H), 1.87 (s, 1H), 1.73 (d, J = 6.7 Hz, 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-diazaheptan-1-yl)methanone

(6-((5-fluoro-4-(1-isopropyl-2-methyl-1H-benzo[d1imidazole-6-yl)pyrimidin-2-yl)amino)-2-methylpyridine Refer to Example 1 for the preparation of -3-yl)(4-methyl-1,4-diazaheptan-1-yl)methanone.

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

6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2 A method for producing methyl-N-(8-methyl-8-azabicyclo[3.2.1]octane-3-yl)nicotinamide is described in Example 1.

MS m/z (ESI): 561.3 [M+H] ⁺ .

Example 24 (4-cyclopropyl-1,4-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-) Benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridyl Preparation of pyridine-3-yl)methanone

(4-cyclopropyl-1,4-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-) For the preparation of benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone, reference is made to Example 18.

^{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 = 8.5 Hz, 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 = 6.9 Hz, 6H), 1.19 (s, 2H). ¹⁹ F NMR (376 MHz, MeOD) δ: -130.7, -149.8.

MS m/z (ESI): 561.2 [M+H] ⁺ .

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

(4-(2,2-difluoroethyl)-1,4-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl)- A method for producing 2-methyl-1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is described in Example 1.

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-diazepin-1-yl)methanone

(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- A method for preparing 2-methylpyridin-3-yl)(4-(2-hydroxyethyl)-1,4-diazepin-1-yl)methanone is described in Example 18.

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)) Of 2-methylpyridin-3-yl)-1,7-dimethyl-1,4-diazepin-5-one

4-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)) For the preparation of 2-methylpyridin-3-yl)-1,7-dimethyl-1,4-diazoheptyl-5-one, refer 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)) Of 2-methylpyridin-3-yl)-1,3-oxaxan-2-one

3-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)) For the preparation method of 2-methylpyridin-3-yl)-1,3-oxaxanthone-2-one, refer 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)) Of 2-methylpyridin-3-yl)-1-methyl-1,4-diazepin-5-one

4-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)) For the preparation of 2-methylpyridin-3-yl)-1-methyl-1,4-diazepin-5-one, refer 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) Of -amino)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 -amino)amino)-2-methylpyridin-3-yl)-1,4-diazepin-5-one- is described 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) Of -amino)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) The preparation method of -amino)amino)-2-methylpyridin-3-yl)-7-methyl-1,4-diazepin-5-one is referred to 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 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 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 = 8.3 Hz, 1H), 5.19 (s, 1H), 3.51 (s, 1H), 3.09 (d, J = 6.8 Hz, 3H), 3.03 (s, 3H), 2.25 ( s, 2H), 1.86 (d, J = 6.4 Hz, 6H), 1.76 (s, 4H), 1.46 (s, 2H), 1.43-1.30 (m, 5H), 0.96 (t, J = 6.5 Hz, 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 of 1-H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

^{1 H NMR (400MHz, MeOD)} ): δ: 8.97 (d, J = 3.1Hz, 1H), 8.60 (s, 1H), 8.35-8.15 (m, 2H), 7.80-7.54 (m, 1H), 6.39 (t, J = 53.7 Hz, 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 (400 MHz, 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)- For the preparation of 2-methylpyridin-3-yl)(4-((2,2,2-trifluoroethyl)amino)piperidin-1-yl)methanone, refer to Example 3.

^{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 = 8.9 Hz, 1H), 5.25-5.10 (m, 1H), 4.17 (q, J = 9.0 Hz, 2H), 3.67 (s, 1H), 3.37 (m, 4H), 3.00 (s, 3H), 2.39-2.19 (m, 2H), 1.83 (m, J = 11.6 Hz, 8H).

¹⁹ F NMR (376 MHz, 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-ylpyrimidin-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-) For the preparation of benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone, reference is made to Example 3.

^{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, 6.8 Hz, 1H), 3.79 (d, J = 13.6 Hz, 1H), 3.52 (s, 1H), 3.01 (d, J = 7.0 Hz, 6H), 2.78 ( s, 3H), 2.30 (d, J = 11.0 Hz, 1H), 2.17 (d, J = 10.2 Hz, 1H), 1.85 (d, J = 6.9 Hz, 6H), 1.74 (s, 2H), 1.15 ( Td, J = 7.8, 3.9 Hz, 1H), 0.76 (q, J = 5.8 Hz, 2H), 0.47 (q, J = 4.8 Hz, 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][d Preparation of imidazolium-6-ylpyrimidin-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][d Refer to Example 3 for the preparation of imidazole-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

^{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 = 11.9 Hz, 1H), 3.86 (d, J = 7.1 Hz, 1H), 3.65 (s, 1H), 3.35 (s, 1H), 2.90 (d) , J = 7.7 Hz, 4H), 2.66 (s, 3H), 2.31-2.18 (m, 3H), 2.7-1.97 (m, 2H), 1.88 (d, J = 16.2 Hz, 2H), 1.72 (t, J = 8.8 Hz, 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-yl) Preparation of keto-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-yl) A method for producing keto-1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is described in Example 3.

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)- A method for producing 2-methylpyridin-3-yl)(4-((2-fluorocyclopropyl)amino)piperidin-1-yl)methanone is described in Example 3.

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][d Preparation of imidazolium-6-ylpyrimidin-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][d Refer to Example 3 for the preparation of imidazole-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

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 of 1-H-benzo[d]imidazol-6-ylpyrimidin-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 = 12.7 Hz, 1H), 3.60 (s, 1H), 3.19 (t, J = 12.7 Hz, 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, 16.7 Hz, 7H), 1.73 (d, J = 6.9 Hz, 6H), 1.49 (d , J = 9.9 Hz, 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 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)- The preparation method of 2-methylpyridin-3-yl)(4-((2-methoxyethyl)amino)piperidin-1-yl)methanone is referred to Example 3.

MS m/z (ESI): 579.3 [M+H] ⁺ .

Example 44 (6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole-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 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 = 12.1 Hz, 1H), 3.82-3.69 (m, 4H), 3.65 (d, J = 13.0 Hz, 1H), 3.17 (t, J = 12.3 Hz, 1H), 2.92 (dd, J = 27.2, 15.4 Hz, 1H), 2.78-2.53 (m, 8H), 2.45 (s, 3H), 2.10 (d, J = 10.2 Hz, 1H), 1.94 (d, J = 12.0 Hz) , 1H), 1.73 (d, J = 6.9 Hz, 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 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]octane-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)- Preparation method of 2-methylpyridin-3-yl)(4-(4-methyl-4,7-diazaspiro[2.5]octane-7-yl)piperidin-1-yl)methanone 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-yl) -1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-yl Preparation of pyridin-3-yl)methanone

(4-((3,3-Difluorocyclobutyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-yl) A method for producing keto-1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is described in Example 3.

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 = 13.5 Hz, 1H), 3.97 (dd, J = 12.9, 7.2 Hz, 1H), 3.79 (d, J = 12.4 Hz, 1H), 3.56 (s, 1H), 3.22 - 2.91 (m, 8H), 2.78 (s, 3H), 2.21 (dd, J = 54.2, 9.7 Hz, 2H), 1.85 (d, J = 6.9 Hz, 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-diazepin-1-yl)methanone

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

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

(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- A method for preparing 2-methylpyridin-3-yl)(6-methyl-3,6-diazabicyclo[3.2.1]octane-3-yl)methanone is described in Example 1.

^{1 H NMR (400MHz, MeOD)} δ: 8.58 (J = 3.8Hz d,, 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 = 6.9 Hz, 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-ylpyrimidin-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][d Imidazole-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone (200 mg, 0.357 mmol), 30% aqueous formaldehyde (2 ml), stirred in methanol (10 ml) Sodium triethoxy borohydride (227 mg) was added and stirred at room temperature for 3 h. Water was added, extracted with methylene chloride, dried and purified to give a white solid (201.7mg, yield 98.4%).

^{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 = 9.4 Hz, 2H), 3.35 (s, 1H), 3.02 (d, J = 9.3 Hz, 8H), 2.78 (s, 3H) , 2.36 (t, J = 48.6 Hz, 2H), 1.94 (s, 2H), 1.85 (d, J = 6.5 Hz, 6H), 1.29 (d, J = 8.6 Hz, 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) A method for producing benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is described in 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]decane-7-yl)methanone

(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- A method for preparing 2-methylpyridin-3-yl)(2-methyl-2,7-diazaspiro[3.5]decane-7-yl)methanone is described in Example 1.

MS m/z (ESI): 56]. 6 [M+H] ⁺ .

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

(4-(2-(Dimethylamino)ethyl)-1,4-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl) A method for producing benzyl-2-methyl-1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is shown in Example 18.

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 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-ylpyrimidin-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-yl) A method for producing keto-1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is described in Example 3.

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 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 = 6.9 Hz, 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)pyrimidin-2-) Of amino)amino)-2-methylnicotinyl)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)pyrimidin-2-) Refer to Example 3 for the preparation of the amino)amino)-2-methylnicotinyl)piperidin-4-yl)amino)cyclopropane-1-carbonitrile .

^{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 = 11.8 Hz, 1H), 7.58 (d, J = 8.5 Hz, 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 = 6.9 Hz, 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]decane-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]decane-4-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H) -Preparation method of benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

^{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 = 8.8 Hz, 1H), 5.09 (dt, J = 13.7, 6.8 Hz, 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 = 6.3 Hz, 2H), 2.19 (d, J = 4.9 Hz, 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-diazaheptan-1-yl)methanone

(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)- A method for preparing 2-methylpyridin-3-yl)(4-(3,3,3-trifluoropropyl)-1,4-diazepin-1-yl)methanone is described in Example 1.

MS m/z (ESI): 617.6 [M+H] ⁺ .

Example 61 [1,4'-bipiperidinyl]-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'-bipiperidinyl]-1'-yl (6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole) Refer to Example 1 for the preparation of -6-ylpyrimidin-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 = 12.8 Hz, 1H), 3.59 (s, 3H), 3.37 (s, 1H), 3.17 - 2.93 (m , 6H), 2.78 (s, 3H), 2.34 (d, J = 11.6 Hz, 1H), 2.20 (d, J = 8.9 Hz, 1H), 2.01 (d, J = 14.0 Hz, 2H), 1.97-1.88 (m, 3H), 1.85 (d, J = 6.9 Hz, 8H), 1.56 (d, J = 12.5 Hz, 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-) For the preparation of benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)pyridin-3-yl)methanone, reference is made to Example 3.

^{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 = 11.4 Hz, 1H), 8.02-7.87 (m, 1H), 5.22-5.05 (m, 1H), 3.83 (s, 1H), 3.62 (t, J = 11.6 Hz, 1H), 2.97 (s) , 3H), 2.89-2.77 (m, 1H), 2.25 (dd, J = 32.2, 24.6 Hz, 2H), 1.83 (d, J = 6.9 Hz, 6H), 1.68 (dd, J = 12.3, 4.3 Hz, 2H), 1.33 (d, J = 19.0 Hz, 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 Of -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 Refer to Example 3 for the preparation method of -yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

^{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 = 7.9 Hz, 1H), 5.19 (s, 1H), 4.82-4.72 (m, 2H), 3.72 (d, J = 57.5 Hz, 2H), 3.04 (d, J =15.4 Hz, 4H), 2.80 (d, J = 24.0 Hz, 4H), 2.46-2.16 (m, 2H), 1.85 (d, J = 6.4 Hz, 8H), 1.08-0.87 (m, 4H).

MS m/z (ESI): 543.2 [M+H] ⁺ .

Example 64 (S)-(3,4-Dimethyl-1,4-diazepine-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

(S)-(3,4-Dimethyl-1,4-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2) A method for producing methyl-1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is described in 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 = 6.6 Hz, 2H), 0.93 (d, J = 6.3 Hz, 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-methylnicotinyl)piperidin-4-yl)acetamide

(4-((3,3-Difluorocyclobutyl)amino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-yl) -1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone (200 mg, 0.328 mmol) dissolved in dichloromethane (10 ml Triethylamine (1 ml) was added, and acetic anhydride (1 ml) was added dropwise and stirred at room temperature for 3 h. Water was added, dichloromethane was extracted, dried and purified to give 180.3 mg of desired product.

^{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, 1.6 Hz, 8H), 3.02 (s, 4H), 2.78 (s, 3H), 2.65 (s, 1H), 2.22 (s, 3H), 1.82 (t, J = 18.9 Hz, 9H). MS m/z (ESI): 653.2 [M +H] ⁺ .

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

(4-allyl-1,4-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-) For the preparation of benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone, reference is made to Example 18.

^{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, 14.5 Hz, 2H), 4.82 (d, J = 6.7 Hz, 1H), 3.84 (d, J = 16.7 Hz, 2H), 3.47 (d, J = 15.2 Hz, 2H), 3.20 (d, J = 5.7 Hz, 1H), 2.98 (s, 1H), 2.81 (s, 2H), 2.71 (s, 1H), 2.60 (d, J = 7.4 Hz, 3H), 2.41 (d, J) = 4.9 Hz, 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-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-yl) Preparation of keto-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone

(4-(cyclopropylmethyl)-1,4-diazepine-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-yl) A method for producing keto-1H-benzo[d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is shown in Example 18.

^{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 = 9.0 Hz, 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 pyrimido-2-yl)amino)-2-methylpyridin-3-yl)(4-(N-azetidinyl)piperidin-1-yl)methanone is as follows:

1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1 H -benzo[ d ]imidazol-6-yl)pyrimidin-2-yl)) Amino)-2-methylindolyl)piperidin-4-one (350 mg, 0.67 mmol), azetidine hydrochloride (126 mg, 1.34 mmol) dissolved in dichloromethane (5 mL) In a mixed solvent of 15 mL), tetraethyl titanate (458 mg, 2.0 mmol) was added, and the reaction was stirred at room temperature for 10 hours, sodium borohydride (425 mg, 2.0 mmol) was added to the reaction mixture, and the reaction was stirred at room temperature. After 3 hours, LCMS showed the reaction was complete. The reaction mixture was poured into saturated sodium bicarbonate solution (5 mL), stirred for 30 min, anhydrous sodium sulfate was added, filtered, and directly dried, and the residue was purified by a flashing gel column and then reversed. Purification by phase column chromatography gave a pale grey solid product (159 mg, yield 42%).

^{1 H NMR (400MHz, DMSO- d} 6) δ: 10.22 (s, 1H), 8.71 (s, 1H), 8.31 (s, 1H), 8.14 (d, J = 8.2Hz, 1H), 7.70 (d, J =11.9 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 4.94-4.76 (m, 1H), 4.08 (s, 1H), 3.12 (d, J = 44.4 Hz, 6H), 2.65 ( s, 3H), 2.28 (d, J = 47.8 Hz, 4H), 1.91 (s, 2H), 1.60 (t, J = 20.1 Hz, 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][d Preparation of imidazolium-6-ylpyrimidin-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][d For the preparation of imidazolium-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone, refer 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 = 17.7 Hz, 10H), 2.06 (t , J = 27.0Hz, 3H), 1.83-1.57 (m, 8H), 1.43-1.06 (m, 5H).

¹⁹ F NMR (376 MHz, 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)piperidine-]-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 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 = 8.5 Hz, 1H), 4.74 (d, J = 12.6 Hz, 1H), 3.67 (d, J = 12.2 Hz, 1H), 3.37 (s, 1H), 3.23 (t, J = 13.5 Hz, 1H) , 3.17-3.06 (m, 3H), 3.00 (t, J = 12.5 Hz, 1H), 2.71 (s, 3H), 2.55 (dt, J = 15.7, 9.2 Hz, 2H), 2.46 (s, 3H), 2.20 (dd, J = 17.7, 10.0 Hz, 1H), 2.01 (d, J = 10.2 Hz, 1H), 1.73 (d, J = 6.9 Hz, 6H), 1.46 (dd, J = 45.8, 11.0 Hz, 1H) ), 1.33 (d, J = 19.4 Hz, 1H).

MS m/z (ESI): 617.2 [M+H] ⁺ .

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

(4-(Third-butylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo) The preparation method of [d]imidazol-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone is referred to in 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)- The preparation method of 2-methylpyridin-3-yl)(4-(isopropylamino)piperidin-1-yl)methanone is referred to Example 3.

^{1 H NMR (400MHz, MeOD)} δ: 8.52 (d, J = 3.8Hz, 1H), 8.33-8.18 (m, 2H), 7.76 (d, J = 11.9Hz, 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, 6.5 Hz, 2H), 3.22 (m, 1H), 2.90 (d) , J =13.0 Hz, 1H), 2.64 (s, 3H), 2.40 (s, 3H), 2.17 (s, 1H), 2.00 (s, 1H), 1.68 (t, J = 11.1 Hz, 6H), 1.47 (d, J = 43.5 Hz, 2H), 1.30 (d, J = 6.5 Hz, 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) And [d]imidazole-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) And [d] imidazole-6-ylpyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone was prepared by referring to Example 3.

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) Of -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) Refer to Example 3 for the preparation method of -yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone.

MS m/z (ESI): 557.2 [M+H] ⁺ .

Biological test evaluation

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

1. The method for analyzing the enzymatic activity of the compound of the present invention:

In this experiment, the LANCE (Lanthanide chelate excite) kinase detection technique was used to detect and analyze the enzymatic inhibitory activity of the test compound on CDK4/6. The method is briefly described as follows: 1) Adding different concentrations of compounds in a 384-well experimental plate (Greiner, Cat. No. 784076), each double-well, and then adding CDK4 (Carna, Cat. No. 04-105), Or CDK6 kinase CDK6 (Carna, Cat. No. 04-107), after mixing evenly; 2) adding a mixture of Ulight-MBP peptide (PerkinElmer, Cat. No. TRF0109-D) and ATP; 3) After 60 minutes of warm reaction, the reaction was terminated by adding EDTA. After 5 minutes of termination, the antibody Europium-anti-phospho-Myelin BasicProtein (MBP) (PerkinElmer, Cat. No. TRF0109-D) was added; 4) After 60 minutes incubation at room temperature, the machine was tested. (λ ex = 330 nm, λ em = 620 nm and λ em = 665 nm) 5) According to the following formula, the calculation data: 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 data is as follows:  

As can be seen from the above experimental results, the compounds of the examples of the present invention have a strong inhibitory activity against CDK kinase activity, and particularly have a good inhibitory activity and selectivity for CDK 4 and/or 6 kinase activity.

2. Determination of Proliferative Activity of Compounds of the Invention on Colon Cancer Cell Colo205

The compound's proliferation activity against colon cancer tumor cell colo205 was tested by the following method.

This method was used to determine the inhibitory effect of the compound of the present invention on the proliferative activity of colon cancer tumor cell colo205.

Experimental steps:

The method of the present study, the inhibition of a test compound on the colo205 CellTiter-Glo cell proliferation, and to obtain the compound inhibited cell proliferation half maximal inhibitory concentration IC ₅₀ activity.

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

2. Add gradient dilutions of different concentrations of the test compound solution to the culture plate cells, and incubate the plates for 6 days in the incubator (37 ° C, 5% CO ₂ ).

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

4. The plate reader measures the chemiluminescence signal value of each plate.

5. Calculate the inhibition rate by the value of the chemiluminescence signal.

6. The inhibition rate of different concentration of IC ₅₀ obtained by curve fitting of the compound.

The compound of the present invention was assayed for the proliferative activity of colon cancer tumor cell colo205, and the measured IC ₅₀ values are shown in Table 2.

It can be seen from the above experimental results that the compound of the present invention has a strong inhibitory effect on the proliferation activity of colon cancer tumor cell colo205.

3. Determination of pharmacokinetics in rats

1. Research purposes:

SD rats were used as test animals, and Compound 3, Compound 34 and Compound 63 were studied, and the pharmacokinetic behavior of the rats in vivo (plasma) was orally administered.

2. Test plan

2.1 Test drugs:

Inventive Example 3, Compound 34 and Compound 63 were prepared by themselves.

2.2 Test animals:

3 SD rats, male, Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

2.3 Drug preparation:

10 g of hydroxyethyl cellulose (HEC) was weighed, dissolved in 1000 mL of purified water, and 2.5 mL of Tween 80 and 0.5 mL of antifoaming agent were added. Mix well to form a clear solution. 6.1 mg of Example Compound 3, 6.9 mg of Example Compound 34, 5.8 mg of Example Compound 63 were weighed and dissolved in the solution, shaken and sonicated for 15 minutes to give a colorless clear solution at a concentration of 0.5 mg/mL.

2.4 Administration:

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

2.5 Sample Collection:

0.2 mL of jugular vein blood was collected before and after administration, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 24.0 h, and placed in EDTA-2K test tube. The plasma was separated by centrifugation at 6000 rpm for 6 min at 4 ° C, and stored at -80 ° C; Eat 4 h after dosing.

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

Experimental conclusions: The data in the table show that the three compounds of the present invention, Example 3, Example 34 and Example 63, reached a high exposure amount in rat plasma at a dose of 5 mg/kg orally. The highest blood drug concentration and duration of action vary widely, but the AUC difference is small. Both can guarantee an effective concentration of action.

4. Determination of pharmacokinetics in tumor-bearing mice

1. Research purposes:

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

2. Test plan

2.1 Test drugs:

Inventive Example Compound 3, Compound 34 and Compound 63 were prepared.

2.2 Test animals:

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

2.3 Drug preparation:

10 g of hydroxyethyl cellulose (HEC) was weighed, dissolved in 1000 mL of purified water, and 2.5 mL of Tween 80 and 0.5 mL of antifoaming agent were added. Mix well to form a clear solution. 36.6 mg of Example Compound 3, 22.6 mg of Example Compound 34, and 35.2 mg of Example Compound 63 were weighed and dissolved in the solution, shaken, and sonicated for 15 minutes to obtain a colorless clear solution at a concentration of 5.0 mg/mL.

2.4 Administration:

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

2.5 Sample Collection:

Before and after the administration of the mice, the CO _{2 was} sacrificed, 0.2 ml of blood was collected from the heart, placed in an EDTA-2K test tube, and the plasma was separated by centrifugation at 6000 rpm for 6 min at 4 ° C, and stored at -80 ° C. After the tumor tissue was weighed, it was placed in 2 mL. Store in a centrifuge tube at -80 °C.

2.5 Determination results: The final measurement results were obtained by LCMS/MS method, see Table 4.

Experimental conclusions: As shown in the data in the table, the exposure of Example 3, Example 34 and Example 63 in mouse plasma and tumor reached a very high level at a dose of 50 mg/kg, Example 3 and Example 63 Exposure in the tumor is significantly higher than in the blood, and Tmax and MRT can be seen that the concentration in the tumor is a gradually increasing process, and the metabolic rate is slower, indicating that the compound will gradually accumulate in the tumor and has been Maintain a high concentration in the tumor to ensure a better anti-tumor effect.

5. Inhibition of tumor on Colo205 xenograft model

5.1 Purpose of the experiment:

The BALB/c nude mice were used as test animals, and the human colorectal cancer cell Colo205 xenograft tumor (CDX) model was used for in vivo pharmacodynamic experiments to evaluate the antitumor effect 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)

CO ₂ incubator (Thermo)

Centrifuge (Centrifuge 5720R, Eppendorf)

Automatic Cell Counter (Countess II, Life Technologies)

Pipette (10-20μL, 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)

Streptomycin double antibody (SV30010, GE)

Phosphate buffer (PBS) (10010-023, Gibco)

5.3 Experimental operation:

A Colo205 cell was removed from the cell bank, and the cells were resuscitated with 1640 medium (1640 + 10% FBS + 1% Glu + 1% SP). The resuscitated cells were placed in a cell culture flask (cell type and date were marked on the wall). The culture name, etc.) were placed in a CO ₂ incubator (incubator temperature 37 ° C, CO ₂ concentration 5%). After the cells were covered with 80-90% of the bottom of the culture flask, the cells were subcultured, and the cells were further cultured in a CO ₂ incubator. This process is repeated until the number of cells meets the in vivo efficacy requirements. The cultured cells were collected, counted by a fully 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). Place in an ice box for use.

BALB/c nude mice, female, 6-8 weeks old, weigh approximately 18-22 grams. Mice were maintained in a special pathogen-free environment and in a single ventilated cage, 5 mice per cage. All cages, litter and water are sterilized prior to use. All animals are free to access a standard certified commercial laboratory diet. Nude mice were labeled with a disposable large mouse universal ear tag prior to inoculation and the skin of the inoculated site was disinfected with 75% medical alcohol. Each mouse was inoculated subcutaneously into the right flank and at a density of 4 x 10 ⁶ cells per 0.1 ml for tumor growth. Dosing begins when the average tumor volume reaches 100-200 cubic millimeters. The test compound was orally administered orally daily at a dose of 50 mg/kg. Tumor volume was measured with a vernier caliper twice a week. The 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. The anti-tumor efficacy is determined by dividing the average tumor-increased volume of the compound-treated animals by the average tumor-increased volume of the untreated animals. Tumor inhibition rate = 1 - [(Vt - V0) administration group / (Vt - V0) solvent control group] * 100%. Animals were euthanized after the experiment.

Experimental Conclusions: As can be seen from the data in the table, Compounds of Example 3, Example 34 and Example 63 of the present invention significantly inhibited the growth of transplanted tumors of Colo205 nude mice at a dose of 50 mg/kg.

In the case where the tumor in the placebo group was increased to 1763 mm 3 , the tumor of the animal group administered in Example 34 was increased to 430 mm 3 , which showed an excellent effect of inhibiting tumor growth. The administration of Example 3 and Example 63 was carried out. In the animal group, tumor growth was slower and the effect was more pronounced.

Sixth, hERG potassium channel inhibition activity test

6.1 Cell culture

6.1.1 The cells used in this assay were CHO cell lines transfected with hERG, cDNA and stably expressing hERG channels (supplied by Sophion Bioscience, Denmark) with cell numbers P14 to P16. The cells were cultured in a medium containing the following components: Ham's F12 medium, 10% (v/v) inactivated fetal bovine serum, 100 μg/ml hygromycin B, and 100 μg/ml Geneticin.

6.1.2 CHO hERG cells were grown in culture dishes containing the above culture medium and cultured in an incubator containing 5% CO ₂ at 37 °C. 24 to 48 hours before the electrophysiological experiment, CHO hERG cells were transferred to a circular glass plate placed in a petri dish and grown under the same culture medium and culture conditions as above, and the density of CHO hERG cells on each circular slide. The need to reach the vast majority of cells is an independent, single requirement.

6.2 Experimental solution

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

6.3 Electrophysiological Recording System

This experiment used a manual patch clamp system (HEKA EPC-10 signal amplifier and digital conversion system, purchased from HEKA Electronics, Germany) for the recording of whole cell currents. A circular slide with CHO hERG cells grown on it was placed in an electrophysiology recording trough under an inverted microscope. The extracellular fluid was continuously perfused in the recording tank (about 1 ml per minute). The experimental procedure uses conventional whole-cell patch clamp current recording techniques. Unless otherwise stated, the experiments were carried out at regular room temperature (~25 ° C). The cells were clamped at a voltage of -80 mV. The cell clamp voltage was depolarized to +20 mV to activate the hERG potassium channel, and after 5 seconds it was clamped to -50 mV to eliminate inactivation and generate tail current. The tail current peak is used as the value of the hERG current magnitude. After the hERG potassium current recorded in the above step is stabilized under the continuous extracellular fluid perfusion in the recording tank, the drug to be tested can be superimposed and filled until the inhibitory effect of the drug on the hERG current reaches a steady state. Generally, the recent three consecutive current recording lines are recombined as a criterion for judging whether or not the state is stable. After reaching a steady state, rinse with extracellular fluid until the hERG current returns to the size before the drug is added. One cell can test one or more drugs, or multiple concentrations of the same drug, but need to be flushed with extracellular fluid between different drugs. Cisapride (cisapride, purchased from Sigma) was used in the experiment as a positive control to ensure that the cells used were of normal quality.

6.4 Compound treatment and dilution

In order to obtain the IC _{50 of the} compound, 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. Before the test, first use DMSO was diluted to 10, 3, 1, 0.3, and 0.1 mM stocks in a gradient dilution, and then diluted 1000 times with extracellular fluid to a final μM test concentration, except for a final concentration of 0.3% for the 30 μM test concentration of DMSO. The final concentration of DMSO in the other concentrations of the compound solution was 0.1%. The positive control Cisapride (West sapride) was tested at a concentration of 0.1 μM. All compound solutions were sonicated and shaken for 5 to 10 minutes to ensure complete dissolution of the compound. .

6.5 Data analysis

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

6.6 Quality Control

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

Record parameters:

Membrane resistance Rm>500MΩ

Access resistance (Ra) <5MΩ

Tail current amplitude >300pA

Current rundown (spontaneous reduction) <2% per minute

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

Pharmacological parameters:

0.1 μM cisapride (C4740-10 mg, Sigma) blocked more than 50% of the hERG current as a positive control.

6.7 Experimental results

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

The inhibition of cardiac hERG potassium channels by drugs is the main cause of drug-induced QT prolongation syndrome. As can be seen from the experimental results, Example Compound 3, Compound 34 and Compound 63 had substantially no inhibitory effect on cardiac hERG potassium ion channels.

In summary, the present invention provides a series of highly active, highly selective CDK4/6 kinase inhibitors having novel structures with stronger enzymatic activity and cell viability, and better selectivity to kinases. It shows better pharmacokinetic properties in both rats and mice, and it also shows better drug efficacy. Cardiac toxicity is significantly reduced. There is great potential to be developed as a drug for diseases of cell cycle proliferative disorders. Especially for HR+/Her-type breast cancer drugs.

Claims (33)

A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: Wherein: L is a bond, -C(O)- or -C(O)NH-; ring A is a heterocyclic group, wherein the heterocyclic group is selected from the group consisting of a monocyclic heterocyclic group, a spirocyclic heterocyclic group, and a fused ring a cyclic group and a bridged ring heterocyclic group; R is selected from a hydrogen atom, a halogen atom or a halogen; and R _{1 is} selected from a halogen atom, an alkyl group, a decyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, a halogen, an amine Base, 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 group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from the group consisting of a halogen atom, an alkyl group, a halogen alkyl group, a halogen group, an amine group, a nitro group, and a cyano group. Base, 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 Substituting one or more substituents in R ₈ ; R _{2 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a decyl group, a haloalkyl group, an alkoxy group, an alkoxy group. , 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 group, the alkyl group, the haloalkyl group, the amino alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group Further selected from the group consisting of a halogen atom, an alkyl group, a halogen alkyl group, a halogen group, an amine group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, or a cycloalkyl group. , heterocyclic group, 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 One or more substituents in R ₈ Substituted; R _{3 is} selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a decyl group, a halogenated alkyl group, a hydroxyl group, an amine group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group. And wherein the alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from the group consisting of a halogen atom, an alkyl group, a halogen group, an amine group, a nitro group, a cyano group, a hydroxyl group, 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 one or more substituents; same or different, R ₄ and R _5, and are each independently selected from a hydrogen atom, a deuterium atom, an alkyl, deuterated alkyl, haloalkyl, hydroxyl, amine , 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 group, the ring The alkyl group, heterocyclic group, aryl group and heteroaryl group are further selected from the group consisting of a halogen atom, an alkyl group, a halogen group, a hydroxyl group, an amine group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, and the like. 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 ) Substituted by one or more substituents in _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 ; _{6 is} selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a decyl group, a haloalkyl group, a hydroxyl group, an amine group, an alkoxy group, a haloalkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; The alkyl group, haloalkyl group, cycloalkyl group, heterocyclic group, aromatic And the heteroaryl group is further selected from the group consisting of a halogen atom, an alkyl group, a halogen group, an amine group, a nitro group, a cyano group, a hydroxyl group, a hydroxyalkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group. Substituted by one or more substituents; R ₇ and R _{8 are the} same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen atom, an alkyl group, a decyl group, a haloalkyl group, a hydroxyl group, an amine group, and an ester group. a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group are further selected from a halogen atom, an alkyl group, a halogen group, and a hydroxyl group as needed. Substituting one or more substituents of an amine group, a nitro group, a cyano group, an ester group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; x is 0, An integer of 1, 2, 3, 4 or 5; m is an integer of 0, 1 or 2; and n is an integer of 0, 1, 2, 3, 4 or 5. A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to the first aspect of the invention, which is a compound represented by the formula (II), or a stereoisomer thereof Or a pharmaceutically acceptable salt thereof: Wherein: Ring B is selected from the group consisting of a 3-8 membered monocyclic heterocyclic group, a 6-10 membered spirocyclic heterocyclic group, a 6-10 membered fused ring heterocyclic group or a 6-10 membered bridged heterocyclic group; -C(O)-; R, R ₁ , R ₂ and x are as described in the first item of the patent application.  A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to the second aspect of the invention, wherein the ring B is a 3-8 membered monocyclic heterocyclic group.   a compound represented by the above (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (II), a stereoisomer thereof or A pharmaceutically acceptable salt which is a compound of the formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: Wherein: Rings B, R, R ₁ , R ₂ and x are as described in item 2 of the scope of the patent application. a compound represented by the above (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (II), a stereoisomer thereof or A pharmaceutically acceptable salt which is a compound of the formula (IV), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: Wherein: Rings B, R, R ₁ , R ₂ and x are as described in item 2 of the scope of the patent application. a compound represented by the above formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (III), a stereoisomer thereof or A pharmaceutically acceptable salt which is a compound of the formula (V), a stereoisomer thereof 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; R ₁ is an alkyl group or a halogen, wherein the alkyl group is a C _1-6 alkyl group; R _{2 are the} same or different and are each independently Selected from a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group, a C _1-6 amino alkoxy group, a C _1-6 haloalkoxy group, a halogen, an amine a base, a pendant oxy group, a nitro group, a hydroxyl group, a cyano group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, -(CH ₂ ) _n OR ₃ and -(CH ₂ ) _n NR ₄ R ₅ , Wherein the C _1-6 alkyl group, the C _1-6 haloalkyl group, the C _1-6 amino alkoxy group, the C _3-8 cycloalkyl group and the 3-8 membered heterocyclic group are further selected from the group consisting of C _{1 -6} alkyl, C _1-6 haloalkyl, halogen, amine, cyano, hydroxy, alkenyl, alkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkane One or more of a group, a C _3-8 cycloalkyl group, a 3-8 membered heterocyclic group, -(CH ₂ ) _n -, -(CH ₂ ) _n OR ₆ and -(CH ₂ ) _n NR ₇ R ₈ Substituted by a substituent; or two R ₂ are bonded to each other to form a 3-10 membered cycloalkyl or heterocyclic group, wherein the 3-8 membered cycloalkyl or heterocyclic group is further protected by one or more C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy a substituent of a C _1-6 aminoalkoxy group, a C _1-6 haloalkoxy group, a halogen, an amine group, a pendant oxy group, a hydroxy group, a cyano group, and a C _3-8 cycloalkyl group; and y is An integer of 0, 1, 2 or 3; R ₃ to R ₈ , n and x are as described in item 3 of the patent application.  A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to the invention, wherein the compound represented by the formula (V), or a stereoisomer thereof Or a pharmaceutically acceptable salt thereof, R is a fluorine atom.   A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to the invention, wherein the compound represented by the formula (V), or a stereoisomer thereof Or a pharmaceutically acceptable salt thereof, R ₁ is C _1-3 alkyl. A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to the invention, wherein the compound represented by the formula (V), or a stereoisomer thereof Or a pharmaceutically acceptable salt thereof, two R ₂ are bonded to each other to form a 5- to 8-membered cycloalkyl group or a heterocyclic group. A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to the invention, wherein the compound represented by the formula (V), or a stereoisomer thereof Or a pharmaceutically acceptable salt thereof: wherein: M is selected from CHR ₂ or NR ₂ ; and R _{2 is} selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _1-6 alkoxy group, C _1-6 aminoalkoxy, C _1-6 haloalkoxy, halogen, amine, pendant oxy, hydroxy, cyano, C _3-8 cycloalkyl, 3-8 membered heterocyclic, -( CH ₂ ) _n OR ₃ and -(CH ₂ ) _n NR ₄ R ₅ , wherein the C _1-6 alkyl group, the C _1-6 haloalkyl group, the C _1-6 amino alkoxy group, the C _3-8 ring The alkyl group and the 3-8 membered heterocyclic group are further selected from C _1-6 alkyl, C _1-6 haloalkyl, halogen, amine, cyano, hydroxy, C _2-6 alkenyl, C ₂ as needed. _-6 alkynyl, C _1-6 alkoxy, C _1-6 haloalkoxy, C _1-6 hydroxyalkyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, -(CH ₂ Substituting one or more substituents of _n -, -(CH ₂ ) _n OR ₆ and -(CH ₂ ) _n NR ₇ R ₈ ; R, R ₁ , R ₃ to R ₈ , x, n and y As described in item 6 of the patent application. A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to the invention of claim 6, wherein the compound represented by the formula (V) is a formula ( a compound represented by VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof: Wherein: R ₄ and R ₅ are each independently selected from the group consisting of a hydrogen atom, a C _1-6 alkyl group, a C _1-6 haloalkyl group, a C _3-8 cycloalkyl group, —(CH ₂ ) _n OR ₆ , —(CH) ₂ ) _n C(O)R ₆ , wherein the C _1-6 alkyl group, the C _1-6 haloalkyl group, and the C _3-8 cycloalkyl group are further selected from a C _1-6 alkyl group, a halogen group, a hydroxyl group, Substituted by one or more substituents in the amine group, cyano group, C _1-6 alkoxy group, C _1-6 hydroxyalkyl group and C _1-6 cycloalkyl group; or R ₄ and R ₅ form a 3- An 8-membered heterocyclic group wherein the 3-8 membered heterocyclic group is further selected from C _1-6 alkyl, -(CH ₂ ) n-, halogen, hydroxy, amine, cyano, C ₁ as needed Substituting one or more substituents of _-6 alkoxy, C _1-6 hydroxyalkyl and C _1-6 cycloalkyl; R, R ₁ and n are as described in claim 6 of the scope of the patent application. A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to the invention of claim 11, wherein the compound represented by the formula (VI), or a stereoisomer thereof Or a pharmaceutically acceptable salt thereof, the heterocyclic group formed by R ₄ and R ₅ is a 4-6 member.  The compound represented by the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, wherein R is selected from a hydrogen atom and a halogen.    A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to the invention of claim 13, wherein the halogen is fluorine.   The compound of the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, wherein R _{1 is} selected from C _1-8 An alkyl group and a halogen, wherein the C _1-8 alkyl group; wherein the halogen is fluorine. A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to the invention of claim 15, wherein R ₁ is a C _1-6 alkyl group. A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to the invention of claim 16, wherein R ₁ is a C _1-3 alkyl group. A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 17, wherein R ₁ is a methyl group. The compound of the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, wherein R _{2 is} selected from a hydrogen atom, C _1-8 alkyl, 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 Further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C _1-8 alkyl, -(CH ₂ ) _n OR ₆ and C _1-8 alkoxy, as needed. A compound represented by the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 19, wherein R _{2 is} selected from C _1-6 alkyl, C _{1- a 6} haloalkyl group, a pendant oxy group, a —(CH ₂ ) _n NR ₄ R ₅ and a 3-6 heterocyclic group, wherein the C _1-6 alkyl group is further selected from one selected from the group consisting of halogen, hydroxy and cyano. Substituted by a plurality of substituents. A compound represented by the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to the invention of claim 19, wherein the C _1-6 alkyl group is a C _1-3 alkyl group. . The compound of the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 11, wherein R ₄ and R ₅ are each independently Selected from a hydrogen atom, a C _1-8 alkyl group, a C _1-8 haloalkyl group, a C _3-8 cycloalkyl group, a —(CH ₂ ) _n C(O)R ₆ and a C _1-8 alkoxy group, wherein The C _1-8 alkyl group, C _1-8 haloalkyl group, C _3-8 cycloalkyl group and C _1-8 alkoxy group are further selected from halogen, hydroxy, cyano, C _1-8 alkyl as needed. Substituting one or more substituents of C _3-8 cycloalkyl, -(CH ₂ ) _n OR ₆ and C _1-8 alkoxy; R _{6 is} selected from a hydrogen atom, a C _1-6 alkyl group, and C _1-6 alkoxy. A compound represented by the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 22, wherein R ₄ and R ₅ are each independently selected from C _1-6 An alkyl group and a C _3-6 cycloalkyl group, wherein the C _1-6 alkyl group and the C _3-6 cycloalkyl group are further selected from the group consisting of halogen, hydroxy, cyano, C _1-6 alkyl, C ₃ as needed Substituted by one or more substituents of _-6 cycloalkyl and -(CH ₂ ) _n OR ₆ . a compound represented by the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 22, wherein the C _1-6 alkyl group is a C _1-3 alkyl group. . A compound represented by the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to claim 22, wherein R _{6 is} selected from C _1-3 alkyl and C _{1- 3} alkoxy. A compound of the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is selected from the group consisting of: A process for the preparation of a compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 26, comprising the steps of: The compound of the formula (I) is coupled with the compound of the formula (VB) to give a compound of the formula (I), which is further reacted as needed, or further deprotected to give a different compound of the formula (I) Wherein the catalytic reagent in the coupling reaction is Pd ₂ (dba) ₃ and Xantphos reagent; wherein: X is a halogen; and rings A, L, R, R ₁ , R ₂ and x are as described in claim 1 of the scope of the patent application.  The preparation method according to claim 27, wherein X is chlorine.    A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) according to any one of claims 1 to 26, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and one or more A pharmaceutically acceptable carrier, diluent or excipient.    A compound of the formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, or a pharmaceutical composition according to claim 29 Use for the preparation of a medicament for the treatment and/or prevention of cancer or tumor-associated diseases mediated by CDK kinase 4 and/or 6.    The use according to claim 30, wherein the cancer or tumor-related disease is selected from the group consisting of brain tumor, lung cancer, liver cancer, stomach cancer, oral cancer, head and neck cancer, intestinal cancer or rectal cancer, colon cancer, kidney cancer, and esophagus. Adenocarcinoma, esophageal squamous cell carcinoma, squamous cell carcinoma, thyroid cancer, bone cancer, skin cancer, non-small cell lung 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 genital tract cancer, testicular cancer, gastrointestinal stromal tumor or prostate tumor.    The use according to claim 31, wherein the cancer or tumor-related disease is selected from the group consisting of 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 tumor or prostate tumor.    The use of claim 32, wherein the breast cancer comprises: a locally advanced or metastatic breast cancer that is negative for estrogen receptor positive and/or negative for human epidermal growth factor receptor 2 in postmenopausal women.