WO2021139775A1

WO2021139775A1 - Pyridone compound and application

Info

Publication number: WO2021139775A1
Application number: PCT/CN2021/070887
Authority: WO
Inventors: 李桢; 唐锋; 赵春艳; 陈平; 张国宝; 唐任宏; 任晋生
Original assignee: 江苏先声药业有限公司
Priority date: 2020-01-10
Filing date: 2021-01-08
Publication date: 2021-07-15
Also published as: CN114901664A

Abstract

A compound as represented by general formula (A) or a pharmaceutically-acceptable salt thereof, a pharmaceutical composition and a preparation method therefor, and use thereof as an MAT2A inhibitor.

Description

Pyridone compounds and applications

This application claims the priority of the following five earlier applications. The full text of the following earlier applications is incorporated into this application by reference:

The prior application filed with the State Intellectual Property Office of China on January 10, 2020, the patent application number is 202010026786.X, and the invention title is "pyridone compound";

The prior application filed with the State Intellectual Property Office of China on April 30, 2020, the patent application number is 202010362378.1, and the invention title is "Pyridone Compounds and Applications";

The prior application filed with the State Intellectual Property Office of China on July 9, 2020, the patent application number is 202010658579.6, and the invention title is "Pyridone Compounds and Applications";

The prior application filed with the State Intellectual Property Office of China on August 26, 2020, the patent application number is 202010871227.9, and the invention title is "Pyridone Compounds and Applications";

An earlier application filed with the State Intellectual Property Office of China on September 14, 2020, with a patent application number of 202010958603.8 and an invention title of "Pyridone Compounds and Applications".

Technical field

The present invention relates to a novel pyridone compound or pharmaceutically acceptable salt, a pharmaceutical composition containing them, and use as a MAT2A inhibitor.

Background technique

Methionine adenosyltransferase (methionine adenosyltransferase, MAT), also known as S-adenosyl methionine synthetase, can catalyze the reaction of methionine (Met) with ATP to generate S-adenosyl methyl sulfide A class of enzymes of S-Adenosyl-L-methionine (SAM). SAM is the main methyl donor in the body, which can regulate gene expression, transcription and translation through the methylation reaction, which in turn has an important impact on cell growth, death and differentiation. Not only that, SAM is also involved in the biosynthesis of polyamines and glutathione.

There are three main subtypes of MAT enzyme, MAT1A, MAT2A and MAT2B. MAT1A is mainly found in normal liver cells, while MAT2A is widely distributed in extrahepatic cells. These two subtypes have differences in catalytic efficiency and control methods. MAT2B does not have the ability to catalyze the synthesis of SAM, but as a regulatory subunit of MAT2A, after forming a complex with MAT2A, it regulates the catalytic activity of MAT2A.

Studies have pointed out that in liver cancer cells, the expression level of MAT1A is down-regulated and the expression of MAT2A is increased, thereby promoting the proliferation of liver cancer cells. In addition, the abnormally elevated expression of MAT2A also exists in many types of other tumors, and silencing the gene encoding MAT2A can lead to the death of cancer cells. Furthermore, Marjon et al. (Cell Reports 15(3) (2016) 574-587) found that cancer cell lines lacking MTAP are sensitive to MAT2A inhibition. MTAP is also called methylthioadenosine phosphorylase, which is widely expressed in normal tissue cells. The enzyme can catalyze the conversion of methylthioadenosine (MTA) into 5-methylthioribose-1-phosphate and adenine. This process is also an important part of the methionine compensation pathway in the human body. When MTAP is missing, the metabolic pathway of MTA is inhibited, leading to a large accumulation of MTA in the body, and ultimately increasing the sensitivity of cancer cells to MAT2A inhibition.

The gene encoding human MTAP is located in the 9p21 region (chr9p21) of chromosome. The frequency of homozygous deletion in all tumors is about 15%, and the frequency of deletion is different in different tumors. Tumor types with a higher frequency of deletion include glioma, mesothelioma, melanoma, gastric cancer, esophageal cancer, bladder cancer, pancreatic cancer, non-small cell lung cancer, astrocytoma, osteosarcoma, head and neck cancer, and mucinous chondrosarcoma , Ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin’s lymphoma, etc.

In the human chromosome 9p21 region not only contains the gene encoding MTAP, this region also contains the tumor suppressor genes p16INK4A (also known as CDKN2A) and p15INK4B. In 80%-90% of tumors with CDKN2A deletion, MTAP is also in a state of deletion.

Given that the expression level of MAT2A is abnormally elevated in many types of tumors, including gastric cancer, colon cancer, liver cancer and pancreatic cancer, and selective inhibition of MAT2A can reduce the proliferation activity of MTAP-deficient cancer cells. Therefore, selective inhibition of MAT2A can be used as an effective tumor treatment.

WO2018039972, WO2018045071 and WO2019191470 disclose MAT2A inhibitor heterocyclic compounds for the treatment of tumors.

Summary of the invention

The present invention provides a compound represented by general formula (A) or a pharmaceutically acceptable salt thereof:

Wherein, ring Q is a 5-6 membered heterocyclic group, a C ₆ -C ₁₀ aryl group or a 5-10 membered heteroaryl group, the 5-6 membered heterocyclic group, a C ₆ -C ₁₀ aryl group or a 5-10 membered heteroaryl group membered heteroaryl optionally substituted with R ^a, R ^a is selected from a F, Cl, Br, I, OH, CN or an optionally substituted group consisting of R ^b: C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₁₀ alkoxy;

R ^{b is} selected from F, Cl, Br, I, OH or CN;

Ring W is a phenyl group, a pyridyl group, a pyridonyl group or a 9-10 membered heteroaryl group, and the phenyl group, a pyridyl group, a pyridonyl group or a 9-10 membered heteroaryl group is optionally ^{substituted by R c} , and the R ^{c is} selected from OH or the following groups ^{optionally substituted by R c1} _{: C 1} -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₃ -C ₁₀ cycloalkyl, P(O)(C _1- C ₃ alkyl) ₂ , 4-6 membered heterocycloalkyl;

R ^{c1 is} selected from F, Cl, Br, I, CN, OH, NH ₂ or the following groups optionally substituted by R ^c2 _{: C 1} -C ₃ alkyl, C ₁ -C ₃ alkoxy, NHC(O ) O (C ₁ -C ₆ alkyl), (C ₁ -C ₆ alkyl) NHC(O)O, NH (C ₁ -C ₃ alkyl), N (C ₁ -C ₃ alkyl) ₂ , S(O) ₂ (C ₁ -C ₃ alkyl), 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, (C ₃ -C ₁₀ cycloalkyl) CH ₂ O, 5-6 Membered heteroaryl, 5-6 membered heteroaryloxy;

R ^{c2 is} selected from 4-6 membered heterocycloalkyl, =0, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halogenated C ₁ -C ₃ alkyl, F, Cl, Br, I , CN, OH, CH ₂ OH or NH ₂ ;

R ^{1 is} selected from H, C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl, said C ₁ -C ₁₀ alkyl or C ₃ -C ₁₀ cycloalkyl is optionally ^{substituted by R d} , said R ^{d is} selected from F, Cl, Br, I, OH, CN or C ₁ -C ₃ alkyl;

X is selected from N or CH;

L is selected from O or NH;

requirement is,

When W is a phenyl ring optionally substituted by R ^c, ring Q is substituted with one or more R ^a phenyl or pyridyl, said R ^a is C ₁ -C ₁₀ alkoxy group, a C ₁ -C ₁₀ alkoxy optionally substituted with a R ^b, and when ring Q is phenyl substituted with one or more of R ^a, wherein R ^a 4 is connected with a phenyl group;

When ring Q is a 5-6 membered heterocyclic group, L is selected from O.

In some embodiments, ring Q is a 5-6 membered heterocyclic group, a C ₆ -C ₁₀ aryl group, or a 5-10 membered heteroaryl group, the 5-6 membered heterocyclic group, a C ₆ -C ₁₀ aryl group or 5-10 membered heteroaryl optionally substituted with R ^a, R ^a is selected from a F, Cl, Br, I, OH, CN or an optionally substituted group consisting of R ^b: C ₁ -C ₁₀ alkyl Group, C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₁₀ alkoxy;

R ^{b is} selected from F, Cl, Br, I, OH or CN;

Ring W is phenyl, pyridyl, pyridonyl or 9-10 membered heteroaryl, said phenyl, pyridyl, pyridonyl or 9-10 membered heteroaryl is optionally ^{substituted by R c} , said R ^{c is} selected from OH or the following groups ^{optionally substituted by R c1} _{: C 1} -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₃ -C ₁₀ cycloalkyl, P(O)(C _1- C ₃ alkyl) ₂ , 4-6 membered heterocycloalkyl;

R ^{c2 is} selected from 4-6 membered heterocycloalkyl, =0, C ₁ -C ₃ alkyl, halo C ₁ -C ₃ alkyl, F, Cl, Br, I, CN, OH, CH ₂ OH or NH ₂ ;

X is selected from N or CH;

L is selected from O or NH;

requirement is,

When ring Q is a 5-6 membered heterocyclic group, L is selected from O.

R ^{b is} selected from F, Cl, Br, I, OH or CN;

R ^{c1 is} selected from F, Cl, Br, I, CN, OH, NH ₂ or the following groups optionally substituted by R ^c2 _{: C 1} -C ₃ alkyl, C ₁ -C ₃ alkoxy, NHC(O ) O (C ₁ -C ₆ alkyl), NH (C ₁ -C ₃ alkyl), N (C ₁ -C ₃ alkyl) ₂ , S (O) ₂ (C ₁ -C ₃ alkyl), 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, 5-6 membered heteroaryl, 5-6 membered heteroaryloxy;

R ^{c2 is} selected from 4-6 membered heterocycloalkyl, =0, C ₁ -C ₃ alkyl, F, Cl, Br, I, CN, OH or NH ₂ ;

X is selected from N or CH;

L is selected from O or NH;

requirement is,

When ring Q is a 5-6 membered heterocyclic group, L is selected from O.

R ^{b is} selected from F, Cl, Br, I, OH or CN;

Ring W is phenyl, pyridyl, pyridonyl or 9-10 membered heteroaryl, said phenyl, pyridyl, pyridonyl or 9-10 membered heteroaryl is optionally ^{substituted by R c} , said R ^{c is} selected from the following groups ^{optionally substituted by R c1} _{: C 1} -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, C ₃ -C ₁₀ cycloalkyl, P(O)(C ₁ -C ₃ Alkyl) ₂ ;

R ^{c1 is} selected from F, Cl, Br, I, CN, OH, C ₁ -C ₃ alkoxy, NH ₂ , NH (C ₁ -C ₃ alkyl), N (C ₁ -C ₃ alkyl) ₂ , S(O) ₂ (C ₁ -C ₃ alkyl);

X is selected from N or CH;

L is selected from O or NH;

requirement is,

When ring Q is a 5-6 membered heterocyclic group, L is selected from O.

In some embodiments, ring Q is a C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl group, a C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl optionally substituted with R ^a, as said R ^a is selected from F, Cl, Br, I, OH, CN , or optionally substituted R ^b group consisting of: C ₃ -C ₁₀ cycloalkyl, C ₁ -C ₁₀ alkoxy;

R ^{b is} selected from F, Cl, Br, I, OH or CN;

Ring W is a phenyl group or a 9-10 membered heteroaryl group, the phenyl group or a 9-10 membered heteroaryl group is optionally ^{substituted by R c} , and the R ^{c is} selected from a C ₁ -C ₁₀ alkyl group or a C _1- C ₁₀ alkoxy;

X is selected from N or CH;

L is selected from O or NH;

With the proviso that, when W is a phenyl ring optionally substituted by R ^c, ring Q is substituted with one or more R ^a phenyl or pyridyl, said R ^a is C ₁ -C ₁₀ alkoxy, the C ₁ -C ₁₀ alkoxy optionally substituted with a R ^b, and when ring Q is substituted with one or more R ^a substituted phenyl group, wherein R ^a 4 is connected with a phenyl group.

R ^{b is} selected from F, Cl, Br, I, OH or CN;

R ^{1 is} selected from C ₁ -C ₁₀ alkyl group or C ₃ -C ₁₀ cycloalkyl group, said C ₁ -C ₁₀ alkyl group or C ₃ -C ₁₀ cycloalkyl group is optionally ^{substituted by Rd} , said R ^d Selected from F, Cl, Br, I, OH or CN;

X is selected from N or CH;

L is selected from O or NH;

In some embodiments, ring Q is piperidinyl, phenyl or pyridinyl group, a piperidinyl group, a phenyl or pyridinyl optionally substituted with R ^a.

In some embodiments, Ring Q is piperidinyl optionally substituted with ^Ra.

In some embodiments, ring Q is an optionally substituted phenyl group of R ^a or R ^a optionally substituted pyridyl.

In some embodiments, ring Q is an optionally substituted phenyl group of R ^a or R ^a optionally substituted pyridin-3-yl.

In some embodiments, R ^a is F, Cl, Br, I, C 1 -C 6 alkyl, C ₃ -C ₆ cycloalkyl or optionally substituted with F, C ₁ -C ₆ alkoxy.

In some embodiments, R ^a is F, Cl, Br, I, C 3 -C 6 cycloalkyl or optionally substituted with F, C ₁ -C ₆ alkoxy.

In some embodiments, R ^a is F, Cl, Br, I, methyl, cyclopropyl optionally substituted with F or methoxy.

In some embodiments, R ^a is F, Cl, Br, I, F cyclopropyl or optionally substituted methoxy.

In some embodiments, ring Q is selected from

In some embodiments, ring W is phenyl, pyridyl, 2-pyridonyl, or 9-10 membered heteroaryl, said phenyl, 2-pyridonyl, pyridyl, or 9-10 membered heteroaryl Optionally substituted by R ^c.

In some embodiments, ring W is optionally substituted with ^{R c}

In some embodiments, ring W is an optionally substituted phenyl, or R ^c of R ^c is optionally substituted 9-10 membered heteroaryl.

In some embodiments, ring W is pyridyl optionally substituted with ^{R c.}

In some embodiments, ring W is

Wherein ring M is a 5-6 membered heteroaryl group, and said ring M is optionally substituted ^{by R c.}

In some embodiments, ring W is optionally substituted with ^{R c}

In some embodiments, R ^{c is} selected from OH or the following groups ^{optionally substituted with R c1} _{: C 1} -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, P (O) (C ₁ -C ₃ alkyl) ₂ , 4-6 membered heterocycloalkyl.

In some embodiments, R ^{c is} selected from OH or the following groups ^{optionally substituted with R c1} _{: C 1} -C ₃ alkyl, C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, P (O) (C ₁ -C ₃ alkyl) ₂ , 4-5 membered heterocycloalkyl.

In some embodiments, R ^{c is} selected from OH or the following groups ^{optionally substituted with R c1} _{: C 1} -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, P (O) (C ₁ -C ₃ alkyl) ₂ , 4-5 membered heterocycloalkyl.

In some embodiments, R ^{c is} selected from OH or ^{the following groups optionally substituted with R c1} : methyl, ethyl, isobutyl, methoxy, ethoxy, isobutyloxy, cyclopropyl , P(O)(CH ₃ ) ₂ ,

In some embodiments, R ^{c is} selected from OH or ^{the following groups optionally substituted with R c1} : methyl, ethyl, isobutyl, methoxy, ethoxy, cyclopropyl, P(O)( CH ₃ ) ₂ ,

In some embodiments, R ^{c is} selected from ^{the following groups optionally substituted with R c1} : methyl, ethyl, methoxy, cyclopropyl, P(O)(CH ₃ ) ₂ .

In some embodiments, R ^{c1 is} selected from F, CN, OH, NH ₂ or the following groups optionally substituted by R ^c2 _{: C 1} -C ₃ alkyl, C ₁ -C ₃ alkoxy, NHC(O )OC(CH ₃ ) ₃ , (CH ₃ ) ₂ CHNHC(O)O, NH(C ₁ -C ₃ alkyl), N(C ₁ -C ₃ alkyl) ₂ , S(O) ₂ (C ₁ -C ₃ alkyl), 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, (C ₃ -C ₆ cycloalkyl) -CH ₂ -O, 6-membered heteroaryl, 6-membered hetero Aryloxy.

In some embodiments, R ^{c1 is} selected from F, CN, OH, NH ₂ or the following groups optionally substituted by R ^c2 _{: C 1} -C ₃ alkyl, C ₁ -C ₃ alkoxy, NHC(O )OC(CH ₃ ) ₃ , NH(C ₁ -C ₃ alkyl), N(C ₁ -C ₃ alkyl) ₂ , S(O) ₂ (C ₁ -C ₃ alkyl), 4-10 yuan Heterocyclyl, 4-10 membered heterocyclyloxy, 6-membered heteroaryl, 6-membered heteroaryloxy.

In some embodiments, R ^{c2 is} selected from oxetanyl, =0, methyl, methoxy, OH, CH ₂ CH ₂ CH ₂ F, CH ₂ OH.

In some embodiments, R ^{c2 is} selected from oxetanyl, =0, methyl, OH, CH ₂ CH ₂ CH ₂ F, CH ₂ OH.

In some embodiments, R ^{c2 is} selected from oxetanyl, =0, methyl, OH.

In some embodiments, R ^{c is} selected from C ₁ -C ₃ alkyl.

In some embodiments, ring W is selected from

In some embodiments, ring W is selected from

In some embodiments, ring W is selected from

In some embodiments, R ^{c is} selected from the following groups ^{optionally substituted by R c1} _{: C 1} -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, P(O ) (C ₁ -C ₃ alkyl) ₂ .

In some embodiments, R ^{c is} selected from the following groups ^{optionally substituted by R c1} _{: C 1} -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, P(O ) (C ₁ -C ₃ alkyl) ₂ .

In some embodiments, R ^{c1 is} selected from OH, C ₁ -C ₃ alkoxy, NH ₂ , NH (C ₁ -C ₃ alkyl), N (C ₁ -C ₃ alkyl) ₂ , S(O ) ₂ (C ₁ -C ₃ alkyl).

In some embodiments, R ^{c1 is} selected from OH, methoxy, NH ₂ , N(CH ₃ ) ₂ , S(O) ₂ CH ₃ .

In some embodiments, R ^c is C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkyl.

In some embodiments, R ^c is C ₁ -C ₃ alkoxy or C ₁ -C ₃ alkyl.

In some embodiments, R ^c is methoxy or methyl. In some embodiments, ring W is selected from

In some embodiments, ring W is selected from

In some embodiments, ring W is an optionally substituted phenyl group R ^c of the ring Q is substituted with one or more R ^a pyridyl group, a R ^a R ^b is optionally substituted with a C ₁ -C ₆ Alkoxy, the R ^{b is} selected from F, Cl, Br, I, OH or CN.

In some embodiments, ring W is an optionally substituted phenyl group R ^c of, ring Q is substituted with one or more substituents R ^a pyridyl, said R ^a is optionally substituted by a methoxy group R ^b, The R ^{b is} selected from F, Cl, Br, I, OH or CN.

In some embodiments, when the ring W is an optionally substituted phenyl R ^c, ring Q is substituted with one or more R ^a phenyl group, and four R ^a connection with a phenyl group, the The Ra is ^a C ₁ -C ₆ alkoxy group optionally substituted by R ^b , and the R ^{b is} selected from F, Cl, Br, I, OH or CN.

In some embodiments, when W is a phenyl ring optionally substituted by R ^c, ring Q is a substituted C ₁ -C ₆ alkoxy phenyl group, the C ₁ -C ₆ alkoxy group ring The 4-position of the Q phenyl group is connected, and the C ₁ -C ₆ alkoxy group is optionally substituted with F.

In some embodiments, ring W is ^{phenyl optionally substituted with R c} , and ring Q is 4-difluoromethoxy substituted phenyl or 6-trifluoromethoxy substituted pyridin-3-yl.

In some embodiments, when ring Q is

When L is selected from O.

In some embodiments, R ¹ is H, optionally substituted C ₁ -C ₃ alkyl substituted C ₃ -C ₆ cycloalkyl or optionally substituted with F C ₁ -C ₆ alkyl.

In some embodiments, R ¹ is H, cyclopropyl optionally substituted with methyl, isopropyl, or ethyl optionally substituted with F.

In some embodiments, R ¹ is H, cyclopropyl,

Isopropyl, CH ₂ CF ₃ or CH ₂ CH ₃ .

In some embodiments, R ¹ is C ₃ -C ₆ _{cycloalkyl or C 1} -C ₆ alkyl optionally substituted with F.

In some embodiments, R ¹ is cyclopropyl or ethyl optionally substituted with F.

In some embodiments, R ¹ is ethyl.

In some embodiments, the compound represented by general formula (A) or a pharmaceutically acceptable salt thereof is selected from a compound of formula (B) or a pharmaceutically acceptable salt:

Wherein, rings W and X are as defined above.

In some embodiments, the compound or pharmaceutically acceptable salt represented by the general formula (A) is selected from the following compounds or pharmaceutically acceptable salts:

The present invention also provides a pharmaceutical composition, which comprises a compound represented by formula (A) or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients.

Further, the present invention relates to the use of the compound represented by general formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicine for preventing or treating MTAP-deficient tumors.

Further, the present invention relates to the use of the compound represented by general formula (A) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the prevention or treatment of MTAP-deficient tumors.

Further, the present invention relates to a compound of general formula (A) or a pharmaceutically acceptable salt thereof for preventing or treating MTAP-deficient tumors, or a pharmaceutical composition thereof.

The present invention also relates to a method for treating MTAP-deficient tumors, which comprises administering to a patient a therapeutically effective dose of a pharmaceutical preparation containing the compound of the general formula (A) of the present invention or a pharmaceutically acceptable salt thereof.

In the preferred embodiment of the present invention, the MTAP-deficient tumors include, but are not limited to, glioma, mesothelioma, melanoma, gastric cancer, esophageal cancer, bladder cancer, pancreatic cancer, non-small cell lung cancer, astrocytoma, Osteosarcoma, head and neck cancer, mucinous chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin’s lymphoma, etc.

Definition and description of terms

Unless otherwise stated, the definitions of groups and terms described in the specification and claims of this application include definitions as examples, exemplary definitions, preferred definitions, definitions recorded in tables, and definitions of specific compounds in the examples. And so on, can be combined and combined with each other arbitrarily. Such combination and the group definition and compound structure after the combination should fall within the scope of the specification of this application.

The term "pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of non-toxic acids or bases, including salts of inorganic acids and bases, and organic acids and bases.

The term "stereoisomer" refers to the isomers produced by the different arrangements of atoms in the molecule in space, including cis and trans isomers, enantiomers, diastereomers and conformational isomers.

The compound of the present invention may have an asymmetric carbon atom (optical center) or a double bond. Racemates, diastereomers, geometric isomers and individual isomers are all included in the scope of the present invention.

The schematic diagram of the racemate or enantiomerically pure compound herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise specified, wedge-shaped keys and dashed keys are used to indicate the absolute configuration of a solid center. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, they include E and Z geometric isomers. Likewise, all tautomeric forms are included within the scope of the present invention.

The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Conformers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to Within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.

The term "tautomer" refers to an isomer of a functional group resulting from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist in two or more mutually convertible species. Proton shift tautomers result from the migration of covalently bonded hydrogen atoms between two atoms. Tautomers generally exist in an equilibrium form, and an attempt to separate a single tautomer usually produces a mixture whose physical and chemical properties are consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties of the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type is dominant; in phenol, the enol type is dominant. The present invention encompasses all tautomeric forms of the compound.

The term "pharmaceutical composition" means a mixture of one or more of the compounds described in the text or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, such as physiologically/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, as long as the valence of the specific atom is normal and the substituted compound is stable. When the substituent is oxo (ie =O), it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group.

The term "optional" or "optionally" means that the event or situation described later can occur or not occur, and the description includes occurrence of said event or situation and non-occurrence of said event or situation. For example, the ethyl group is "optionally" substituted by halogen, meaning that the ethyl group can be unsubstituted (CH ₂ CH ₃ ), monosubstituted (such as CH ₂ CH ₂ F), or polysubstituted (such as CHFCH ₂ F, CH ₂ CHF ₂ etc.) or completely substituted (CF ₂ CF ₃ ). Those skilled in the art can understand that for any group containing one or more substituents, any substitution or substitution pattern that is impossible to exist in space and/or cannot be synthesized will not be introduced.

The term "C ₁ -C ₁₀ alkyl" should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Group, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; "C ₁ -C ₆ alkyl" It should be understood to mean a linear or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6 carbon atoms; "C ₁ -C ₃ alkyl" should be understood to mean having 1, 2, 3 A straight or branched chain saturated monovalent hydrocarbon group of carbon atoms.

The term "C ₁ -C ₁₀ alkoxy" can be understood as "C ₁ -C ₁₀ alkyloxy" or "C ₁ -C ₁₀ alkyl-O-", referring to the loss of linear or branched alcohols A monovalent group generated by a hydrogen atom on a hydroxyl group; preferably, "C ₁ -C ₁₀ alkoxy" may include "C ₁ -C ₆ alkoxy" and "C ₁ -C ₃ alkoxy".

The term "halogenated C ₁ -C ₃ alkyl" includes monohalogenated C ₁ -C ₃ alkyl or polyhalogenated C ₁ -C ₃ alkyl, including but not limited to trifluoromethyl, 2,2, 2-Trichloroethyl, and 3-fluoropropyl, etc.

The term "C ₃ -C ₁₀ cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which has 3 to 10 carbon atoms. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as decalin ring. The term "C ₃ -C ₆ cycloalkyl" should be understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring, which has 3 to 6 carbon atoms.

The term "4-10 membered heterocyclic group" means a saturated or partially saturated monovalent monocyclic, fused ring, spiro ring or bridged ring, which contains 1-4, preferably 1-2 selected from N, O, Heteroatoms of B and S. Including but not limited to: 4-membered ring, such as azetidinyl, oxetanyl; 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazole Alkyl, pyrrolinyl, 1,3,2-dioxaborolanyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholine Group, piperazinyl or trithiaalkyl, or partially saturated 6-membered ring such as dihydropyridyl, tetrahydropyridyl; or 5,5-membered ring, such as hexahydrocyclopenta[c]pyrrole-2( 1H)-based ring; or 5, 6-membered bicyclic ring, such as hexahydropyrrolo[1,2-a]pyrazine-2(1H)-based ring, 5,6,7,8-tetrahydro-[1, 2,4]triazolo[4,3-a]pyrazinyl ring,. Preferably, "4-10 membered heterocyclic group" includes "5-6 membered heterocyclic group"; optionally, said "4-10 membered heterocyclic group" can also be the aforementioned 4-membered heterocyclic group, 5-membered heterocyclic group A heterocyclic group or a benzo-fused ring group of a 6-membered heterocyclic group; preferably, "4-10 membered heterocyclic group" includes 4-10 membered heterocycloalkyl; preferably, "5-6 membered heterocyclic group" "Includes 5-6 membered heterocycloalkyl.

The term "C ₆ -C ₁₀ aryl" should be understood to preferably mean a monovalent or partially aromatic monocyclic or bicyclic hydrocarbon ring having 6 to 10 carbon atoms. In particular, a ring having 6 carbon atoms ("C ₆ aryl"), such as phenyl; or a ring having 9 carbon atoms ("C ₉ aryl"), such as indanyl or indenyl, or having 10 A ring of three carbon atoms ("C ₁₀ aryl"), such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl.

The term "5-10 membered heteroaryl" should be understood to include monovalent monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9 or 10 ring atoms, especially 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms each independently selected from N, O and S. And, in addition, it may be benzo-fused in each case. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiol Diazolyl, etc. and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole Group, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives, such as quinolinyl, quinoline Azolinyl, isoquinolinyl, etc.; or azepine, indazinyl, purinyl, etc. and their benzo derivatives; or cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, Naphthyridinyl, pterridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, etc. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and it contains 1-3, preferably 1-2, heteroatoms each independently selected from N, O, and S. The term "9-10 membered heteroaryl" refers to an aromatic ring system having 9 or 10 ring atoms, and it contains 1-5, preferably 1-3, heteroatoms each independently selected from N, O, and S.

The term "4-position of the phenyl group" refers to the phenyl group and the structural unit

Alignment of the connection site.

The term "excipients" refers to pharmaceutically acceptable inert ingredients. Examples of types of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of pharmaceutical preparations, that is, make the preparations more suitable for direct compression by increasing fluidity and/or adhesion. Examples of typical "pharmaceutically acceptable carriers" suitable for the above formulations are: sugars, starches, cellulose and its derivatives and other auxiliary materials commonly used in pharmaceutical formulations.

The term "treatment" means administering the compound or formulation described in this application to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) Preventing the occurrence of a disease or disease state in mammals, especially when such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state;

(ii) Suppress the disease or disease state, that is, curb its development;

(iii) Alleviation of the disease or disease state, even if the disease or disease state subsides.

The term "therapeutically effective amount" means (i) treatment or prevention of a particular disease, condition or disorder, (ii) reduction, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay The amount of the compound of the present invention for the onset of one or more symptoms of a particular disease, condition, or disorder described herein. The amount of the compound of the present invention that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but it can be routinely determined by those skilled in the art. Determined by its own knowledge and this disclosure.

The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious stimulating effect on the organism and will not damage the biological activity and performance of the active compound. Suitable auxiliary materials are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.

The words "comprise", "comprise" or "comprise" and their English variants such as comprises or comprising should be understood in an open, non-exclusive meaning, that is, "including but not limited to".

The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.

The present application also includes compounds of the present application that are the same as those described herein, but have one or more atoms replaced by an isotope-labeled atom having an atomic weight or mass number different from the atomic weight or mass number commonly found in nature. Examples of isotopes that can be bound to the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl, etc.

Certain isotope-labeled compounds of the application (such as ^{those labeled with 3} H and ¹⁴ C) can be used in compound and/or substrate tissue distribution analysis. Tritiated (i.e. ³ H) and carbon-14 (i.e. ¹⁴ C) isotopes are especially preferred due to their ease of preparation and detectability. Positron emission isotopes such as ¹⁵ O, ¹³ N, ¹¹ C, and ¹⁸ F can be used in positron emission tomography (PET) studies to determine substrate occupancy. The isotope-labeled compounds of the present application can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by replacing non-isotopically-labeled reagents with isotope-labeled reagents.

In addition, substitution with heavier isotopes (such as deuterium (ie ² H)) can provide certain therapeutic advantages resulting from higher metabolic stability (for example, increased in vivo half-life or reduced dosage requirements), and therefore in certain situations The following may be preferred, where the deuterium substitution can be partial or complete, and partial deuterium substitution refers to the substitution of at least one hydrogen by at least one deuterium.

The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , Granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

Typical routes for administering the compound of the present application or a pharmaceutically acceptable salt or pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, and intravenous administration.

The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method, etc.

In some embodiments, the pharmaceutical composition is in an oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These auxiliary materials enable the compound of the present application to be formulated into tablets, pills, lozenges, sugar-coated agents, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

The solid oral composition can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets Or the core of the dragee. Suitable auxiliary materials include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical composition may also be suitable for parenteral administration, such as a sterile solution, suspension or lyophilized product in a suitable unit dosage form.

In all the administration methods of the compound of general formula I described herein, the daily dose is 0.01 to 100 mg/kg body weight, preferably 0.05 to 50 mg/kg body weight, more preferably 0.1 to 30 mg/kg body weight, in single or divided doses form.

The chemical reaction in the specific embodiment of the present invention is completed in a suitable solvent, and the solvent must be suitable for the chemical change of the present invention and the required reagents and materials. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the existing embodiments.

Detailed ways

The following examples illustrate the technical solutions of the invention in detail, but the protection scope of the invention includes but is not limited thereto.

The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). The unit of NMR shift is 10 ^-6 (ppm). The solvents measured by NMR are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS); "IC ₅₀ "refers to the half inhibitory concentration, which refers to the half of the maximum inhibitory effect Concentration; "DCM" refers to dichloromethane; "m-CPBA" refers to m-chloroperoxybenzoic acid; the following eluent can be formed from two or more solvents to form a mixed eluent, and the ratio is the volume ratio of each solvent, For example, "0-10% methanol/dichloromethane" means that the volume of methanol:dichloromethane in the mixed eluent is 0:100-10:100 during the gradient elution process.

Example 1 Preparation of Compound 001

8-(4-(Difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoro Ethyl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one

Synthetic route and specific synthetic steps:

Step 1: Synthesis of ethyl 4-((4-(difluoromethoxy)phenyl)amino)-2-(methylthio)pyrimidine-5-carboxylate (Intermediate 1-3)

The reactants 1-1 (5 g, 21.49 mmol), 1-2 (3.42 g, 21.49 mmol) and triethylamine (4.35 g, 42.98 mmol) were dissolved in 1,4-dioxane (40 mL). The reaction solution was stirred and reacted at 60°C for 16 hours. After the reaction was detected by TLC, the reaction solution was poured into water (50mL), extracted with ethyl acetate three times (50mL*3), the organic layer was dried with anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated under reduced pressure, and the residue was passed through the column Analytical purification (SiO ₂ , petroleum ether/ethyl acetate=100/1-10/1), to obtain the title compound (7.3g).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.71(s,1H), 7.72(d,J＝9.0Hz,2H), 7.18(d,J＝9.0Hz,2H), 6.82(t,J＝ 74Hz, 1H), 4.42 (q, J = 7.1Hz, 2H), 2.53 (s, 3H), 1.43 (t, J = 7.2Hz, 3H).

MS m/z (ESI): 356.1 [M+H] ⁺ .

Step 2: Synthesis of (4-((4-(difluoromethoxy)phenyl)amino)-2-(methylthio)pyrimidin-5-yl)methanol (Intermediate 1-4)

Intermediate 1-3 (3g, 8.44mmol) was dissolved in tetrahydrofuran (30mL), and the temperature was cooled to 0°C in an ice bath. Lithium tetrahydroaluminum (640.76mg, 16.88mmol) was added, and the reaction solution was stirred at 25°C for 3h. After the reaction was completed, water (0.6 mL), aqueous sodium hydroxide solution (20% aq, 1.2 mL) and water (1.8 mL) were added dropwise to the reaction solution in order under ice bath conditions. The organic layer was dried with anhydrous sodium sulfate and pumped. After filtration, the filter cake was washed three times with ethyl acetate (10mL*3), the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/1) to obtain the title compound (1.6g) ).

MS m/z (ESI): 313.9 [M+H] ⁺ .

Step 3: Synthesis of 4-((4-(difluoromethoxy)phenyl)amino)-2-(methylthio)pyrimidine-5-carbaldehyde (Intermediate 1-5)

Intermediate 1-4 (1.3 g, 4.15 mmol) was dissolved in dichloromethane (20 mL), active manganese dioxide (3.61 g, 41.49 mmol) was added, and the reaction solution was stirred at 20° C. for 16 h. After the reaction was detected by TLC, it was filtered under reduced pressure, the filter cake was rinsed with ethyl acetate, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (1.16 g, 3.73 mmol).

¹ H NMR(400MHz,Methanol-d ₄ )δ9.82(s,1H),8.57(s,1H),7.78-7.73(m,2H),7.19-7.17(m,2H),6.82(t,J ＝74Hz,1H),2.54(s,3H).

Step 4: 6-Chloro-8-(4-(difluoromethoxy)phenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one (intermediate 1-6) Synthesis

Intermediate 1-5 (400 mg, 1.28 mmol) was dissolved in tetrahydrofuran (8 mL), and the temperature was cooled to 0° C. in an ice bath. Sodium hydride (256.98 mg, 6.42 mmol, 60% wt/wt) was added. The reaction solution was stirred at 0°C for 10 min, and chloroacetyl chloride (188.66 mg, 1.67 mmol) was added thereto. The reaction solution was raised to 25°C and stirred for 3 hours. After the reaction was completed, under ice bath conditions, water was added dropwise to the reaction solution to quench the reaction, water (30 mL) was added to dilute the reaction solution, and ethyl acetate was extracted three times (20 mL*3). The organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1) to obtain the title compound (200 mg).

MS m/z (ESI): 370.0 [M+H] ⁺ .

Step 5: 8-(4-(Difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(methylthio)pyrido Synthesis of [2,3-d]pyrimidine-7(8H)-one (Intermediate 1-7)

Intermediate 1-6 (200mg, 540.87μmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-benzo[d]imidazole (209.42mg, 811.31μmol, synthesized with reference to the method reported in patents WO 2017176960 and WO 2015200677) was dissolved in 1,4-dioxane (3.2mL) and water (0.8mL), Add cesium carbonate (352.45mg, 1.08mmol), Pd(dtbpf)Cl ₂ (35.25mg, 54.09μmol). The reaction solution was stirred at 105°C for 15 hours under the protection of nitrogen. After the completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , ethyl acetate/methanol=10/1) to obtain the title compound (200 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ9.01(s,1H),8.30(s,1H),8.25(s,1H),7.98(s,1H),7.71(d,J=8.4Hz, 1H), 7.60-7.56 (m, 1.25H), 7.52-7.47 (m, 2H), 7.40-7.35 (m, 2.5H), 7.19 (s, 0.25H), 3.86 (s, 3H), 2.24 (s ,3H).

MS m/z (ESI): 466.2 [M+H] ⁺ .

Step 6: 8-(4-(Difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(methylsulfinyl) Synthesis of pyrido[2,3-d]pyrimidine-7(8H)-one (Intermediate 1-8)

Intermediate 1-7 (180 mg, 386.70 μmol) was dissolved in dichloromethane (3 mL), cooled to 0° C. in an ice bath, and m-chloroperoxybenzoic acid (117.76 mg, 580.05 μmol) was added. The reaction solution was raised to 25°C and stirred for 15 hours. After the completion of the reaction, a saturated aqueous sodium sulfite solution was added to the reaction solution, and ethyl acetate was extracted twice (20 mL*2). The organic layer was concentrated to dryness under reduced pressure to obtain the title compound (150 mg).

MS m/z (ESI): 482.3 [M+H] ⁺ .

Step 7: 8-(4-(Difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2 Synthesis of -trifluoroethyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one (compound 001)

Intermediate 1-8 (96.78 mg, 201.02 μmol) was dissolved in tetrahydrofuran (0.5 mL), and 2,2,2-trifluoroethylamine (39.82 mg, 402.04 μmol) was added thereto. After the reaction solution was heated to 50°C and stirred for 2h, 2,2,2-trifluoroethylamine (59.74mg, 603.06μmol) was added to the reaction solution at 50°C, and the reaction solution was stirred and reacted at 50°C for 15h. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 45%-65%, 10min) to obtain the title compound (13.3mg).

¹ H NMR (400MHz, Methanol-d ₄ ) δ 8.84 (s, 1H), 8.33 (br s, 0.5H), 8.22 (s, 1H), 8.17 (s, 1H), 8.03 (br s, 0.5H) ),7.94(s,1H),7.68(d,J=8.5Hz,1H),7.53(d,J=8.5Hz,1H),7.43-7.36(m,2H),7.38-7.15(m,3H) ,4.23-4.02(m,1H), 3.85(s,3H), 3.75(br s,1H).

MS m/z (ESI): 517.1 [M+H] ⁺ .

Example 2, 8-(4-(Difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoro Ethyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one (Compound 002)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(methylthio)pyrido[2,3 -d] Synthesis of pyrimidine-7(8H)-one (Intermediate 2-2)

Intermediate 1-6 (90mg, 243.39μmol) and Intermediate 2-1 (94.24mg, 365.09μmol, refer to patents WO 2018118734 and WO 2016180536 for synthesis) were dissolved in 1,4-dioxane (1.6mL) and In water (0.4 mL), cesium carbonate (158.60 mg, 486.78 μmol) and Pd(dtbpf)Cl ₂ (15.86 mg, 24.34 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 15 hours. After the completion of the reaction, the reaction solution was filtered under reduced pressure, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=1/5) to obtain the title compound (63 mg).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.99(s,1H), 8.43(s,1H), 8.27(s,1H), 8.14(s,1H), 7.66-7.62(m,1H), 7.59-7.54(m,1H),7.51-7.46(m,2H),7.40-7.34(m,3H),4.19(s,3H),2.24(s,3H);

MS m/z (ESI): 466.2 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-(methylsulfonyl)pyrido[2, Synthesis of 3-d]pyrimidine-7(8H)-one (Intermediate 2-3)

Intermediate 2-2 (50mg, 107.42μmol) was dissolved in dichloromethane (2mL), cooled to 0°C in an ice bath, and m-chloroperoxybenzoic acid (32.71mg, 161.13μmol, 85% purity) was added. After stirring the reaction solution at 0°C for 10 min, it was raised to 25°C, and the stirring was continued for 1 h. After the reaction was completed, dichloromethane (20 mL) was added to the reaction solution, the organic layer was washed with saturated sodium sulfite aqueous solution, and the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (50 mg).

MS m/z (ESI): 498.2 [M+H] ⁺ .

Step 3: 8-(4-(Difluoromethoxy)phenyl)-6-(2-methyl-2H-indazol-5-yl)-2-((2,2,2-trifluoroethane Synthesis of yl)amino)pyrido[2,3-d]pyrimidin-7(8H)-one (compound 2)

Intermediate 2-3 (50 mg, 100.51 μmol) was dissolved in tetrahydrofuran (1 mL), and 2,2,2-trifluoroethylamine (19.91 mg, 201.02 μmol) was added. The reaction solution was stirred at 50°C for 15h. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (column: YMC Triart C18 150*25mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 46%-66%, 10min), to obtain the title compound (1.1mg).

¹ H NMR(400MHz, Methanol-d ₄ )δ8.76(s,1H), 8.26(s,1H), 8.10-8.04(m,2H), 7.63(s,2H), 7.40-7.34(m,4H) ), 6.94(s, 1H), 4.24(s, 3H), 4.15(s, 1H), 3.78(s, 1H);

MS m/z (ESI): 517.2 [M+H] ⁺ .

Example 3, 8-(4-(difluoromethoxy)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido [2,3-d] Pyrimidine-7(8H)-one (Compound 003)

Step 1: 6-Chloro-8-(4-(difluoromethoxy)phenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (middle Body 3-1) Synthesis

Intermediate 1-6 (210mg, 567.92μmol) was dissolved in DCM (10mL), m-CPBA (288.24mg, 1.42mmol) was added at 0℃, the reaction solution was heated to 15℃ and stirred at 15℃ for reaction 16 hours. LC-MS detects that the reaction is complete. The reaction solution was diluted with DCM (10mL), the organic layer was washed three times with saturated sodium bicarbonate aqueous solution (20mL*3), the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the title compound (209.9mg ).

MS m/z (ESI): 402.1 [M+H] ⁺ .

Step 2: 6-Chloro-8-(4-(difluoromethoxy)phenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[2,3-d]pyrimidine Synthesis of -7(8H)-one (Intermediate 3-2)

Intermediate 3-1 (150mg, 373.35μmol) was dissolved in THF (7mL), 2,2,2-trifluoroethylamine (739.67mg, 7.47mmol) was added dropwise at 15°C, and the reaction solution was heated to 63 And react at 63°C for 15 hours. LC-MS detects that the reaction is complete. The reaction solution was concentrated under reduced pressure to obtain the title compound (150 mg), which was directly used in the next reaction.

MS m/z (ESI): 421.2 [M+H] ⁺ .

Step 3: 8-(4-(Difluoromethoxy)phenyl)-6-(4-methoxyphenyl)-2-((2,2,2-trifluoroethyl)amino)pyrido[ Synthesis of 2,3-d]pyrimidine-7(8H)-one (Compound 003)

Intermediate 3-2 (50mg, 118.84μmol) was dissolved in 1,4-dioxane (4mL) and Pd(dtbpf)Cl ₂ (15.49mg, 23.77μmol), 4-methoxyphenylboronic acid Ester (36.12 mg, 237.69 μmol), K ₂ CO ₃ (32.85 mg, 237.69 μmol) and water (1 mL), the reaction solution was stirred and reacted at 95° C. for 15 hours under nitrogen protection. LCMS detects the completion of the reaction. The reaction solution was diluted with ethyl acetate, the organic layer was washed with water, the organic layer was dried with anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (column type: YMC Triart C18 150*25mm*5μm ; Mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 56%-76%, 10 min) to obtain the title compound (15 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.73(s,1H),7.97(s,1H),7.64(d,J=8.9Hz,2H),7.35(s,4H),6.94(d, J = 8.8Hz, 2H), 6.93 (t, J = 73.6Hz, 1H), 4.32-3.99 (m, 1H), 3.84 (s, 3H), 3.77 (br s, 1H)

MS m/z (ESI): 493.2 [M+H] ⁺ .

Example 4, 8-(4-(Difluoromethoxy)phenyl)-6-(2,3-dimethyl-2H-indazol-5-yl)-2-((2,2,2 -Trifluoroethyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one (Compound 004)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-6-(2,3-dimethyl-2H-indazol-5-yl)-2-((2,2,2- Synthesis of trifluoroethyl)amino)pyrido[2,3-d]pyrimidine-7(8H)-one (Compound 004)

Intermediate 3-2 (50mg, 118.84μmol) and 2,3-dimethyl-2H-indazole-5-boronic acid pinacol ester (48.51mg, 178.26μmol) were dissolved in 1,4-dioxane (4mL) and water (1mL) were added cesium carbonate (77.44mg, 237.68μmol) and Pd(dtbpf)Cl ₂ (15.49mg, 23.77μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with dichloromethane (30mL), the organic layer was washed three times (30mL) with water, and purified by preparative liquid chromatography (column: YMC-Actus Triart C18 100*30mm*5μm; mobile phase: (A: 0.05% ammonia) (v/v), B: acetonitrile; B%: 20%-60%, 10 min), and then concentrated to dryness under reduced pressure. The organic layer was filtered with ethyl acetate and the filter cake was reduced to dryness to obtain the title compound ( 25.5mg).

¹ H NMR (400MHz, DMSO-d ₆ ) δppm 8.90-8.74 (m, 1H), 8.30 (br s, 0.5H), 8.13 (s, 1H), 8.02 (s, 1H), 8.01 (br s, 0.5 H),7.50(s,2H),7.45-7.38(m,2H),7.36-7.27(m,2H),7.34(t,J=70.0Hz,1H),4.13(br s,1H),4.06( s, 3H), 3.73 (br s, 1H), 2.61 (s, 3H).

MS m/z (ESI): 531.2 [M+H] ⁺ .

Example 5, 6-(benzo[d]thiazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-((2,2,2-trifluoroethyl) Amino)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 005)

Step 1: 6-(Benzo[d]thiazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-((2,2,2-trifluoroethyl)amino ) Synthesis of pyrido[2,3-d]pyrimidine-7(8H)-one (Compound 005)

Intermediate 3-2 (50mg, 118.84μmol) was dissolved in 1,4-dioxane (4mL) and Pd(dtbpf)Cl ₂ (15.49mg, 23.77μmol), benzo[d]thiazole-6 -Boronic acid (42.55 mg, 237.69 μmol), K ₂ CO ₃ (32.85 mg, 237.69 μmol) and water (1 mL), the reaction solution was stirred at 95° C. for 5 hours under the protection of nitrogen. LCMS detects the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (column type: YMC Triart C18 150*25mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 50%-70%, 10min), to obtain the title compound (12.6mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ9.29(s,1H), 8.78(br s,1H), 8.45(s,1H), 8.17(s,1H), 8.13(d,J=8.6Hz ,1H),7.92-7.87(m,1H),7.43-7.32(m,4H), 6.97(t,J=73.6,1H), 4.17(br s,1H), 3.79(br s,1H)

MS m/z (ESI): 520.1 [M+H] ⁺ .

Example 6, 6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)-8-(6-( (Trifluoromethoxy)pyridin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 006)

Step 1: 6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one( Intermediate 6-2) Synthesis

Intermediate 6-1 (100mg, 367.48μmol, can be prepared according to the patent WO 2018153373 report method) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxin) Boropentan-2-yl)-1H-benzo[d]imidazole (142.28mg,551.22μmol) was dissolved in 1,4-dioxane (4mL) and water (1mL), and cesium carbonate (239.47mg) was added ,734.97μmol) and Pd(dtbpf)Cl ₂ (23.95mg, 36.75μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 95°C for 16 hours. LC-MS detects that the reaction is complete. The reaction solution was diluted with water (20 mL), extracted with dichloromethane three times (20 mL), and the organic layer was concentrated to dryness under reduced pressure to obtain the title compound (80 mg).

MS m/z (ESI): 324.2 [M+H] ⁺ .

Step 2: 6-(1-Methyl-1H-benzo[d]imidazol-6-yl)-2-(methylthio)-8-(6-(trifluoromethoxy)pyridin-3-yl ) Synthesis of pyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate 6-3)

Intermediate 6-2 (70mg, 216.47μmol) and (6-(trifluoromethoxy)pyridin-3-yl)boronic acid (44.79mg, 216.47μmol) were dissolved in anhydrous dichloromethane (2mL), and acetic acid was added Copper (43.25mg, 238.12μmol), pyridine (51.37mg, 649.41μmol). Under oxygen, the reaction solution was stirred and reacted at 40°C for 16 hours. LC-MS detects that the reaction is complete. The reaction solution was diluted with water (30 mL), dichloromethane (30 mL) was added for extraction three times, and the organic layer was concentrated to dryness under reduced pressure. After purification by thin-layer preparative chromatography (dichloromethane/methanol 20:1), the organic layer was concentrated to dryness under reduced pressure to obtain the title compound (30 mg).

MS m/z (ESI): 485.2 [M+H] ⁺ .

Step 3: 6-(1-Methyl-1H-benzo[d]imidazol-6-yl)-2-(methylsulfinyl)-8-(6-(trifluoromethoxy)pyridine-3 -Yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate 6-4)

Intermediate 6-4 (20 mg, 41.28 μmol) was dissolved in dichloromethane (1.5 mL), m-chloroperoxybenzoic acid (8.38 mg, 41.28 μmol) was added, and the reaction was stirred for 16 hours. LCMS detects the completion of the reaction. The organic layer was washed by adding saturated sodium bicarbonate aqueous solution (2 mL) of dichloromethane to the reaction solution, and the organic layer filtrate was concentrated to dryness under reduced pressure to obtain the title compound (5 mg).

MS m/z (ESI): 501.2 [M+H] ⁺ .

Step 4: 6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-((2,2,2-trifluoroethyl)amino)-8-(6-(tri Synthesis of fluoromethoxy)pyridin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 006)

Intermediate 6-4 (5 mg, 9.99 μmol) was dissolved in tetrahydrofuran (1 mL), and 2,2,2-trifluoroethylamine (1.98 mg, 19.98 μmol) was added. The reaction solution was stirred at 40°C for 16h. LCMS detects the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: YMC Triart C18 150*25mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 46) %-66%, 10min), to obtain the title compound (1.4mg).

¹ H NMR (400MHz, Chloroform-d) δ 8.80 (br s, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 8.03 (d, J = 6.5 Hz, 1H), 7.97 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.87-3.59 (m, 2H).

MS m/z (ESI): 536.3 [M+H] ⁺ .

Example 7, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pyrido[2,3- d) Pyrimidine-7(8H)-one (Compound 011)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pyrido[2,3-d ] Synthesis of Pyrimidine-7(8H)-one (Compound 011)

Intermediate 2-3 (21.61 mg, 43.44 μmol) was dissolved in THF (2.5 mL), and EtONa (14.78 mg, 217.19 μmol) was added at 25°C. The reaction solution was stirred and reacted at 25°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (column type: YMC Triart C18 100*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 30%-70%, 10min), to obtain the title compound (7.5mg).

¹ H NMR(400MHz,DMSO-d ₆ )δ9.01(s,1H), 8.42(s,1H), 8.27(s,1H), 8.11(s,1H), 7.68-7.59(m,1H), 7.56-7.52(m,1H),7.47(d,J=8.8Hz,2H),7.38(t,J=74Hz,1H),7.36(d,J=8.8Hz,2H),4.24-4.16(m, 5H), 1.22 (t, J=7.0 Hz, 3H).

MS m/z (ESI): 464.2 [M+H] ⁺ .

Example 8. 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrido[ 2,3-d)pyrimidine-7(8H)-one (compound 024) and 8-(4-(difluoromethoxy)phenyl)-2-hydroxy-6-(1-methyl-1H-benzene) And [d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 025)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(methylsulfonyl)pyridine Synthesis of and [2,3-d]pyrimidine-7(8H)-one (Intermediate 24-1)

Intermediate 1-7 (76 mg, 163.27 μmol) was dissolved in DCM (4 mL), m-CPBA (132.59 mg, 653.10 μmol) was added at 0°C, and the reaction solution was stirred at 15°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with DCM (20mL) and washed with saturated aqueous sodium bicarbonate solution three times (20mL*3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness under reduced pressure and concentrated to dryness to obtain the title compound (100mg) , Directly use the next step reaction.

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrido[2 ,3-d)pyrimidine-7(8H)-one (compound 024) and 8-(4-(difluoromethoxy)phenyl)-2-hydroxy-6-(1-methyl-1H-benzo Synthesis of [d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 025)

Intermediate 24-1 (100 mg, 201.02 μmol) was dissolved in THF (4 mL), EtONa (27.36 mg, 402.03 μmol) was added at 15°C, and the reaction solution was stirred and reacted at 15°C for 15 hours. LCMS detects the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: Phenomenex Gemini C18 250*50mm*10μm; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B%: 40%- 60%, 10 min), to obtain compound 024 (12.9 mg). The residue was further purified by preparative liquid chromatography (column: YMC Triart C18 150*25mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 10%-30%, 10min) compound 025 (6mg) was obtained.

¹ H NMR-024(400MHz,Methanol-d ₄ )δ8.93(s,1H), 8.22(s,1H), 8.18(s,1H), 7.97(d,J=1.0Hz,1H), 7.75 7.71(m,1H),7.62(dd,J=1.6,8.5Hz,1H),7.45-7.40(m,2H),7.38-7.34(m,2H),6.96(t,J=73.6Hz,1H) , 4.17 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H).

MS-024 m/z (ESI): 464.2 [M+H] ⁺ .

¹ H NMR-025(400MHz,Methanol-d ₄ )δ8.54(s,1H),8.17(s,1H),7.98(s,1H),7.90(s,1H),7.71(d,J=8.5 Hz, 1H), 7.55 (dd, J = 1.5, 8.5 Hz, 1H), 7.40-7.33 (m, 2H), 7.33-7.28 (m, 2H), 6.92 (t, J = 74 Hz, 1H), 3.92 ( s,3H).

MS-025 m/z(ESI): 436.1 [M+H] ⁺ .

Example 9, 8-(4-(Difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(1-methyl ring Propoxy)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 026)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(1-methylcyclopropyl) Synthesis of oxy)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 026)

Dissolve 1-methylcyclopropanol (1.50mg, 20.77μmol) in tetrahydrofuran (0.5mL), cool to 0°C and add sodium tert-butoxide (2.00mg, 20.77μmol), and stir for 10min. Intermediate 1-8 (10 mg, 20.77 μmol) was dissolved in tetrahydrofuran (2 mL) and added to the reaction solution. After stirring at 0°C for 30 minutes, the temperature was raised to room temperature and reacted for 16 hours. LCMS detected that the reaction was complete. Purified by preparative liquid chromatography (column: YMC-Actus Triart C18 100*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 48%-68%, 10min ) To obtain the title compound (0.9 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δppm 8.92(s,1H),8.23(s,1H),8.19(s,1H),7.99(s,1H),7.74(d,J=8.8Hz,1H ), 7.68-7.60(m,1H),7.49-7.44(m,2H),7.42-7.35(m,2H),6.94(t,J=73.6Hz,1H),3.94(s,3H),1.32( s, 3H), 0.83 (s, 2H), 0.46 (s, 2H).

MS m/z (ESI): 490.2 [M+H] ⁺ .

Example 10, 8-(4-(Difluoromethoxy)phenyl)-2-(ethylamino)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyridine And [2,3-d]pyrimidine-7(8H)-one (Compound 027)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-(ethylamino)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrido Synthesis of [2,3-d]pyrimidine-7(8H)-one (Compound 027)

Intermediate 1-8 (50 mg, 103.85 μmol) was dissolved in THF (0.5 mL), and anhydrous ethylamine (1.03 g, 22.84 mmol) was added. The reaction solution was heated to 50° C., and the reaction was stirred for 16 h. LCMS detected that the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: YMC-Actus Triart C18 100*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%) : 44%-64%, 10 min). Title compound (2.1 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.75-8.60(m,1H), 8.12(s,1H), 8.04(s,1H),7.92(s,1H), 7.72(d,J=8.5 Hz,1H),7.59(d,J=8.5Hz,1H),7.43-7.28(m,4H),6.88(t,J=76Hz,1H),3.93(s,3H),3.50-3.41(m, 1H), 3.20-3.00 (m, 1H), 1.17-1.05 (m, 1H), 1.04-0.90 (m, 2H).

MS m/z (ESI): 463.3 [M+H] ⁺ .

Example 11, 8-(4-(Difluoromethoxy)phenyl)-2-(isopropylamino)-6-(1-methyl-1H-benzo[d]imidazol-6-yl) Pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 028)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-(isopropylamino)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyridine Synthesis of and [2,3-d]pyrimidine-7(8H)-one (Compound 028)

Intermediate 1-8 (50 mg, 103.85 μmol) was dissolved in THF (0.5 mL), and isopropylamine (1.03 g, 17.46 mmol,) was added. The reaction solution was heated to 50° C., and the reaction was stirred for 16 h. LCMS detected that the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: YMC-Actus Triart C18 100*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%) : 48%-68%, 10min) to obtain the title compound (13.8mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.75-8.60(m,1H), 8.14(s,1H), 8.04(s,1H),7.91(s,1H), 7.69(d,J=8.5 Hz, 1H), 7.58 (dd, J = 1.5, 8.5 Hz, 1H), 7.44-7.27 (m, 4H), 6.93 (t, J = 76 Hz, 1H), 4.25-4.10 (m, 0.5H), 3.91 (s, 3H), 3.70-3.50 (m, 0.5H), 1.25-0.99 (m, 6H).

MS m/z (ESI): 477.3 [M+H] ⁺ .

Example 12, 2-(cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl) Pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 029)

Step 1: 2-(Cyclopropylamino)-8-(4-(difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyridine Synthesis of and [2,3-d]pyrimidine-7(8H)-one (Compound 029)

Intermediate 1-8 (50 mg, 103.85 μmol) was dissolved in THF (0.5 mL), and cyclopropylamine (1.24 g, 21.65 mmol) was added. The reaction solution was heated to 50° C., and the reaction was stirred for 16 h. LCMS detected that the reaction was complete. The reaction solution was evaporated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: YMC-Actus Triart C18 100*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%) : 44%-64%, 10min) to obtain the title compound (5.8mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.80-8.60(m,1H), 8.14(s,1H), 8.07(s,1H),7.92(s,1H), 7.72(d,J=8.5 Hz,1H),7.59(dd,J=1.5,8.5Hz,1H),7.42-7.29(m,4H),6.90(t,J=76Hz,1H),3.93(s,3H),2.84-2.65( m,0.5H), 2.63-2.18(m,0.5H), 0.65-0.25(m,4H).

MS m/z (ESI): 475.3 [M+H] ⁺ .

Example 13, 8-(4-(Difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2 -Trifluoroethoxy)pyrido[2,3-d]pyrimidine-7(8H)-one (compound 030)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-2-(2,2,2- Synthesis of Trifluoroethoxy)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 030)

Dissolve trifluoroethanol (6.23mg, 62.31μmol) in tetrahydrofuran (0.5mL), add sodium tert-butoxide (5.99mg, 62.31μmol) at 0°C and stir for 10min. Intermediate 1-8 (30mg, 62.31μmol) was dissolved in tetrahydrofuran (2mL), then added to the reaction solution, stirred at 0°C for 30 minutes and then heated to room temperature to react for 16h. LCMS detected that the reaction was complete. Purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 50%-70%, 10min ) To obtain the title compound (4.3 mg).

¹ H NMR(400MHz, Methanol-d ₄ )δ9.02(s,1H), 8.34-8.17(m,2H), 8.07-7.96(m,1H),7.82-7.72(m,1H), 7.66(d , J = 8.3 Hz, 1H), 7.51-7.35 (m, 4H), 6.98 (t, J = 73.2 Hz, 1H), 4.70 (q, J = 8.4 Hz, 2H), 3.96 (s, 3H).

MS m/z (ESI): 518.1 [M+H] ⁺ .

Example 14, 2-Ethoxy-6-(4-methoxyphenyl)-8-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[2,3-d]pyrimidine- 7(8H)-ketone (Compound 031)

Step 1: Synthesis of 6-(4-methoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate 31-1)

Intermediate 6-1 (140mg, 514.48μmol) and (4-methoxyphenyl)boronic acid (117.27mg, 771.71μmol) were dissolved in 1,4-dioxane (2mL) and water (0.5mL), Cesium carbonate (335.25mg, 1.03mmol) and Pd(dtbpf)Cl ₂ (33.53mg, 51.45μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with water (30 mL), extracted with dichloromethane three times (30 mL), and the organic layer was concentrated to dryness under reduced pressure. After purification by thin-layer preparative chromatography (dichloromethane/methanol 10:1), the organic layer was concentrated to dryness under reduced pressure to obtain the title compound (42 mg).

MS m/z (ESI): 300.1 [M+H] ⁺ .

Step 2: 6-(4-Methoxyphenyl)-2-(methylthio)-8-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[2,3-d]pyrimidine Synthesis of -7(8H)-one (Intermediate 31-2)

Intermediate 31-1 (27mg, 90.20μmol) and (6-(trifluoromethoxy)pyridin-3-yl)boronic acid (18.66mg, 90.20μmol) were dissolved in anhydrous dichloromethane (9mL), and acetic acid was added Copper (18.02mg, 99.22μmol), pyridine (21.40mg, 270.59μmol). Under oxygen, the reaction solution was stirred and reacted at 40°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with water (50 mL), dichloromethane (50 mL) was added for extraction three times, and the organic layer was concentrated to dryness under reduced pressure. After purification by thin-layer preparative chromatography (dichloromethane/methanol 20:1), the organic layer was concentrated to dryness under reduced pressure to obtain the title compound (48 mg).

MS m/z (ESI): 461.0 [M+H] ⁺ .

Step 3: 6-(4-Methoxyphenyl)-2-(methylsulfonyl)-8-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[2,3-d] Synthesis of Pyrimidine-7(8H)-one (Intermediate 31-3)

Intermediate 31-2 (40 mg, 86.88 μmol) was dissolved in dichloromethane (4 mL), and m-chloroperoxybenzoic acid (52.91 mg, 260.63 μmol) was added to the mixture and the reaction was stirred at room temperature for 16 hours. LCMS detects the completion of the reaction. Dichloromethane (20 mL) was added to the reaction solution for dilution, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL). The organic layer filtrate was concentrated to dryness under reduced pressure to obtain the title compound (69 mg).

MS m/z (ESI): 493.0 [M+H] ⁺ .

Step 4: 2-Ethoxy-6-(4-methoxyphenyl)-8-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[2,3-d]pyrimidine-7 Synthesis of (8H)-ketone (Compound 031)

Intermediate 31-3 (59 mg, 119.81 μmol) was dissolved in anhydrous tetrahydrofuran (1.5 mL), sodium ethoxide (24.46 mg, 359.44 μmol) was added, and the mixture was stirred at room temperature for 3 hours. LCMS detected that the reaction was complete. Purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 56%-76%, 10min ) To obtain the title compound (1.2 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.93(s,1H), 8.39(d,J=2.5Hz,1H), 8.12(s,1H), 8.04(dd,J=2.6,8.7Hz, 1H), 7.79-7.61 (m, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 9.0 Hz, 2H), 4.21 (q, J = 7.0 Hz, 2H), 3.86 ( s, 3H), 1.28 (t, J=7.0 Hz, 3H).

MS m/z (ESI): 459.1 [M+H] ⁺ .

Example 15, 8-(4-chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pyrido[2,3-d]pyrimidine-7( 8H)-ketone (Compound 013)

Step 1: Synthesis of 6-bromo-2-(methylsulfinyl)pyrido[2,3-d]pyrimidine-7(8H)-one (Intermediate 13-1)

The reactant 6-1 (0.5 g, 1.84 mmol) was dissolved in dichloromethane (40 mL), and m-chloroperoxybenzoic acid (932.57 mg, 4.59 mmol, 85% purity) was added at 0°C. The reaction solution was stirred and reacted for 12 hours at 20°C. TLC detects the completion of the reaction. The reaction solution was poured onto silica gel (30 g), and purified by column chromatography (SiO ₂ , tetrahydrofuran/petroleum ether=0-100% to ethanol/dichloromethane=1:1) to obtain the title compound (0.36 g).

MS m/z (ESI): 288.0 [M+H] ⁺ .

Step 2: Synthesis of 6-bromo-2-ethoxypyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate 13-2)

Intermediate 13-1 (0.36 g, 1.25 mmol) was dissolved in ethanol (5 mL), and an ethanol solution of sodium ethoxide (3M, 624.74 μL) was added at 0°C. The reaction solution was stirred for 3 hours at 20°C. LCMS detects the completion of the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude title compound (0.45 g), which was directly used in the next reaction.

MS m/z (ESI): 269.9 [M+H] ⁺ .

Step 3: 2-Ethoxy-6-(2-methyl-2H-indazol-5-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate 13-3) Synthesis

Intermediate 13-2 (450mg, 1.67mmol) was dissolved in 1,4-dioxane (18mL) and water (6mL), and 2-methyl-5-(4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (516.09mg, 2.00mmol), Pd(dppf)Cl ₂ (34.02mg, 41.65μmol) and sodium carbonate ( 441.48mg, 4.17mmol). The reaction solution was stirred at 100°C for 12 hours under the protection of nitrogen. LCMS detects the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure, and purified by column chromatography (SiO ₂ , petroleum ether/tetrahydrofuran = 5/1 to 0:1) to obtain the title compound (300 mg).

MS m/z (ESI): 322.2 [M+H] ⁺ .

Step 4: 8-(4-Chlorophenyl)-2-ethoxy-6-(2-methyl-2H-indazol-5-yl)pyrido[2,3-d]pyrimidine-7(8H )-Synthesis of Ketone (Compound 013)

Intermediate 13-3 (40mg, 124.48μmol) and (4-chlorophenyl)boronic acid (58.40mg, 373.44μmol) were dissolved in dichloromethane (10mL), and copper acetate (45.22mg, 248.96μmol) and pyridine were added. (29.54mg, 373.44μmol, 30.14μL), the reaction was stirred at 40°C under an oxygen atmosphere (15Psi) for 12 hours. LCMS showed that the starting material had reacted completely. The reaction solution is directly concentrated and purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 50%) -70%, 10min), the title compound (8.1mg) was obtained after lyophilization.

¹ H NMR (400MHz, METHANOL-d4) δ 8.88 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.67-7.59 (m, 2H), 7.57 -7.45(m,2H),7.33(s,1H),7.31(s,1H),4.22(s,3H),4.16(d,J=7.0Hz,2H),1.25(t,J=6.8Hz, 3H).

MS m/z (ESI): 432.1 [M+H] ⁺ .

Example 16, 6-(1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d ]Pyrimidine-7(8H)-one (Compound 032)

Step 1: 6-Chloro-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate 32- 1) Synthesis

Intermediate 3-1 (1.5 g, 3.73 mmol) was dissolved in ethanol (15 mL), sodium ethoxide (762.19 mg, 11.20 mmol) was added, and the mixture was stirred at room temperature and 25° C. for 1 h. LCMS detects the completion of the reaction. The reaction solution was diluted with ethyl acetate (50 mL), the organic layer was washed three times (50 mL) with water, and the organic layer was concentrated to dryness under reduced pressure. Purification by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3/1 to 1/1), to obtain the title compound (575 mg).

MS m/z (ESI): 368.1 [M+H] ⁺ .

Step 2: 6-(1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d] Synthesis of Pyrimidine-7(8H)-one (Compound 032)

Mix 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (39.83mg, 163.16μmol) and react Compound 2 (30mg, 81.58μmol) was dissolved in dioxane (2mL) and water (0.5mL), cesium carbonate (53.16mg, 163.16μmol) and Pd(dtbpf)Cl ₂ (5.32mg, 8.16μmol) were added to it ), the reaction solution was stirred at 90°C for 16 hours under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 45 %-65%, 10min) to obtain the title compound (13.4mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.94(s,1H), 8.24(s,1H), 8.20(s,1H), 8.03(s,1H), 7.75-7.62(m,2H), 7.50-7.41(m,2H),7.40-7.35(m,2H), 6.975(t,J=74Hz,1H), 4.19(d,J=7.0Hz,2H), 1.26(t,J=7.0Hz, 3H).

MS m/z (ESI): 450.2 [M+H] ⁺ .

Example 17, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-7(8H )-Ketone (Compound 033)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-6-(4-methoxyphenyl)-2-(methylthio)pyrido[2,3-d]pyrimidine-7( Synthesis of 8H)-ketone (Intermediate 33-1)

Intermediate 1-6 (113mg, 305.59μmol), (4-methoxyphenyl)boronic acid (69.65mg, 458.39μmol) and Pd(dtbpf)Cl ₂ (19.92mg, 30.56μmol) were dissolved in 1,4- Dioxane (2mL), potassium carbonate (84.47mg, 611.19μmol) dissolved in water (0.5mL) was added dropwise at 25°C under nitrogen protection, and the reaction solution was stirred at 100°C for 16h. LCMS detects the completion of the reaction. The reaction solution was diluted with 10 mL of water and 10 mL of ethyl acetate, and extracted three times with 30 mL of ethyl acetate (10 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified on a silica gel plate (SiO ₂ , petroleum ether/ethyl acetate = 2/1) to obtain the title compound (107.3 mg).

MS m/z (ESI): 441.8 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-6-(4-methoxyphenyl)-2-(methylsulfonyl)pyrido[2,3-d]pyrimidine-7( Synthesis of 8H)-ketone (Intermediate 33-2)

Intermediate 33-1 (107mg, 242.38μmol) was dissolved in dichloromethane (2mL), cooled to 0℃ in an ice bath, and m-chloroperoxybenzoic acid (196.84mg, 969.53μmol, 85% purity) was added under the protection of nitrogen. . The reaction solution was raised to 25°C, and the reaction was stirred for 15 hours. LCMS detects the completion of the reaction. Dichloromethane (50mL) was added to the reaction solution, and the organic layer was washed with saturated aqueous sodium sulfite solution (50mL*3). The organic layer was dried over anhydrous sodium sulfate and filtered with suction. The filtrate was concentrated to dryness under reduced pressure to obtain the crude title compound (145mg). Used directly in the next reaction.

MS m/z (ESI): 474.2 [M+H] ⁺ .

Step 3: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-7(8H) -Synthesis of Ketone (Compound 033)

Intermediate 33-2 (145 mg, 306.26 μmol) was dissolved in tetrahydrofuran (2 mL), and sodium ethoxide (41.68 mg, 612.53 μmol) was added under nitrogen protection. The reaction solution was stirred at 25°C for 15h. LCMS detects the completion of the reaction. Add 50 mL of dichloromethane and 50 mL of water to the reaction solution, and then extract 150 mL (50 mL*3) with dichloromethane three times. The organic layer is dried over anhydrous sodium sulfate and filtered with suction. The filtrate is concentrated to dryness under reduced pressure and subjected to liquid chromatography. Purification (alkaline chromatography column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B%: 53%-73%, 10min), get the title Compound (15.2 mg).

¹ H NMR (400MHz, METHANOL-d ₄ )δ = 8.85 (s, 1H), 8.01 (s, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.37-7.30 (m, 4H), 6.96 ( d, J = 8.8 Hz, 2H), 6.83 (t, J = 73.6 Hz, 1H), 4.14 (q, J = 7.0 Hz, 2H), 3.83 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H)

MS m/z (ESI): 439.9 [M+H] ⁺ .

Example 18. 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(quinolin-6-yl)pyrido[2,3-d]pyrimidine-7(8H )-Ketone (Compound 034)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(quinolin-6-yl)pyrido[2,3-d]pyrimidine-7(8H) -Synthesis of Ketone (Compound 034)

Intermediate 32-1 (10mg, 27.19μmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (13.88mg, 54.39 μmol) dissolved in 1,4-dioxane (0.2mL), Pd(dtbpf)Cl ₂ (1.77mg, 2.72μmol), potassium carbonate (7.52mg, 54.39μmol) and water (0.05mL) were added under nitrogen protection ), the reaction solution was stirred at 100°C for 16h. LCMS detects the completion of the reaction. The reaction solution was concentrated by rotary evaporation under reduced pressure and purified by liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 50%-70%, 10min) to obtain the title compound (1.7mg).

¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.95 (s, 1H), 8.87 (dd, J = 1.7, 4.3 Hz, 1H), 8.41 (d, J = 7.8 Hz, 1H), 8.36-8.29 ( m,2H),8.15-8.04(m,2H),7.57(dd,J=4.4,8.3Hz,1H),7.45-7.31(m,4H),6.91(t,74Hz,1H),4.18(q, J=7.1Hz, 2H), 1.25(t, J=7.1Hz, 3H)

MS m/z (ESI): 461.2 [M+H] ⁺ .

Example 19, 8-(4-(Difluoromethoxy)phenyl)-6-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-2-ethoxy Pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 035)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-6-(1,2-dimethyl-1H-benzo[d]imidazol-6-yl)-2-ethoxypyridine Synthesis of and [2,3-d]pyrimidine-7(8H)-one (Compound 035)

The intermediate 32-1 (30mg, 110.23μmol) and 1,2-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Base)-1H-benzo[d]imidazole (27.72mg, 72.75μmol, can be synthesized according to the method reported in WO 2016057834) was dissolved in 1,4-dioxane (0.8mL) and water (0.2mL), added Cesium carbonate (71.83mg, 220.47μmol) and Pd(dtbpf)Cl ₂ (7.18mg, 11.02μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure, and purified twice by preparative liquid chromatography (first column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B : Acetonitrile; B%: 45%-65%, 10min; second chromatographic column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 46%-66%, 10min) to obtain the title compound (9.2mg).

¹ H NMR (400MHz, METHANOL-d ₄ ) δppm 8.94 (s, 1H), 8.22 (s, 1H), 7.88 (s, 1H), 7.65-7.60 (m, 1H), 7.60-7.56 (m, 1H) ,7.47-7.42(m,2H),7.41-7.36(m,2H),6.98(t,J=73.8Hz,1H), 4.19(q,J=7.2Hz,2H), 3.83(s,3H), 2.64(s,3H),1.26(t,J=7.0Hz,3H).

MS m/z (ESI): 478.2 [M+H] ⁺ .

Example 20, 2-Ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-8-(1-methylpiperidin-4-yl)pyrido[2 ,3-d)pyrimidin-7(8H)-one (Compound 036)

Step 1: Synthesis of ethyl 4-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)-2-(methylthio)pyrimidine-5-carboxylate (Intermediate 36-1)

4-aminopiperidine-1-carboxylic acid tert-butyl ester (10.0g, 50.10mmol), starting material 1-1 (10.5g, 45.45mmol) and K ₂ CO ₃ (11.89g, 86.20mmol) were dissolved in 1, 4-Dioxane (100mL). The reaction solution was stirred and reacted at 60°C for 16 hours. TLC detects the completion of the reaction. The reaction solution was poured into water (50mL), extracted with ethyl acetate three times (50mL*3), the organic layer was dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and purified by column chromatography (SiO ₂ , petroleum ether /Ethyl acetate=100/1-10/1) to obtain the title compound (13.02g).

Step 2: Synthesis of tert-butyl 4-((5-(hydroxymethyl)-2-(methylthio)pyrimidin-4-yl)amino)piperidine-1-carboxylate (Intermediate 36-2)

Intermediate 36-1 (13.02 g, 32.87 mmol) was dissolved in tetrahydrofuran (30 mL). The reaction solution was cooled to 0°C with an ice-water bath, lithium tetrahydroaluminum (640.76mg, 16.88mmol) was added, and the reaction was stirred at 0°C for 8h. LC-MS detects that the reaction is complete. In an ice bath, add Na ₂ SO ₄ .10H ₂ O (50g) to the reaction solution for quenching, add anhydrous sodium sulfate to dry, filter with suction, wash the filter cake three times with ethyl acetate (100mL*3), and reduce the filtrate. It was concentrated to dryness and purified by column chromatography (SiO2, petroleum ether/ethyl acetate=1/1) to obtain the title compound (9g).

MS m/z (ESI): 355.1 [M+H] ⁺ .

Step 3: Synthesis of tert-butyl 4-((5-formyl-2-(methylthio)pyrimidin-4-yl)amino)piperidine-1-carboxylate (Intermediate 36-3)

Intermediate 36-2 (9g, 25.56mmol) was dissolved in THF (20mL), and activated manganese dioxide (22g, 25.56mmol, 10.00eq) was added. The reaction solution was stirred and reacted at 60°C for 16 hours. TLC detects the completion of the reaction. Filter under reduced pressure, rinse the filter cake with ethyl acetate, and concentrate the filtrate to dryness under reduced pressure to obtain the title compound (7g).

MS m/z (ESI): 353.1 [M+H] ⁺ .

Step 4: 4-((5-(3-Ethoxy-3-carbonylprop-1-en-1-yl)-2-(methylthio)pyrimidin-4-yl)amino)piperidine-1- Synthesis of tert-butyl formate (Intermediate 36-4)

Under an ice water bath, ethyl 2-(diethoxyphosphorus) ethyl acetate (4.5 g, 20.33 mmol) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (803 mg, 20.08 mmol, 60% wt/wt) was added. The reaction solution was stirred and reacted at 0°C for 10 min, and Intermediate 36-3 (6 g, 16.94 mmol) was added thereto. The reaction solution was raised to 70°C and stirred for 18 hours. LC-MS detects that the reaction is complete. In an ice-water bath, water (1 ml) was slowly added dropwise to the reaction solution to quench the reaction, followed by dilution with water (30 mL), and extraction with ethyl acetate three times (50 mL*3). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain the crude title compound (7 g). The crude product was directly used in the next reaction.

MS m/z (ESI): 423.1 [M+H] ⁺ .

Step 5: 4-(2-(Methylthio)-7-carbonylpyrido[2,3-d]pyrimidine-8(7H)-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 36-5 )Synthesis

Intermediate 36-4 (7g, crude) was dissolved in ethanol (20mL), cooled to 0°C in an ice bath, and sodium ethoxide (3.38g, 49.76mmol) was added. The reaction solution was reacted at 25°C with stirring for 7 hours. TLC detects the completion of the reaction. The reaction solution was diluted with water (100ml), and extracted three times with ethyl acetate (200mL*3). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The concentrated residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain the title compound (2.9 g).

Step 6: 4-(6-Bromo-2-(methylthio)-7-carbonylpyrido[2,3-d]pyrimidine-8(7H)-yl)piperidine-1-carboxylic acid tert-butyl ester (middle Body 36-6) synthesis

Intermediate 36-5 (1 g, 26.52 mmol) was dissolved in acetonitrile (10 mL), NBS (533 mg, 39.78 mmol) was added, and the reaction was stirred at 20° C. for 16 h. LCMS detects the completion of the reaction. The reaction solution was diluted with water (100ml) and extracted three times with ethyl acetate (50mL*3). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The concentrated residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to obtain the title compound (500 mg).

MS m/z (ESI): 455.1 [M+H] ⁺ .

Step 7: 4-(6-(1-Methyl-1H-benzo[d]imidazol-6-yl)-2-(methylthio)-7-carbonylpyrido[2,3-d]pyrimidine- Synthesis of tert-butyl 8(7H)-yl)piperidine-1-carboxylate (Intermediate 36-7)

Under a nitrogen atmosphere, the intermediate 36-6 (300 mg, 659.34 μmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-benzo[d]imidazole (256mg, 989mmol) was dissolved in 1,4-dioxane (3.2mL) and water (0.8mL), cesium carbonate (428mg, 1318.68μmol) was added, Pd(dtbpf)Cl ₂ (48.19 mg, 65.93 μmol). The reaction solution was stirred and reacted at 105° C. for 15 h. LC-MS detects that the reaction is complete. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The concentrated residue was purified by column chromatography (SiO ₂ , ethyl acetate/methanol=10/1) to obtain the title compound (320 mg).

MS m/z (ESI): 507.2 [M+H] ⁺ .

Step 8: 4-(6-(1-Methyl-1H-benzo[d]imidazol-6-yl)-2-(methylsulfonyl)-7-carbonylpyrido[2,3-d]pyrimidine- Synthesis of tert-butyl 8(7H)-yl)piperidine-1-carboxylate (Intermediate 36-8)

Intermediate 36-7 (320 mg, 631.16 μmol) was dissolved in dichloromethane (3 mL), cooled to 0° C. in an ice bath, and m-chloroperoxybenzoic acid (271.40 mg, 1557.90 μmol, 85% purity) was added. The reaction solution was raised to 25°C and stirred for 2 hours. LC-MS detects that the reaction is complete. A saturated aqueous sodium sulfite solution (10 ml) was added to the reaction solution, and the mixture was stirred for 30 minutes. The mixture was extracted twice with ethyl acetate (100 mL*2). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain the crude title compound (350 mg). The crude product was directly used in the next reaction.

Step 9: 4-(2-Ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-7-carbonylpyrido[2,3-d]pyrimidine-8( Synthesis of 7H)-yl)piperidine-1-carboxylic acid tert-butyl ester (Intermediate 36-9)

Intermediate 36-8 (350 mg, crude) was dissolved in ethanol (5 mL), cooled to 0° C. in an ice bath, and sodium ethoxide (132.46 mg, 1948.05 μmol) was added. Subsequently, the reaction solution was raised to 25° C. and stirred for 3 hours. TLC detects the completion of the reaction. The reaction solution was diluted with water (30 ml), and extracted three times with ethyl acetate (20 mL*3). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The concentrated residue was purified by column chromatography (SiO ₂ , DCM/MeOH=10/1) to obtain the title compound (180 mg).

MS m/z (ESI): 505.2 [M+H] ⁺ .

Step 10: 2-Ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-8-(piperidin-4-yl)pyrido[2,3-d] Synthesis of Pyrimidine-7(8H)-one (Intermediate 36-10)

Intermediate 36-9 (100 mg, 198.01 μmol) was dissolved in dioxane (3 ml, 4N, 12 mmol) of hydrogen chloride. The reaction solution was stirred and reacted at 20°C for 0.5h, and then diluted with water (20ml). Under ice water bath, saturated sodium hydroxide solution was added to the above mixture to adjust pH=11, and it was extracted three times with ethyl acetate (20 mL*3). The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to obtain the title compound (80 mg, crude). The crude product was directly used in the next reaction.

MS m/z (ESI): 405.2 [M+H] ⁺ .

Step 11: 2-Ethoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)-8-(1-methylpiperidin-4-yl)pyrido[2, Synthesis of 3-d]pyrimidine-7(8H)-one (Compound 036)

Intermediate 36-10 (80 mg, crude) was dissolved in formic acid (1 mL), and aqueous formaldehyde solution (49.38 mg, 591.32 μmol) was added. After the reaction solution was raised to 100°C and stirred for 2 hours, the reaction was completed by LC-MS. The reaction solution was filtered, and the filtrate was purified by preparative liquid chromatography [YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH ₄ HCO ₃ ) and a mixture of decreasing polarity of acetonitrile as the elution Solution; acetonitrile gradient ratio 30%-42%, elution time 12 minutes] to obtain the title compound (12.4 mg).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.95(s,1H), 8.24(s,1H), 8.12(s,1H), 7.90(d,J=1.9Hz,1H), 7.69(d, J = 8.4Hz, 1H), 7.50 (dd, J = 8.5, 1.7Hz, 1H), 5.35 (s, 1H), 4.52-4.45 (m, 2H), 3.88 (s, 3H), 2.95 (t, J = 11.1Hz, 4H), 2.23 (s, 3H), 2.02 (t, J = 11.3 Hz, 2H), 1.58 (d, J = 10.5 Hz, 2H), 1.42 (t, J = 7.0 Hz, 3H).

MS m/z (ESI): 419.1 [M+H] ⁺ .

Example 21, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-((1-methyl-1H-benzo[d]imidazol-5-yl)amino) -1,8-naphthalene-2(1H)-one (Compound 037)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-((1-methyl-1H-benzo[d]imidazol-5-yl)amino)- Synthesis of 1,8-naphthalene-2(1H)-one (Compound 037)

Intermediate 32-1 (20mg, 135.89μmol) and 1-methyl-1H-benzo[d]imidazole-5-amine (49.97mg, 135.89μmol) were dissolved in toluene (0.7mL), and BrettPhos Pd G3 ( 12.32mg, 13.59μmol), BrettPhos (7.29mg, 13.59μmol) and sodium tert-butoxide (39.18mg, 407.67μmol). The reaction solution was heated to 100°C and stirred for 20 hours. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%) : 46%-66%, 10min) to obtain the title compound (2.2mg).

¹ H NMR(400MHz,METHANOL-d ₄ )δppm 8.64(s,1H), 8.16(s,1H), 7.67(d,J=1.6Hz,1H), 7.61(d,J=8.6Hz,1H), 7.46-7.41 (m, 2H), 7.39 (s, 2H), 7.35 (d, J = 1.9 Hz, 1H), 7.29 (s, 1H), 6.98 (t, J = 73.8 Hz, 1H), 4.11 (q ,J=7.1Hz,2H),3.95(s,3H),1.23(t,J=7.1Hz,3H)

MS m/z (ESI): 479.1 [M+H] ⁺ .

Example 22, 1-(4-(difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1, 8-Naphthalazine-2(1H)-one (Compound 038)

Step 1: Synthesis of 3-bromo-7-chloro-1,8-naphthalene-2(1H)-one (Intermediate 38-2)

The starting material 38-1 (0.2g, 1.11mmol) was dissolved in 10mL of pyridine, and liquid bromine (707.93mg, 4.43mmol) was added dropwise at 0°C. After the addition, the reaction solution was heated to 65°C and stirred for 16 hours. . After the reaction is complete, cool to room temperature, add 30 mL of water, and then extract 3 times with ethyl acetate (10ml*3), collect the extracted organic phase and dry with anhydrous sodium sulfate, filter and spin dry the filtrate to obtain the title compound (0.17 g), the crude product is directly used in the next reaction.

MS m/z (ESI): 258.7 [M+H] ⁺ .

Step 2: Synthesis of 3-bromo-7-ethoxy-1,8-naphthalene-2(1H)-one (Intermediate 38-3)

Intermediate 38-2 (0.15 g, 578.06 μmol) was dissolved in 5 mL of ethanol to obtain a yellow solution, to which sodium ethoxide (786.74 mg, 11.56 mmol) was added all at once. The reaction solution was heated to 80°C and stirred overnight to react for 16 hours. After the reaction was completed, it was spin-dried under reduced pressure, 10ml of water was added and extracted with ethyl acetate 3 times, 3ml each time. The obtained organic phase was spin-dried under reduced pressure to obtain a yellow oil. The oil was purified by reverse-phase preparative column chromatography (YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% formic acid) and a mixture of acetonitrile with decreasing polarity as eluent; acetonitrile gradient The ratio is 33%-53%, and the elution time is 10 minutes) to obtain the title compound (23 mg).

MS m/z (ESI): 269.1 [M+H] ⁺ .

Step 3: 3-Bromo-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-1,8-naphthalene-2(1H)-one (Intermediate 38-4 )Synthesis

Intermediate 38-3 (23 mg, 85.47 μmol) and (4-(difluoromethoxy)phenyl)boronic acid (48.19 mg, 256.42 μmol) were dissolved in 1 ml of dichloromethane. Pyridine (20.28 mg, 256.42 μmol) was added dropwise thereto and then copper acetate (17.08 mg, 94.02 μmol) was added. The reaction solution was heated to 40° C. and stirred for 16 hours. After the reaction was completed, it was cooled to room temperature, and 1 ml of water was added to it, and extracted with dichloromethane three times, 1 ml each time. The obtained organic phase was dried over anhydrous sodium sulfate, filtered to obtain a filtrate, and spin-dried the filtrate to obtain a yellow oil. The oil was purified by preparative chromatography (petroleum ether: ethyl acetate = 2:1 volume ratio), and the main spots were collected to obtain the title compound (0.030 g).

MS m/z (ESI): 410.8 [M+H] ⁺ .

Step 4: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-1H-benzo[d]imidazol-6-yl)-1,8 Synthesis of -Naphthalene-2(1H)-one (Compound 038)

Intermediate 38-4 (30mg, 72.96μmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-benzo[d]imidazole (28.25mg, 109.44μmol) was dissolved in 2ml dioxane and 1ml water. Cesium carbonate (71.31mg, 218.87μmol) was added to it under the protection of nitrogen, and then Pd(dtbpf)Cl ₂ (4.75mg, 7.30μmol) was added. The reaction solution was heated to 100°C and reacted for 16 hours. After the reaction was completed, it was cooled to room temperature, 2 ml of water was added thereto, and the mixture was extracted 3 times with 1 ml of ethyl acetate. The obtained organic phase was concentrated to dryness under reduced pressure to obtain a yellow oil. The oil was purified by preparative column chromatography (YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% ammonia) and a mixture of decreasing polarity of acetonitrile as eluent; acetonitrile gradient ratio 53 %-73%, elution time 10 minutes) to obtain the title compound (13.9 mg).

MS m/z (ESI): 462.9 [M+H] ⁺ .

¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.18 (d, J = 5.99 Hz, 2H), 8.08 (d, J = 8.44 Hz, 1H), 7.98 (s, 1 H), 7.69-7.78 (m ,1H), 7.64(d,J=8.44Hz,1H),7.32-7.46(m,4H),6.96(t,J=76Hz,1H),6.70(d,J=8.44Hz,1H),4.03( q, J = 7.05 Hz, 2H), 3.94 (s, 3H), 1.17 (t, J = 7.03 Hz, 3H).

Example 23, 2-Ethoxy-8-(4-methoxyphenyl)-6-(2-methyl-2H-indazol-5-yl)pyrido[2,3-d]pyrimidine-7 (8H)-ketone (Compound 039)

Step 1: 2-Ethoxy-8-(4-methoxyphenyl)-6-(2-methyl-2H-indazol-5-yl)pyrido[2,3-d]pyrimidine-7( Synthesis of 8H)-ketone (Compound 039)

Intermediate 13-3 (40mg, 124.48μmol) and (4-methoxyphenyl)boronic acid (56.75mg, 373.44μmol) were dissolved in dichloromethane (10mL), and copper acetate (45.22mg, 248.96μmol) and Pyridine (29.54 mg, 373.44 μmol), the reaction was stirred at 40°C for 12 hours under an oxygen atmosphere. LCMS showed that the starting material had reacted completely. The reaction solution is directly concentrated and purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 43%) -63%, 10min), the title compound (1.8mg) was obtained after lyophilization.

¹ H NMR(400MHz,CHLOROFORM-d)δ8.78(s,1H),8.18(s,1H),7.94(s,1H),7.91(s,1H),7.75(d,J=8.8Hz,1H ), 7.60(d,J=8.8Hz,1H),7.25-7.20(m,2H),7.11-7.07(m,2H),4.26(s,3H),4.23-4.20(m,2H),3.91( s, 3H), 1.32 (t, J=7.5 Hz, 3H).

MS m/z (ESI): 428.2 [M+H] ⁺ .

Example 24, 2-ethoxy-6-(2-methyl-2H-indazol-5-yl)-8-(4-(trifluoromethoxy)phenyl)pyrido[2,3- d) Pyrimidine-7(8H)-one (Compound 040)

Step 1: 2-Ethoxy-6-(2-methyl-2H-indazol-5-yl)-8-(4-(trifluoromethoxy)phenyl)pyrido[2,3-d ] Synthesis of Pyrimidine-7(8H)-one (Compound 040)

Intermediate 13-3 (40mg, 124.48μmol) and (4-trifluoromethoxyphenyl)boronic acid (76.90mg, 373.44μmol) were dissolved in dichloromethane (10mL), and copper acetate (45.22mg, 248.96μmol) ) And pyridine (29.54mg, 373.44μmol), the reaction was stirred at 40°C for 12 hours under an oxygen atmosphere. LCMS showed that the starting material had reacted completely. The reaction solution is directly concentrated and purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A water (0.225% FA), B: ACN; B%: 58%-78%) , 10min), the title compound (1.3mg) was obtained after lyophilization.

¹ H NMR (400MHz, CHLOROFORM-d) δ 8.82 (s, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.62-7.56 (m, 1H), 7.46-7.41 (m, 2H), 7.40-7.36 (m, 2H), 4.27 (s, 3H), 4.25-4.18 (m, 2H), 1.33-1.29 (m, 3H).

MS m/z (ESI): 482.1 [M+H] ⁺ .

Example 25. 8-(4-(Difluoromethoxy)phenyl)-6-(4-(dimethylphosphoryl)phenyl)-2-ethoxypyrido[2,3-d] Pyrimidine-7(8H)-one (Compound 041)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-6-(4-(dimethylphosphoryl)phenyl)-2-ethoxypyrido[2,3-d]pyrimidine Synthesis of -7(8H)-one (Compound 041)

Dimethyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)phosphine oxide (27.42mg, 97.90μmol ) And Intermediate 32-1 (30mg, 81.58μmol) were dissolved in dioxane (2mL) and water (0.5mL), cesium carbonate (53.16mg, 163.16μmol) and Pd(dtbpf)Cl ₂ ( 5.32mg, 8.16μmol), the reaction solution was stirred at 90°C for 16h under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 45 %-65%, 10min) to obtain the title compound (9.7mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.95(s,1H),8.26(s,1H),7.98-7.82(m,4H),7.47-7.32(m,4H),6.97(t,J = 73.6Hz, 1H), 4.19 (q, J = 7.0Hz, 2H), 1.86 (s, 3H), 1.82 (s, 3H), 1.26 (t, J = 7.1Hz, 3H).

MS m/z (ESI): 486.1 [M+H] ⁺ .

Example 26, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-(2-hydroxyethyl)-1H-benzo[d]imidazole-6- Yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 042)

Step 1: 2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl ) Synthesis of ethane-1-ol (Intermediate 42-2)

Intermediate 42-1 (75mg, 311.09μmol, can be synthesized according to the method reported in WO 2017043636), KOAc (183.19mg, 1.87mmol), Pd(dppf)Cl ₂ (11.38mg, 15.55μmol), B ₂ Pin ₂ ( 118.50mg, 466.64μmol) was dissolved in dioxane (5mL). The reaction was stirred at 100°C for 12 hours under a nitrogen atmosphere. LC-MS detects that the reaction is complete. The reaction solution was extracted with 30 mL of ethyl acetate (10 mL*3). The organic phase was dried with anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and purified by preparative thin-layer chromatography (SiO ₂ , PE:EA=1:1) to obtain the title compound (25 mg).

MS m/z (ESI): 289.2 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-6-yl ) Synthesis of pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 042)

Intermediate 42-2 (25mg, 86.76μmol) was dissolved in dioxane/H ₂ O (4:1) (2mL), KOAc (183.19mg, 1.87mmol), Pd(dppf)Cl ₂ (11.38mg, 15.55) was added μmol), B ₂ Pin ₂ (118.50 mg). The reaction was stirred at 90°C for 15 hours under a nitrogen atmosphere. LC-MS detects that the reaction is complete. The reaction solution was extracted with 15 mL of ethyl acetate (5 mL*3). After the organic phase was dried with anhydrous sodium sulfate, it was evaporated to dryness under reduced pressure to prepare SFC (Column: DAICEL CHIRALCEL OJ-H (250mm*30mm, 5μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; : 35%-35%, 10min) to obtain the title compound (5.9mg).

MS m/z (ESI): 494.3 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δ=8.93(s,1H), 8.24(s,1H), 8.22(s,1H), 8.02(d,J=1.0Hz,1H), 7.74(d, J = 8.4Hz, 1H), 7.63 (dd, J = 1.5, 8.4 Hz, 1H), 7.49-7.41 (m, 2H), 7.41-7.33 (m, 2H), 7.20-6.76 (m, 1H), 4.42 (t, J = 5.1 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.94 (t, J = 5.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H).

Example 27, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(methylsulfonyl)ethyl)-2H-indazole-5- Yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 043)

Step 1: Synthesis of 5-bromo-2-(2-(methylsulfonyl)ethyl)-2H-indazole (Intermediate 43-2)

The starting material 43-1 (3g, 15.23mmol) was dissolved in N,N-dimethylformamide (30mL), (methylsulfonyl)ethylene (1.94g, 18.27mmol), and potassium carbonate (2.10g) were added , 15.23mmol), the reaction solution was stirred at 50°C for 16h. LC-MS detects that the reaction is complete. The reaction solution was diluted with ethyl acetate (50 mL), water (50 mL) was added to wash the organic layer three times, and the organic layer filtrate was concentrated to dryness under reduced pressure. Purified by column chromatography (

80g

Silica gel column, ethyl acetate/petroleum ether=0-65%@50mL/min). The title compound (720 mg) was obtained.

MS m/z (ESI): 304.8 [M+H] ⁺ .

Step 2: 2-(2-(Methanesulfonyl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H -Synthesis of indazole (Intermediate 43-3)

Intermediate 43-2 (200mg, 659.68μmol) was dissolved in 1,4-dioxane (2mL), added double pinacol borate (251.28mg, 989.53μmol), potassium acetate (194.23mg, 1.98mmol) ) And Pd(dppf)Cl ₂ (24.13 mg, 32.98 μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with ethyl acetate (50 mL), the organic layer was washed three times (50 mL) with water, and the organic layer was concentrated to dryness under reduced pressure to obtain the title compound (200 mg).

MS m/z (ESI): 351.5 [M+H] ⁺ .

Step 3: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(methylsulfonyl)ethyl)-2H-indazol-5-yl ) Synthesis of pyrido[2,3-d]pyrimidine-7(8H)-one (Compound 043)

Dissolve Intermediate 43-3 (50mg, 142.76μmol) and Intermediate 32-1 (52.50mg, 142.76μmol) in 1,4-dioxane (0.8mL) and water (0.2mL), add cesium carbonate (93.03mg, 285.52μmol) and Pd(dtbpf)Cl ₂ (9.30mg, 14.28μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LC-MS detects that the reaction is complete. The organic layer was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water(0.225%FA)-ACN]; B%: 45%- 65%, 10min), to obtain the title compound (10.2mg).

MS m/z (ESI): 556.2 [M+H] ⁺ .

¹ H NMR (400MHz, METHANOL-d ₄ ) δppm 8.93 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.71-7.68 (m, 1H), 7.67 -7.63(m,1H),7.46-7.41(m,2H),7.41-7.35(m,2H),6.98(t,J=73.8Hz,1H),5.01-4.94(m,2H),4.19(q ,J=7.0Hz,2H),3.90(t,J=6.4Hz,2H),2.79(s,3H),1.26(t,J=7.1Hz,3H)

Example 28, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-(2-(methylsulfonyl)ethyl)-6-oxo-1, 6-Dihydropyridin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 044)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-(2-(methylsulfonyl)ethyl)-6-oxo-1,6 -Dihydropyridin-3-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 044)

The starting material 44-1 (30mg, 91.69μmol, can be synthesized according to the method reported in WO 2008141119) and the intermediate 32-1 (23.60mg, 64.18μmol) were dissolved in 1,4-dioxane (2.8mL) To water (0.7 mL), cesium carbonate (59.75 mg, 183.37 μmol) and Pd(dtbpf)Cl ₂ (5.98 mg, 9.17 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LC-MS detects that the reaction is complete. The organic layer was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B) %: 38%-58%, 10min) to obtain the title compound (1.4mg).

MS m/z (ESI): 533.2 [M+H] ⁺ .

¹ H NMR(400MHz,CHLOROFORM-d)δppm 8.71(s,1H), 8.12(d,J=2.5Hz,1H), 7.74(s,1H), 7.69(dd,J=2.6,9.6Hz,1H) , 7.27-7.20 (m, 4H), 6.58 (d, J = 9.5 Hz, 1H), 6.53 (t, J = 73.4 Hz, 1H), 4.34 (t, J = 6.5 Hz, 2H), 4.13 (q, J = 7.0Hz, 2H), 3.50 (t, J = 6.5Hz, 2H), 2.85 (s, 3H), 1.22 (t, J = 7.1Hz, 3H).

Example 29. 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazole -6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 045)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazole- Synthesis of 6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 045)

Intermediate 45-1 (20mg, 69.41μmol, can be synthesized according to the method reported in patent JP 2013189395) and intermediate 32-1 (30.63mg, 83.29μmol) were dissolved in dioxane (2mL) and water (0.5mL) , Cesium carbonate (67.84mg, 208.23μmol) and Pd(dtbpf)Cl ₂ (4.52mg, 6.94μmol) were added to it, and the reaction solution was stirred at 100°C for 16h under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 45 %-65%, 10min) to obtain the title compound (3.0mg).

MS m/z (ESI): 494.2 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δppm 8.78(s,1H),7.94(s,1H),7.91(s,1H),7.71(d,J=8.5Hz,1H),7.52(d,J =8.5Hz, 1H), 7.31-7.29 (m, 4H), 6.60 (t, J = 72Hz, 1H), 4.83 (s, 2H), 4.16 (q, J = 7.0Hz, 2H), 3.86 (s, 3H), 1.26 (t, J = 7.2Hz, 3H)

Example 30, 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(4-methoxy-3-methylphenyl)pyrido[2,3-d ]Pyrimidine-7(8H)-one (Compound 046)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(4-methoxy-3-methylphenyl)pyrido[2,3-d] Synthesis of Pyrimidine-7(8H)-one (Compound 046)

Intermediate 32-1 (30mg, 81.58μmol) and (4-methoxy-3-methylphenyl)boronic acid (20.31mg, 122.37μmol) were dissolved in 1,4-dioxane (0.4mL), _{A solution of Pd(dtbpf)Cl 2} (5.32 mg, 8.16 μmol) and potassium carbonate (22.55 mg, 163.16 μmol) dissolved in water (0.1 mL) was added under nitrogen protection at 25°C, and the reaction solution was stirred at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was concentrated under reduced pressure and purified by liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 58%) -78%, 10min) to obtain the title compound (10.5mg).

¹ H NMR (400MHz, METHANOL-d ₄ )δ = 8.87 (s, 1H), 8.05 (s, 1H), 7.53 (dd, J = 2.3, 8.5 Hz, 1H), 7.49 (d, J = 1.6 Hz, 1H),7.41-7.32(m,4H), 6.96(d,J=8.4Hz,1H), 6.95(t,J=74Hz 1H), 4.15(q,J=7.0Hz,2H), 3.86(s, 3H), 2.23 (s, 3H), 1.23 (t, J=7.0 Hz, 3H).

MS m/z (ESI): 454.2 [M+H] ⁺ .

Example 31, 6-(benzo[d]isothiazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d] Pyrimidine-7(8H)-one (Compound 047)

Step 1: 6-(Benzo[d]isothiazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d]pyrimidine Synthesis of -7(8H)-one (Compound 047)

Intermediate 32-1 (30mg, 81.58μmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]iso Thiazole (29.99mg, 122.37μmol) was dissolved in 1,4-dioxane (1mL), and Pd(dtbpf)Cl ₂ (5.32mg, 8.16μmol), potassium carbonate (22.55mg, 163.16) were added under nitrogen protection at 25°C μmol) and water (0.25mL), the reaction solution was stirred at 100°C for 16h. LCMS detects the completion of the reaction. The reaction solution was concentrated by rotary evaporation under reduced pressure and purified by liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 26%-46%, 10min) to obtain the title compound (14.2mg).

¹ H NMR (400MHz, DMSO-d6) δ = 12.31-10.59 (m, 1H), 8.97 (s, 1H), 8.28 (s, 1H), 7.97 (d, J = 2.3 Hz, 1H), 7.87 (dd ,J=2.4,8.9Hz,1H),7.47-7.41(m,2H),7.37(t,J=74Hz,1H),7.37-7.34(m,2H),7.08(d,J=8.8Hz,1H ), 4.19(d,J=7.0Hz,2H),1.21(t,J=7.0Hz,3H)

MS m/z (ESI): 451.1 [M+H] ⁺ .

Example 32, 6-(benzo[d]oxazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d] Pyrimidine-7(8H)-one (Compound 048)

Step 1: 6-(Benzo[d]oxazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d]pyrimidine Synthesis of -7(8H)-one (Compound 048)

Intermediate 32-1 (30mg, 81.58μmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo(d)oxa Azole (29.99mg, 122.37μmol) was dissolved in 1,4-dioxane (0.4mL), and Pd(dtbpf)Cl ₂ (5.32mg, 8.16μmol), potassium carbonate (22.55mg, 163.16μmol) and water (0.1mL), the reaction solution was stirred at 100°C for 16h. LCMS detects the completion of the reaction. The reaction solution was concentrated by rotary evaporation under reduced pressure and purified by liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile;; B%) : 48%-68%, 10min) to obtain the title compound (2.5mg).

¹ H NMR(400MHz,METHANOL-d ₄ )δ=8.95(s,1H),8.54(s,1H),8.24(s,1H),8.13(s,1H),7.83-7.79(m,1H), 7.78-7.75(m,1H),7.46-7.42(m,2H),7.40-7.36(m,2H),7.16(t,J=73.6Hz,1H), 4.19(q,J=6.9Hz,2H) ,1.26(t,J=7.0Hz,3H)

MS m/z (ESI): 451.1 [M+H] ⁺ .

Example 33, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-methyl-2H-indazol-5-yl)-1,8-diazepine Phthalo-2(1H)-one (Compound 049)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-methyl-2H-indazol-5-yl)-1,8-diazepine Synthesis of naphthalene-2(1H)-one (compound 049)

Under the protection of nitrogen, the intermediate 38-4 (87mg) and 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-2H-indazole (75.6mg, 0.293mmol) was dissolved in a mixed solution of 2ml dioxane and 1ml water. Subsequently, cesium carbonate (190.6 mg, 0.585 mmol) and Pd(dtbpf)Cl ₂ (13 mg, 0.02 mmol) were added to the reaction solution. The above reaction solution was heated to 100°C and stirred for 16 hours. The completion of the reaction was detected by TLC, the reaction solution was cooled to room temperature, 2ml of water was added to it, and it was extracted with ethyl acetate (3ml*3). The extract phase was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. After purification by column chromatography (PE:EA=10:1-2:1), the title compound (35mg) was obtained.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.39(s,1H), 8.22(s,1H), 8.17-8.11(m,2H), 7.60-7.54(m,2H),7.44-7.42(m ,2H),7.36-7.17(m,3H),6.72(d,J=8.0Hz,1H),4.18(s,3H),3.96-3.94(m,2H),3.94(s,3H),1.09( t,J=8.0Hz,3H).

MS m/z (ESI): 463.0 [M+H] ⁺ .

Example 34, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(4-methoxyphenyl)-1,8-naphthalene-2(1H) -Ketone (Compound 050)

In a nitrogen atmosphere, the intermediate 38-4 (40mg, 97.32μmol) and 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboron Pentane (34.2mg, 146.34μmol) was dissolved in 2.00mL of dioxane and 1.00mL of water. Cesium carbonate (95.1mg, 292.68μmol) and Pd(dtbpf)Cl ₂ (8mg, 10.02μmol) were added to the above reaction solution. . The above reaction liquid was heated to 90°C and stirred for 15 hours. After the completion of the reaction monitored by TLC, it was cooled to room temperature, the reaction solution was filtered, and purified by HPLC-PREP to obtain the title compound (7.0 mg).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.15(t,J=4.2Hz,2H),7.75-7.66(m,2H),7.46-7.32(m,5H),7.05-6.97(m,2H ), 6.72(d,J=8.4Hz,1H), 4.07–3.95(m,2H), 3.81(s,3H), 1.09(t,J=7.0Hz,3H).

MS m/z (ESI): 439.1 [M+H] ⁺ .

Example 35. 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(6-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidine -7(8H)-one (Compound 051)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(6-methoxypyridin-3-yl)pyrido[2,3-d]pyrimidine- Synthesis of 7(8H)-one (Compound 051)

The starting material 51-1 (45.00mg, 294.23μmol) and intermediate 32-1 (36.07mg, 98.08μmol) were dissolved in 1,4-dioxane (0.8mL) and water (0.2mL) at room temperature Cesium carbonate (63.91mg, 196.15μmol) and Pd(dtbpf)Cl ₂ (6.39mg, 9.81μmol) were added. Under the protection of nitrogen, the reaction solution was heated to 100°C and stirred for 16 hours. LCMS detected the completion of the reaction, and the reaction solution was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: YMC Triart C18 150*30mm*5μm; mobile phase: [water(0.225%FA v/v)-ACN]; B%: 48%-68%, 10min) to obtain the title Compound (2.2 mg).

MS m/z (ESI): 441.1 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δppm 8.93(s,1H), 8.50(d,J=2.3Hz,1H), 8.19(s,1H), 8.07(dd,J=2.3,8.8Hz,1H ),7.45-7.39(m,2H),7.39-7.34(m,2H), 6.97(t,J=73.8Hz,1H), 6.89(d,J=8.8Hz,1H), 4.18(q,J= 7.0Hz,2H),3.97(s,3H),1.25(t,J=7.0Hz,3H).

Example 36, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-2H-indazol-5-yl)pyrido [2,3-d]pyrimidin-7(8H)-one (Compound 052)

Step 1: 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)ethane- Synthesis of 1-alcohol (Intermediate 52-2)

Intermediate 52-1 (200mg, 829.59μmol, can be synthesized according to the method reported in WO 2015036964) was dissolved in 1,4-dioxane (7mL), and double pinacol borate (231.73mg, 912.54) was added. μmol), potassium acetate (244.25mg, 2.49mmol) and Pd(dppf)Cl ₂ (60.70mg, 82.96μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with ethyl acetate (50 mL), the organic layer was washed three times (50 mL) with water, and the organic layer was concentrated to dryness under reduced pressure. Purification by preparative thin layer chromatography (SiO ₂ , ethyl acetate = 100%) gave the title compound (110 mg).

MS m/z (ESI): 289.1 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-2H-indazol-5-yl)pyrido[ Synthesis of 2,3-d]pyrimidin-7(8H)-one (Compound 052)

Intermediate 52-2 (110 mg, 381.75 μmol) and intermediate 32-1 (140.38 mg, 381.75 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and cesium carbonate ( 248.76mg, 763.49μmol) and Pd(dtbpf)Cl ₂ (24.88mg, 38.17μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B) : Acetonitrile; B%: 40%-60%, 10min). The title compound (37.8mg) was obtained.

MS m/z (ESI): 494.2 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δ8.93(s,1H), 8.34(s,1H), 8.20(s,1H), 8.13(s,1H), 7.70-7.61(m,2H), 7.48-7.42(m,2H),7.40-7.34(m,2H),6.98(t,J=73.8Hz,1H),4.57(t,J=5.3Hz,2H), 4.19(q,J=7.0Hz ,2H),4.06(t,J=5.3Hz,2H),1.26(t,J=7.0Hz,3H).

Example 37, 6-(2-(2-aminoethyl)-2H-indazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido [2,3-d]pyrimidin-7(8H)-one (Compound 053)

Step 1: 2-(5-(8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-7-oxo-7,8-dihydropyrido[2,3-d ]Pyrimidine-6-yl)-2H-indazol-2-yl)ethyl methanesulfonate (Intermediate 53-1)

Compound 052 (180mg, 364.77μmol) was dissolved in dichloromethane (4mL), cooled to 0℃ in an ice bath, triethylamine (73.82mg, 729.54μmol) and methanesulfonyl chloride (45.96mg, 401.25μmol) were added, and the reaction After stirring the solution at 0°C for 10 min, it was raised to 25°C. Continue to stir the reaction for 30 min. LCMS detects the completion of the reaction. Dichloromethane (50 mL) was added to the reaction solution, and the organic layer was washed three times with saturated sodium sulfite aqueous solution (50 mL). The organic layer filtrate was concentrated to dryness under reduced pressure to obtain the title compound (600 mg). The crude product was directly used in the next step.

MS m/z (ESI): 572.1 [M+H] ⁺ .

Step 2: 6-(2-(2-Aminoethyl)-2H-indazol-5-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[ Synthesis of 2,3-d]pyrimidin-7(8H)-one (Compound 053)

Intermediate 53-1 (300 mg, 524.89 μmol) was dissolved in methanol (3 mL), ammonia water (89.39 mg, 5.25 mmol) was added, and the mixture was stirred at room temperature for 10 min. The reaction solution was heated to 60° C., and stirring was continued for 20 h. LCMS detects the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water(0.225%FA)-ACN]; B%: 33%-53 %, 10min), to obtain the title compound (5.5mg).

MS m/z (ESI): 493.1 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ9.03(s,1H),8.53-8.44(m,1H),8.28(s,1H),8.14(s,1H),7.67(d,J=8.3 Hz, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.40 (s, 1H), 7.39 (t, J = 68.9 Hz, 1H), 7.37 (s, 1H), 4.49(s,2H),4.22(q,J=7.2Hz,2H),3.20-3.08(m,2H),1.26-1.22(m,3H)

Example 38, 8-(4-(Difluoromethoxy)phenyl)-6-(2-(2-(dimethylamino)ethyl)-2H-indazol-5-yl)-2-ethyl Oxypyrido[2,3-d]pyrimidin-7(8H)-one (Compound 054)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-6-(2-(2-(dimethylamino)ethyl)-2H-indazol-5-yl)-2-ethoxy Synthesis of pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 054)

Stir dimethylamine hydrochloride (142.67mg, 1.75mmol) and triethylamine (106.23mg, 1.05mmol, 146.11μL, 3eq) at room temperature for 10min, and then dissolve Intermediate 53-1 (200mg, 349.92μmol) Methanol (3 mL) was added to the reaction system. After stirring at room temperature for 10 minutes, the temperature was raised to 60°C, and stirring was continued for 20 hours. LCMS detects the completion of the reaction, and the reaction solution is concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 50%-70%, 10min ) To obtain the title compound (4.7 mg).

MS m/z (ESI): 521.2 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δppm 9.01(s,1H), 8.46(s,1H), 8.26(s,1H), 8.10(s,1H), 7.64(d,J=9.0Hz,1H ), 7.57-7.52 (m, 1H), 7.47 (d, J = 8.9 Hz, 2H), 7.39-7.34 (m, 2H), 7.37 (t, J = 72.6 Hz, 1H), 4.53 (t, J = 6.5Hz, 2H), 4.20 (q, J = 7.1Hz, 2H), 2.80 (t, J = 6.2Hz, 2H), 2.18 (s, 6H), 1.22 (t, J = 7.1Hz, 3H)

Example 39, 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl )Pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 055)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl) Synthesis of pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 055)

The starting material 55-1 (28.77mg, 122.37μmol) and intermediate 32-1 (30mg, 81.58μmol) were dissolved in 1,4-dioxane (0.4mL) and water (0.1mL), and carbonic acid was added Cesium (53.16mg, 163.16μmol) and Pd(dtbpf)Cl ₂ (5.32mg, 8.16μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, the filtrate was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B) : Acetonitrile; B%: 38%-58%, 10 min) to obtain the title compound (22.2 mg).

MS m/z (ESI): 441.1 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δppm 8.91(s,1H), 8.28(d,J=2.4Hz,1H), 8.19(s,1H), 7.96(dd,J=2.5,9.2Hz,1H ), 7.43-7.39 (m, 2H), 7.39-7.35 (m, 2H), 6.97 (t, J = 73.8 Hz, 1H), 6.64 (d, J = 9.4 Hz, 1H), 4.18 (q, J = 7.1Hz, 2H), 3.66 (s, 3H), 1.25 (t, J = 7.1Hz, 3H).

Example 40, 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(4-methoxy-2-methylphenyl)pyrido[2,3-d ]Pyrimidine-7(8H)-one (Compound 056)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(4-methoxy-2-methylphenyl)pyrido[2,3-d] Synthesis of Pyrimidine-7(8H)-one (Compound 056)

The starting material 56-1 (20.31 mg, 122.37 μmol) and intermediate 32-1 (30 mg, 81.58 μmol) were dissolved in 1,4-dioxane (0.4 mL) and water (0.1 mL), and carbonic acid was added Cesium (53.16mg, 163.16μmol) and Pd(dtbpf)Cl ₂ (5.32mg, 8.16μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, the filtrate was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B) : Acetonitrile; B%: 56%-76%, 10min) to obtain the title compound (12.3mg).

MS m/z (ESI): 454.2 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δppm 8.90(s,1H),7.93(s,1H),7.43-7.38(m,2H),7.38-7.34(m,2H),7.21(d,J= 8.3Hz, 1H), 6.96 (t, J = 73.8Hz, 1H), 6.88-6.80 (m, 2H), 4.18 (q, J = 7.0Hz, 2H), 3.83 (s, 3H), 2.25 (s, 3H), 1.26 (t, J = 7.1Hz, 3H).

Example 41, 6-(benzo[d]oxazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d] Pyrimidine-7(8H)-one (Compound 057)

Step 1: 6-(Benzo[d]oxazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d]pyrimidine Synthesis of -7(8H)-one (Compound 057)

The starting material 57-1 (30 mg, 122.41 μmol) and intermediate 32-1 (45.01 mg, 122.41 μmol) were dissolved in dioxane (2 mL) and water (0.5 mL), and cesium carbonate (119.65) was added thereto. mg, 367.22μmol) and Pd(dtbpf)Cl ₂ (7.98mg, 12.24μmol), the reaction solution was stirred at 90°C for 16h under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was extracted with ethyl acetate (6mL) and water (6mL), the organic phase (2mL x 3) was washed with water, an appropriate amount of anhydrous sodium sulfate was added to the organic phase, filtered and concentrated under reduced pressure to dryness. The reaction solution was concentrated under reduced pressure to Dry, purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 45%-65%, 10min ) To obtain the title compound (6.3 mg).

MS m/z (ESI): 454.2 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δppm 8.96(s,1H),8.55(s,1H),8.27(s,1H),8.11(d,J=1.0Hz,1H),7.88-7.82(m ,1H),7.81-7.76(m,1H),7.50-7.43(m,2H),7.41-7.36(m,2H),7.19-6.77(t,J=74Hz,1H), 4.20(q,J= 7.0Hz, 2H), 1.27 (t, J = 7.0Hz, 3H).

Example 42, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(methoxymethyl)-1-methyl-1H-benzo[d ]Imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 058)

Step 1: 2-(Methoxymethyl)-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- Synthesis of 1H-Benzo[d]imidazole (Intermediate 58-2)

Intermediate 58-1 (75mg, 293.99μmol, can be synthesized according to the method reported in WO 2013105676) and dual pinacol borate (82.12mg, 323.39μmol) were dissolved in anhydrous dioxane (2mL), Potassium acetate (86.56 mg, 881.97 μmol) and Pd(dppf)Cl ₂ (21.51 mg, 29.40 μmol) were added thereto, and the reaction solution was stirred at 100° C. for 15 h under the protection of nitrogen. LC-MS detects that the reaction is complete. After the reaction was cooled to room temperature, water (5 mL) and ethyl acetate (5 mL) were sequentially added, the organic phase was washed with water (2 mL*2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. The title compound (85 mg) was obtained by preparative thin layer chromatography (silica, dichloromethane: methanol = 10:1).

MS m/z (ESI): 303.1 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(methoxymethyl)-1-methyl-1H-benzo[d] Synthesis of Imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 058)

Intermediate 58-2 (85 mg, 281.29 μmol) and intermediate 32-1 (68.96 mg, 187.53 μmol) were dissolved in dioxane (2 mL) and water (0.5 mL), and cesium carbonate (122.20 mg) , 375.06μmol) and Pd(dtbpf)Cl ₂ (12.22mg, 18.75μmol), the reaction solution was stirred at 90°C for 16h under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative high performance liquid chromatography (column: Gemini NX C18 5μm*10*150mm; mobile phase: water (0.225% FA)-ACN; B%: 30%-50% , 11min) to obtain the title compound (16.6mg).

MS m/z (ESI): 508.1 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δ8.95(s,1H),8.25(s,1H),7.96(s,1H),7.75-7.69(m,1H),7.66-7.61(m,1H) ),7.48-7.42(m,2H),7.41-7.35(m,2H),6.98(t,J=74Hz 1H),4.80(s,2H),4.19(q,J=7.0Hz,2H),3.93 (s,3H),3.45(s,3H),1.27(t,J=7.0Hz,3H)

Example 43, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-ethyl-1H-benzo[d]imidazol-6-yl)pyrido[ 2,3-d)pyrimidin-7(8H)-one (Compound 060)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(methoxymethyl)-1-methyl-1H-benzo[d] Synthesis of Imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 060)

Intermediate 60-1 (33.30mg, 122.37μmol), intermediate 32-1 (30mg, 81.58μmol), Cs ₂ CO ₃ (53.16mg, 163.16μmol), Pd(dtbpf)Cl ₂ (5.32mg, 8.16μmol) ) Was dissolved in dioxane/H ₂ O (4:1) (5 mL). The reaction was stirred at 90°C for 12 hours under a nitrogen atmosphere. LC-MS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 48 %-68%, 10min) to obtain the title compound (5mg).

MS m/z (ESI): 478.2 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δ=8.94(s,1H), 8.25(d,J=9.5Hz,2H), 8.01(s,1H), 7.75(d,J=8.4Hz,1H) ,7.63(d,J=8.4Hz,1H),7.51-7.41(m,2H),7.39(s,2H),7.21-6.72(m,1H),4.38(q,J=7.0Hz,2H), 4.19 (q, J = 6.9 Hz, 2H), 1.55 (t, J = 7.3 Hz, 3H), 1.26 (t, J = 7.0 Hz, 3H).

Example 44, 6-(1-cyclopropyl-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido [2,3-d]pyrimidine-7(8H)-one (Compound 061)

Step 1: 6-(1-Cyclopropyl-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[ Synthesis of 2,3-d]pyrimidin-7(8H)-one (Compound 061)

The starting material 61-1 (46.36mg, 163.16μmol, can be synthesized according to the patent WO 2016057834 report method), intermediate 32-1 (50mg, 135.97μmol), cesium carbonate (88.60mg, 271.94μmol), Pd(dtbpf) Cl ₂ (8.86 mg, 13.60 μmol) was dissolved in dioxane/water (4:1) (5 mL). The reaction was stirred at 90°C for 12 hours under a nitrogen atmosphere. LC-MS detects that the reaction is complete. After the reaction solution was evaporated to dryness under reduced pressure, high performance liquid chromatography (column: Gemini NX C18 5μm*10*150mm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 48 %-68%, 2min) to obtain the title compound (11mg).

MS m/z (ESI): 490.1 [M+H] ⁺ .

¹ H NMR(400MHz,CHLOROFORM-d)δ8.83(s,1H),8.13(s,1H),7.99(s,1H),7.96(s,1H),7.85(d,J=8.5Hz,1H ),7.62-7.51(m,1H),7.43-7.32(m,4H),6.62(t,J=74Hz,1H), 4.23(q,J=7.0Hz,2H),3.54-3.33(m,1H ),1.35-1.30(m,3H),1.18(d,J=5.5Hz,2H),1.08(s,2H)

Example 45. 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-1H-benzo[d][1,2,3]triazole -6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 062)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-1H-benzo[d][1,2,3]triazole- Synthesis of 6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 062)

The starting material 62-1 (35.23mg, 135.97μmol, can be synthesized according to the patent WO 2019000237 report method) and the intermediate 32-1 (50mg, 135.97μmol) were dissolved in 1,4-dioxane (0.8mL) and In water (0.2 mL), cesium carbonate (88.60 mg, 271.94 μmol) and Pd(dtbpf)Cl ₂ (8.86 mg, 13.60 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B) : Acetonitrile; B%: 45%-65%, 11min). The title compound (16.3mg) was obtained.

MS m/z (ESI): 465.1 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d6)δppm 9.04(s,1H), 8.39(s,1H), 8.20(s,1H), 8.09(d,J=8.8Hz,1H), 7.73(d,J= 9.3Hz, 1H), 7.47 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 7.0 Hz, 2H), 7.36 (t, J = 73.6 Hz, 1H), 4.33 (s, 3H), 4.25 -4.16(m,2H),1.22(t,J=6.9Hz,3H).

Example 46, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-methyl-1H-benzo[d]imidazol-6-yl)pyrido[ 2,3-d)pyrimidin-7(8H)-one (Compound 063)

Step 1: 6-(8-(4-(difluoromethoxy)phenyl)-2-ethoxy-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine- Synthesis of tert-butyl 6-yl)-2-methyl-1H-benzo[d]imidazole-1-carboxylate (Intermediate 63-2)

The starting material 63-1 (58.45mg, 163.16μmol, can be synthesized according to the patent WO 2011055215 report method), intermediate 32-1 (50mg, 135.97μmol, 1eq), cesium carbonate (88.60mg, 271.94μmol, 2eq) Pd(dtbpf)Cl ₂ (8.86 mg, 13.60 μmol, 0.1 eq) was dissolved in dioxane/water (4:1) (5 mL). The reaction was stirred at 90°C for 12 hours under a nitrogen atmosphere. LC-MS detects that the reaction is complete. After the reaction solution was concentrated under reduced pressure, thin layer chromatography (silica, DCM:MeOH=7:1) was prepared. The title compound (30 mg) was obtained.

MS m/z (ESI): 564.2 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-methyl-1H-benzo[d]imidazol-6-yl)pyrido[2 Synthesis of ,3-d]pyrimidine-7(8H)-one (Compound 063)

Intermediate 63-2 (25 mg, 44.36 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1.54 g, 13.51 mmol) was added dropwise. The reaction was stirred at room temperature for 3 hours. LC-MS detects that the reaction is complete. After the reaction solution was concentrated under reduced pressure, high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B%: 40 %-60%, 11 minutes). The title compound (2.3mg) was obtained.

MS m/z (ESI): 464.1 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δ8.94(s,1H), 8.18(s,1H), 7.89(m,1H), 7.56(s,2H),7.46-7.41(m,2H), 7.40-7.34(m,2H), 6.97(t,J=74Hz,1H), 4.19(m,J=7.0Hz,2H), 2.61(s,3H), 1.26(s,3H)

Example 47. 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-morpholinylethyl)-2H-indazol-5-yl) Pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 064)

Step 1: 2-(5-(8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-7-oxo-7,8-dihydropyrido[2,3-d ]Pyrimidine-6-yl)-2H-indazol-2-yl)ethyl methanesulfonate (Intermediate 64-1)

Compound 052 (100 mg, 202.65 μmol) was dissolved in dichloromethane (2 mL), the reaction solution was cooled to 0° C. and methanesulfonyl chloride (25.54 mg, 222.92 μmol) and triethylamine (41.01 mg, 405.30 μmol) were added. The reaction solution was stirred at 0°C for 10 minutes and then raised to 25°C and stirred for 30 minutes. LCMS detects the completion of the reaction. The reaction solution was diluted with saturated brine (50 mL), dichloromethane (50 mL) was added for extraction three times, and the organic layer was concentrated to dryness under reduced pressure. The crude title compound (300 mg) was obtained and used directly in the next step.

MS m/z (ESI): 572.3 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-morpholinylethyl)-2H-indazol-5-yl)pyridine Synthesis of and [2,3-d]pyrimidine-7(8H)-one (Compound 064)

Intermediate 64-1 (300 mg, 524.89 μmol) was dissolved in anhydrous methanol (3 mL), morpholine (457.28 mg, 5.25 mmol) was added at room temperature, and stirred at room temperature for 10 min. The temperature was raised to 60° C. and the reaction was stirred for 16 h. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: Gemini NX C18 5μm*10*150mm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile) ; B%: 24%-64%, 9min) to obtain the title compound (6.4mg).

MS m/z (ESI): 563.2 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ9.00(s,1H), 8.47(s,1H), 8.25(s,1H), 8.10(s,1H), 7.64(d,J=9.3Hz, 1H), 7.57-7.51 (m, 1H), 7.49-7.42 (m, 2H), 7.36 (t, J = 74Hz, 1H), 7.39-7.33 (m, 2H), 4.56 (t, J = 6.3Hz, 2H), 4.20(q,J=7.0Hz,2H),3.56-3.50(m,4H),2.94-2.82(m,2H),2.43(s,4H),1.26-1.17(m,3H)

Example 48, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-(2-hydroxyethyl)-2H-indazol-5-yl)-1 ,8-Naphthalene-2(1H)-one (Compound 065)

Step 1: 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl)ethane- Synthesis of 1-alcohol (Intermediate 65-2)

The starting material 65-1 (100mg, 414.79μmol, can be synthesized according to the method reported in WO 2015036964) was dissolved in 1,4-dioxane (1mL), and double pinacol borate (115.87mg, 456.27μmol), potassium acetate (122.12mg, 1.24mmol) and Pd(dppf)Cl ₂ (30.35mg, 41.48μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with ethyl acetate (50 mL), the organic layer was washed three times (50 mL) with water, and the organic layer was concentrated to dryness under reduced pressure. Purification by preparative thin layer chromatography (silica, ethyl acetate = 100%) gave the title compound (60 mg).

MS m/z (ESI): 289.1 [M+H] ⁺ .

Step 2: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-(2-hydroxyethyl)-2H-indazol-5-yl)-1, Synthesis of 8-naphthalene-2(1H)-one (Compound 065)

Intermediate 65-2 (52.56 mg, 182.39 μmol) and intermediate 38-4 (50 mg, 121.60 μmol) were dissolved in 1,4-dioxane (0.8 mL) and water (0.2 mL), and cesium carbonate was added (79.24mg, 243.19μmol) and Pd(dtbpf)Cl ₂ (7.92mg, 12.16μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water(0.05% ammonia hydroxide v/v)-ACN]; B%: 50%-70%, 11min) The title compound (21.9 mg) was obtained.

MS m/z (ESI): 493.3 [M+H] ⁺ .

¹ H NMR(400MHz, _{METHANOL-d 4} )δ8.32(s,1H), 8.15(s,1H), 8.11-8.05(m,2H), 7.66(s,2H),7.45-7.32(m,4H) ), 6.96 (t, J = 74 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 4.56 (t, J = 5.4 Hz, 2H), 4.09-3.97 (m, 4H), 1.17 (t, J=7.0Hz, 3H).

Example 49, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazole -6-yl)-1,8-naphthalene-2(1H)-one (Compound 066)

Step 1: (1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole- Synthesis of 2-yl)methanol (Intermediate 66-2)

The starting material 66-1 (300mg, 1.24mmol, can be synthesized according to the method reported in WO 2007135527) and dual pinacol borate (473mg, 1.87mmol) were dissolved in anhydrous dioxane (6mL), Potassium acetate (366.38 mg, 3.73 mmol) and Pd(dppf)Cl ₂ (101.2 mg, 124.44 μmol) were added, and the reaction solution was stirred at 100° C. for 16 h under nitrogen protection. LC-MS detects that the reaction is complete. After the reaction was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were sequentially added, the organic phase was washed with water (10 mL*2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate. The title compound (56 mg) was obtained by preparative thin layer chromatography (silica, dichloromethane: methanol = 10:1).

MS m/z (ESI): 289.2 [M+H] ⁺ .

Step 2: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-(hydroxymethyl)-1-methyl-1H-benzo[d]imidazole- Synthesis of 6-yl)-1,8-naphthalene-2(1H)-one (Compound 066)

Intermediate 66-2 (52.56 mg, 182.39 μmol) and intermediate 38-4 (50 mg, 121.60 μmol) were dissolved in dioxane (2 mL) and water (0.5 mL), and cesium carbonate (79.24 mg) , 243.19μmol) and Pd(dtbpf)Cl ₂ (7.92mg, 12.16μmol), the reaction solution was stirred at 90°C for 16h under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%) : 45%-65%, 10 minutes) to obtain the title compound (3.0 mg).

MS m/z (ESI): 493.2 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δ8.20(s,1H), 8.10(d,J=8.5Hz,1H),7.95(s,1H),7.73-7.68(m,1H),7.65- 7.60(m,1H),7.44-7.38(m,4H), 6.96(t,J=74Hz,1H), 6.72(d,J=8.5Hz,1H),5.00-4.99(m,2H),4.04( q,J=7.0Hz,2H),3.97(s,3H),1.19-1.15(m,3H).

Example 50, 1-(4-(Difluoromethoxy)phenyl)-3-(2-((dimethylamino)methyl)-1-methyl-1H-benzo[d]imidazole-6 -Yl)-7-ethoxy-1,8-naphthalene-2(1H)-one (Compound 069)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-3-(2-((dimethylamino)methyl)-1-methyl-1H-benzo[d]imidazole-6- Yl)-7-ethoxy-1,8-naphthalene-2(1H)-one (Compound 069)

Intermediate 69-1 (40 mg, 126.90 μmol, refer to Examples 365-366 on page 412 of WO2016057834A1, and the starting material dimethylamine was substituted for pyrrolidine) and intermediate 38-4 (52.18 mg, 126.90 μmol) Dissolved in anhydrous dioxane (2mL) and water (0.5mL), cesium carbonate (82.69mg, 253.80μmol) and Pd(dtbpf)Cl ₂ (8.27mg, 12.69μmol) were added to it. The reaction solution was stirred at 90°C for 16 hours under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative HPLC (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 25 %-45%, 11min) to obtain the title compound (1.4mg).

MS m/z (ESI): 520.2 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δ8.52(br s,1H, H COOH), 8.19(s,1H), 8.10(d,J=8.5Hz,1H),7.94(s,1H), 7.74-7.68(m,1H),7.64-7.58(m,1H),7.45-7.34(m,4H),7.16-6.77(m,1H),6.72(d,J=8.5Hz,1H),4.04( d, J = 7.0Hz, 2H), 3.95 (s, 3H), 3.83 (s, 2H), 2.36 (s, 6H), 1.17 (t, J = 7.0 Hz, 3H).

Example 51, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl )-1,8-naphthalene-2(1H)-one (Compound 072)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl) Synthesis of -1,8-naphthalene-2(1H)-one (Compound 072)

Under a nitrogen atmosphere, intermediate 38-4 (50 mg, 121.95 μmol) and starting material 72-1 (42.9 mg, 182.92 μmol) were dissolved in a mixed solution of 0.8 mL of dioxane and 0.4 mL of water. Subsequently, cesium carbonate (118.9 mg, 365.85 μmol) and Pd(dtbpf)Cl ₂ (10 mg, 12.36 μmol) were sequentially added thereto. The reaction solution was heated to 90°C for 15 hours. By TLC monitoring, the reaction was complete. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected. The filtrate was prepared and purified by high pressure preparation [YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH ₄ HCO ₃ ) and a mixture of decreasing polarity of acetonitrile as eluent; gradient ratio of acetonitrile 70%-82%, elution time 12 minutes], the title compound (9.10 mg) was obtained.

MS m/z (ESI): 440.3 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.34(d,J=2.6Hz,1H), 8.21(s,1H), 8.10(d,J=8.5Hz,1H), 7.90-7.85(m, 1H),7.44-7.29(m,5H), 6.73(d,J=8.4Hz,1H), 6.47(d,J=9.5Hz,1H), 4.03-3.94(m,2H), 3.49(s,3H ),1.08(t,J=7.0Hz,3H).

Example 52, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-(2-morpholinylethyl)-2H-indazol-5-yl) -1,8-naphthalene-2(1H)-one (Compound 080)

Step 1: Synthesis of 4-(2-(5-bromo-2H-indazol-2-yl)ethyl)morpholine (Intermediate 80-2)

The starting material 80-1 (1g, 4.35mmol) and N-(2-aminoethyl)morpholine (622.59mg, 4.78mmol) were dissolved in isopropanol (50mL), and the reaction solution was stirred at 80°C for 4h. . After cooling to 25°C, tributylphosphorus (2.64g, 13.04mmol, 3.22mL) was added, and the reaction solution was stirred and reacted at 80°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with ethyl acetate (100 mL), the organic layer was washed three times (100 mL) with water, and the organic layer was concentrated to dryness under reduced pressure to obtain the crude title compound (900 mg), which was directly used in the next reaction.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.36(s,1H),7.99-7.94(m,1H),7.59(d,J=9.0Hz,1H),7.31(dd,J=1.9,9.2 Hz, 1H), 4.59 (t, J = 5.3 Hz, 2H), 3.29 (t, J = 5.6 Hz, 2H), 3.23 (s, 3H)

Step 2: 4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazol-2-yl) Synthesis of Ethyl)morpholine (Intermediate 80-3)

Intermediate 80-2 (200mg, 644.77μmol) was dissolved in 1,4-dioxane (2.5mL), and double pinacol borate (245.60mg, 967.15μmol), potassium acetate (189.84mg) were added , 1.93mmol) and Pd(dppf)Cl ₂ (47.18mg, 64.48μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with ethyl acetate (50 mL), the organic layer was washed three times (50 mL) with water, and the organic layer was concentrated to dryness under reduced pressure. Purification by preparative thin layer chromatography (silica, ethyl acetate: methanol = 30:1), to obtain the title compound (130 mg, 430.21 μmol).

MS m/z (ESI): 358.2 [M+H] ⁺ .

Step 3: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-(2-morpholinylethyl)-2H-indazol-5-yl)- Synthesis of 1,8-naphthalazine-2(1H)-one (Compound 080)

Intermediate 80-3 (130.32 mg, 364.79 μmol) and intermediate 38-4 (100 mg, 243.19 μmol) were dissolved in 1,4-dioxane (1.2 mL) and water (0.3 mL), and cesium carbonate was added (158.47mg, 486.38μmol) and Pd(dtbpf)Cl ₂ (15.85mg, 24.32μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: Phenomenex Gemini C18 250*50mm*10μm; mobile phase: [A: water (0.05% ammonia v/v), B: Acetonitrile]; B%: 53%-73%, 9 minutes). The title compound (33.9 mg) was obtained.

MS m/z (ESI): 562.2 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δppm 8.35(s,1H), 8.15(s,1H), 8.12-8.05(m,2H), 7.66(d,J=1.0Hz,2H),7.43-7.33 (m, 4H), 6.96 (t, J = 74 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 4.88-4.66 (m, 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.70-3.63 (m, 4H), 2.98 (t, J=6.4 Hz, 2H), 2.56-2.48 (m, 4H), 1.17 (t, J=7.0 Hz, 3H).

Example 53, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-2-(((oxetan-3-ylmethyl) (Amino)methyl)-1H-benzo(d]imidazol-6-yl)-1,8-naphthalene-2(1H)-one (Compound 081)

Step 1: (6-(1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-2-oxo-1,2-dihydro-1,8-naphthalene- Synthesis of 3-yl)-1-methyl-1H-benzo[d]imidazol-2-yl)methanesulfonate (Intermediate 81-1)

Compound 066 (30.0 mg, 0.061 mmol) was dissolved in THF (0.3 mL), and triethylamine (12.34 mg, 0.122 mmol) and ethanesulfonyl chloride (11.82 mg, 0.092 mmol) were sequentially added to the above reaction solution. After adding, stir at room temperature for 2h. TLC detected the completion of the reaction, the reaction solution was poured into water (1 mL), and ethyl acetate extracted three times (0.5 mL*3). The combined organic phase was washed with saturated brine (1 mL), the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to dryness to obtain the crude title compound (35.6 mg), which was directly put into the next step.

Step 2: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-2-(((oxetan-3-ylmethyl)amino )Methyl)-1H-benzo[d]imidazol-6-yl)-1,8-naphthalene-2(1H)-one (Compound 081)

Intermediate 81-1 (35.6mg, crude) was dissolved in MeCN (0.5mL), K ₂ CO ₃ (16.86mg, 0.122mmol) and 3-aminomethyloxetane (8.02mg, 0.092mmol) were added ), after adding the reaction solution, stirring at room temperature for 2h. LC-MS detects that the reaction is complete. The reaction solution was filtered, and the filtrate was prepared and purified by high-pressure preparation [YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH ₄ HCO ₃ ) and a mixture of decreasing polarity of acetonitrile as elution Solution; acetonitrile gradient ratio 20%-60%, elution time 12 minutes] to obtain the title compound (10.0 mg).

MS m/z (ESI): 562.2 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δ8.17(s,1H), 8.07(d,J＝8.5Hz,1H),7.94(d,J＝1.6Hz, 1H), 7.69(d,J＝ 8.4Hz, 1H), 7.61 (dd, J = 8.4, 1.6 Hz, 1H), 7.42–7.31 (m, 4H), 6.94 (t, J = 73.8 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H),4.62-4.53(m,2H),4.46(t,J=5.7Hz,2H),4.32(s,2H),4.01(q,J=7.0Hz,2H),3.89(s,3H), 3.26–3.20(m,2H),1.38–1.24(m,1H), 1.15(t,J=7.0Hz,3H).

Example 54, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-isobutyl-2H-indazol-5-yl)-1,8-di Azaphthalene-2(1H)-one (Compound 082)

Step 1: Synthesis of 5-bromo-2-isobutyl-2H-indazole (Intermediate 82-2)

At 25°C, isobutylamine (349.76 mg, 4.78 mmol) was added to a solution of the starting material 82-1 (1 g, 4.35 mmol) in isopropanol (50 mL) under nitrogen protection. The mixture was stirred at 25°C for 10 minutes, and then heated to 80°C for 4 hours. Then, after cooling to 25°C, tributylphosphine (2.64g, 13.04mmol) was added. The reaction was carried out at 80°C for 16 hours. LC-MS showed that all the raw materials had been reacted. The reaction solution was extracted and separated with ethyl acetate (150 mL) and water (150 mL). The organic phase was spin-dried and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 1/0 to 5/1) , The title compound (0.93g) was obtained.

MS m/z (ESI): 253.1 [M+H] ⁺ .

Step 2: 2-Isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (Intermediate 82- 3) Synthesis

Intermediate 82-2 (320.00mg, 1.26mmol), Pd(dppf)Cl ₂ (92.50mg, 126.41μmol), potassium acetate (372.19mg, 3.79mmol) and double pinacol borate (353.11mg, 1.39mmol) was dissolved in dioxane (10mL), and the reaction was stirred at 100°C for 15 hours under a nitrogen atmosphere. LC-MS monitored the complete reaction. The reaction solution was diluted with water (20ml), extracted with 60mL of ethyl acetate (20mL*3), the organic phase was dried over sodium sulfate, filtered, and spin-dried. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 1/0 to 10/1) to obtain the title compound (287 mg).

MS m/z (ESI): 301.2 [M+H] ⁺ .

Step 3: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-isobutyl-2H-indazol-5-yl)-1,8-diazepine Synthesis of Phthalo-2(1H)-one (Compound 082)

Add cesium carbonate (126.78mg, 389.11) to the mixed solution water (1.25mL) and dioxane (5mL) of Intermediate 82-3 (116.81mg, 389.11μmol) and Intermediate 38-4 (80mg, 194.55μmol). μmol) and catalyst Pd(dtbpf)Cl ₂ (12.68mg, 19.46μmol), reacted at 90℃ for 15h. LC-MS monitored the complete reaction. The reaction solution was quenched with 20ml of water, extracted with ethyl acetate (10mL*3), and the organic phases were combined and spin-dried. The residue was purified by high performance liquid chromatography (basic conditions, column: Phenomenex Gemini C18 250*50mm*10μm ; Mobile phase: [A: water (0.05% ammonia v/v), B: acetonitrile]; B%: 60%-80%, 9 minutes) to obtain the title compound (48.5 mg).

¹ H NMR(400MHz, _{METHANOL-d 4} )δ8.28(s,1H), 8.15(s,1H), 8.10(d,J=1.0Hz,1H), 8.08(d,J=8.5Hz,1H) ,7.66(d,J=1.3Hz,2H),7.44-7.38(m,2H),7.38-7.34(m,2H),7.18-6.96(t,J=76Hz,1H),6.71(d,J= 8.5Hz, 1H), 4.28 (d, J = 7.5 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H), 2.45-2.32 (m, J = 6.8, 13.7 Hz, 1H), 1.17 (t, J=7.0 Hz, 3H), 0.97 (d, J=6.8 Hz, 6H).

MS m/z (ESI): 505.2 [M+H] ⁺ .

Example 55, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-methoxyethyl)-2H-indazol-5-yl) Pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 059)

Step 1: 2-(2-Methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indole Synthesis of azole (Intermediate 59-2)

The starting material 59-1 (250mg, 979.97μmol, can be synthesized according to the method reported in WO 2012002577) was dissolved in 1,4-dioxane (4mL), and double pinacol borate (273.74mg, 1.08mmol), potassium acetate (288.52mg, 2.94mmol) and Pd(dppf)Cl ₂ (71.70mg, 98.00μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with ethyl acetate (100 mL), the organic layer was extracted and washed with water three times (100 mL), and the organic layer was concentrated to dryness under reduced pressure. Purified by column chromatography to obtain the title compound (130 mg).

MS m/z (ESI): 303.1 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-methoxyethyl)-2H-indazol-5-yl)pyridine Synthesis of and [2,3-d]pyrimidine-7(8H)-one (Compound 059)

Dissolve Intermediate 59-2 (61.63mg, 203.95μmol) and Intermediate 32-1 (50mg, 135.97μmol) in 1,4-dioxane (1.2mL) and water (0.3mL), add cesium carbonate (88.60mg, 271.94μmol) and Pd(dtbpf)Cl ₂ (8.86mg, 13.60μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: Phenomenex Gemini C18 250*50mm*10μm; mobile phase: ([A: water (0.05% ammonia v/v), B : Acetonitrile]; B%: 45%-65%, 9 minutes). The title compound (39.3 mg) was obtained.

MS m/z (ESI): 508.1 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δ8.93(s,1H), 8.32(s,1H), 8.19(s,1H), 8.11(s,1H), 7.70-7.62(m,2H), 7.48-7.41(m,2H),7.41-7.33(m,2H),6.97(t,J=73.8,1H),4.66-4.63(m,2H),4.19(q,J=7.2Hz,2H), 3.90 (t, J = 5.1 Hz, 2H), 3.34 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H).

Example 56, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-hydroxy-1-methyl-1H-benzo[d]imidazol-6-yl )-1,8-naphthalene-2(1H)-one (Compound 070)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-hydroxy-1-methyl-1H-benzo[d]imidazol-6-yl) Synthesis of -1,8-naphthalene-2(1H)-one (Compound 070)

Dissolve Intermediate 70-1 (50.00mg, 182.39μmol) and Intermediate 38-4 (50mg, 121.60μmol) in 1,4-dioxane (0.8mL) and water (0.2mL), add cesium carbonate (79.24mg, 243.19μmol) and Pd(dtbpf)Cl ₂ (7.92mg, 12.16μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: ([A: water (0.05% ammonia v/v) , B: Acetonitrile]; B%: 50%-70%, 11 minutes). The title compound (22.6 mg) was obtained.

MS m/z (ESI): 479.1 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δ8.12(s,1H), 8.07(d,J=8.5Hz,1H), 7.52(s,1H),7.47-7.42(m,1H),7.41- 7.35(m,4H),7.16-7.12(m,1H), 6.96(t,J=73.6Hz,1H), 6.70(d,J=8.5Hz,1H),4.03(q,J=7.0Hz,2H ),3.44(s,3H),1.16(t,J=7.0Hz,3H)

Example 57, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-(1-methylazetidine-3-yl)-1H-benzene And [d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 077)

Step 1: Synthesis of benzyl 3-((5-bromo-2-nitrophenyl)amino)azetidine-1-carboxylate (Intermediate 77-2)

The starting material 77-1 (1.07g, 4.85mmol) and benzyl 3-aminoazetidine-1-carboxylate (1g, 4.85mmol) were dissolved in tetrahydrofuran (15mL), and triethylamine (490.64mg) was added , 4.85mmol), the reaction solution was stirred at 25°C for 20h. LCMS detects the completion of the reaction. The reaction solution was diluted with water (100 mL), ethyl acetate (100 mL) was added for extraction three times, and the organic layer was concentrated to dryness under reduced pressure. The title compound (2g) was obtained.

MS m/z (ESI): 406.0 [M+H] ⁺ .

Step 2: Synthesis of benzyl 3-(6-bromo-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylate (Intermediate 77-3)

Intermediate 77-2 (650mg, 1.60mmol) was dissolved in anhydrous isopropanol (7mL), iron powder (893.56mg, 16.00mmol), ammonium chloride (855.90mg, 16.00mmol) and formic acid (3.76 g, 80.00mmol). Stir at room temperature for 10 min, raise the temperature to 100° C. and stir and react for 16 h. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by column chromatography (

12g

Silica gel column, 0-100% ethyl acetate/petroleum ether: 50 ml/min). The title compound (300 mg) was obtained.

MS m/z (ESI): 386.0 [M+H] ⁺ .

Step 3: 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl ) Synthesis of Azetidine-1-Benzyl carboxylate (Intermediate 77-4)

Intermediate 77-3 (300mg, 776.72μmol) was dissolved in 1,4-dioxane (4mL), double pinacol borate (295.86mg, 1.17mmol), potassium acetate (228.69mg, 2.33mmol) and Pd(dppf)Cl ₂ (56.83mg, 77.67μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was diluted with ethyl acetate (50 mL), the organic layer was extracted and washed with water three times (50 mL), and the organic layer was concentrated to dryness under reduced pressure. Purified by column chromatography (

12g

Silica gel column, 0-100% ethyl acetate/petroleum ether: 50 ml/min) to obtain the title compound (160 mg).

MS m/z (ESI): 434.1 [M+H] ⁺ .

Step 4: 3-(6-(8-(4-(difluoromethoxy)phenyl)-2-ethoxy-7-oxo-7,8-dihydropyrido[2,3-d ]Pyrimidine-6-yl)-1H-benzo[d]imidazol-1-yl)azetidine-1-carboxylic acid benzyl ester (Intermediate 77-5)

Intermediate 77-4 (160mg, 369.25μmol) and Intermediate 32-1 (100mg, 271.94μmol) were dissolved in 1,4-dioxane (2mL) and water (0.5mL), and cesium carbonate (177.20) was added mg, 543.87μmol) and Pd(dtbpf)Cl ₂ (17.72mg, 27.19μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative thin layer chromatography (silica, ethyl acetate: methanol = 30:1) to obtain the title compound (100 mg).

MS m/z (ESI): 639.5 [M+H] ⁺ .

Step 5: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-(1-methylazetidin-3-yl)-1H-benzo Synthesis of [d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 077)

Intermediate 77-5 (90 mg, 140.93 μmol) was dissolved in methanol (2 mL), palladium carbon (8.99 mg, 8.44 μmol, 10% purity) was added, and the reaction solution was stirred at 25° C. for 32 hours under a hydrogen atmosphere. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: Phenomenex Gemini C18 250*50mm*10μm; mobile phase: [water (0.05% ammonia v/v)-acetonitrile]; B%: 40%-60%, 9 minutes), The title compound (9.8 mg).

MS m/z (ESI): 519.2 [M+H] ⁺ .

¹ H NMR(400MHz, _{METHANOL-d 4} )δ8.95(s,1H), 8.50(s,1H), 8.25(s,1H), 8.05(s,1H), 7.77(d,J=8.0Hz, 1H), 7.66(d,J=8.0Hz,1H),7.47-7.42(m,2H),7.41-7.35(m,2H),6.98(t,J=73.8Hz,1H),5.23-5.16(m ,1H), 4.19(q,J=7.0Hz,2H),4.03-3.96(m,2H),3.74-3.65(m,2H),2.52(s,3H),1.32-1.22(m,3H)

Example 58, 8-(4-(difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-morpholinoethyl)-1H-benzo [d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 084)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-morpholinoethyl)-1H-benzo[ Synthesis of d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 084)

The starting material 84-1 (75.72mg, 203.95μmol, can be synthesized according to the method reported in WO 2016057834) and the intermediate 32-1 (50mg, 135.97μmol) were dissolved in dioxane (2mL) and water (0.5mL) In the reaction solution, cesium carbonate (88.60mg, 271.94μmol) and Pd(dtbpf)Cl ₂ (8.86mg, 13.60μmol) were added to the reaction solution, and the reaction solution was stirred at 90°C for 16h under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm; mobile phase: [A: water (0.05% ammonia v/v), B: acetonitrile]; B% : 45%-68%, 9 minutes) to obtain the title compound (15 mg).

MS m/z (ESI): 577.2 [M+H] ⁺ .

¹ H NMR (400MHz, Methanol-d ₄ ): δppm 8.93(s,1H), 8.21(s,1H), 7.90(s,1H), 7.69-7.63(m,1H), 7.62-7.55(m,1H) ), 7.48-7.41 (m, 2H), 7.40-7.33 (m, 2H), 6.80 (t, J = 74Hz, 1H), 4.20-4.15 (m, 2H), 3.87 (s, 3H), 3.79-3.70 (m, 4H), 3.19 (t, J = 7.5 Hz, 2H), 2.92 (t, J = 7.5 Hz, 2H), 2.78-2.60 (m, 4H), 1.26 (t, J = 7.2 Hz, 3H) .

Example 59, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-2-(2-morpholinoethyl)-1H-benzo [d]imidazol-6-yl)-1,8-naphthalazine-2(1H)-one (Compound 085)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-2-(2-morpholinoethyl)-1H-benzo[ d] Synthesis of imidazol-6-yl)-1,8-naphthalazine-2(1H)-one (Compound 085)

The starting material 84-1 (67.72mg, 182.39μmol) and the intermediate 38-4 (50mg, 121.60μmol) were dissolved in dioxane (2mL) and water (0.5mL), and cesium carbonate was added to the reaction solution (79.24mg, 243.19μmol) and Pd(dtbpf)Cl ₂ (7.92mg, 12.16μmol), the reaction solution was stirred at 90°C for 16h under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was filtered, concentrated to dryness under reduced pressure, and purified by preparative HPLC (column: Gemini NX C18 5μm*10*150mm; mobile phase: (A: 0.05% ammonia (v/v), B: acetonitrile; B%: 53 %-73%, 9 minutes), to obtain the title compound (28.1 mg).

MS m/z (ESI): 576.3 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.22(s,1H), 8.16(d,J=8.5Hz,1H), 7.90(s,1H), 7.60-7.54(m,1H), 7.52 -7.48(m,1H),7.46-7.39(m,2H),7.34(d,J=74Hz,1H),7.39-7.30(m,2H),6.72(d,J=8.3Hz,1H),3.95 (q,J=7.0Hz,2H),3.76(s,3H),3.61-3.56(m,4H),3.11-3.02(m,2H),2.82-2.75(m,2H),2.49-2.45(m , 4H), 1.09 (t, J = 7.0 Hz, 3H).

Example 60, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1 -Methyl-1H-benzo[d]imidazol-6-yl)-1,8-naphthalazine-2(1H)-one (Compound 086)

Step 1: Synthesis of 2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate (Intermediate 86-2)

The starting material 86-1 (2g, 7.84mmol) was dissolved in dichloromethane (28mL), triethylamine (1.59g, 15.68mmol) was added to the mixed solution, and the temperature of the reaction solution was reduced to 0°C. Methanesulfonyl chloride (1.08g, 9.41mmol) was slowly added to the solution, and the reaction solution was stirred at 25°C for 1h under nitrogen protection. LC-MS detects that the reaction is complete. The reaction solution was extracted with dichloromethane and water, the organic phase was washed three times with water, and after removing excess water with anhydrous sodium sulfate, it was concentrated under reduced pressure to dryness to obtain compound 2 (2.6 g).

MS m/z (ESI): 333.0 [M+H] ⁺ .

Step 2: Synthesis of 1-(2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)pyrrolidin-3-ol (Intermediate 86-3)

Intermediate 86-2 (1.3g, 3.90mmol) and 3-hydroxypyrrolidine (679.81mg, 7.80mmol) were dissolved in methanol (17mL), and triethylamine (789.59mg, 7.80mmol) was added to the mixture. Stir at 40°C for 16h under nitrogen protection. LC-MS detects that the reaction is complete. After the reaction was cooled to room temperature and concentrated under reduced pressure to remove methanol, it was extracted with ethyl acetate (30 mL) and water (60 mL), and the organic phase was washed three times with water (20 mL X 3). The title compound (1.18 g) was obtained by preparative column chromatography (dichloromethane: methanol = 50:1 to 10:1).

MS m/z (ESI): 324.1 [M+H] ⁺ .

Step 3: 6-Bromo-2-(2-(3-((tert-butyldiphenylsilyl)oxo)pyrrolidin-1-yl)ethyl)-1-methyl-1H-benzo[ d) Synthesis of imidazole (Intermediate 86-4)

Intermediate 86-3 (500mg, 1.54mmol) was dissolved in anhydrous dichloromethane (7mL), to which was added triethylamine (1.59g, 15.68mmol), 4-dimethylaminopyridine (18.84mg, 154.22μmol) ) And tert-butyldiphenylchlorosilane (508.66mg, 1.85mmol), the reaction solution was stirred at 25°C for 16h under nitrogen protection. LC-MS detects that the reaction is complete. The reaction solution was extracted with water (60 mL) and dichloromethane (20 mL), the organic phase was washed twice with water (20 mL*2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The title compound (600 mg) was obtained by preparative column chromatography (silica, dichloromethane: methanol = 100:1 to 10:1).

MS m/z (ESI): 562.2 [M+H] ⁺ .

Step 4: 2-(2-(3-((tert-butyldiphenylsilyl)oxo)pyrrolidin-1-yl)ethyl)-1-methyl-6-(4,4,5, Synthesis of 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (Intermediate 86-5)

Intermediate 86-4 (590mg, 1.05mmol) and double pinacol borate (532.60mg, 2.10mmol) were dissolved in anhydrous 1,4-dioxane (10mL), and Pd was added to the mixture (dppf) Cl ₂ (38.37mg, 52.43μmol) and potassium acetate (308.76mg, 3.15mmol), the reaction solution was stirred at 100°C for 16h under nitrogen protection. LC-MS detects that the reaction is complete. After the reaction was cooled to room temperature, it was extracted with water (100 mL) and ethyl acetate (50 mL), the organic phase was washed twice with water (100 mL*2), the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The title compound (350 mg) was obtained by preparative column chromatography (silica, dichloromethane: methanol = 40:1 to 10:1).

MS m/z (ESI): 610.4 [M+H] ⁺ .

¹ H NMR (400MHz, Methanol-d ₄ ): δppm 7.69-7.61 (m, 6H), 7.48-7.35 (m, 7H), 4.52-4.43 (m, 1H), 3.83 (s, 3H), 3.19-2.94 (m, 5H), 2.83-2.68 (m, 3H), 2.08-1.98 (m, 1H), 1.94-1.83 (m, 1H), 1.39 (s, 12H), 1.07 (s, 9H).

Step 5: 3-(2-(2-(3-((tert-butyldiphenylsilyl)oxo)pyrrolidin-1-yl)ethyl)-1-methyl-1H-benzo[d ]Imidazol-6-yl)-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-1,8-naphthalene-2(1H)-one (Intermediate 86- 6) Synthesis

Intermediate 86-5 (111.20 mg, 182.39 μmol) and intermediate 38-4 (50 mg, 121.60 μmol) were dissolved in anhydrous dioxane (2 mL) and water (0.5 mL), and cesium carbonate was added to the mixture (79.24mg, 243.19μmol) and Pd(dtbpf)Cl ₂ (7.92mg, 12.16μmol), the reaction solution was stirred at 90°C for 16h under the protection of nitrogen. LC-MS detects that the reaction is complete. After the reaction was cooled to room temperature, water (40mL) and ethyl acetate (20mL) were added successively, the organic phase was washed with water (20mL*2), the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain the title Compound (98mg).

MS m/z (ESI): 814.4 [M+H] ⁺ .

Step 6: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1- Synthesis of methyl-1H-benzo[d]imidazol-6-yl)-1,8-naphthalazine-2(1H)-one (Compound 086)

Intermediate 86-6 (98mg, 120.39μmol) and anhydrous tetrahydrofuran (2mL) were added to the reaction solution with tetrabutylammonium fluoride (1M, 180.59μL), and the reaction solution was stirred at 25°C for 16h under nitrogen protection. LC-MS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm; mobile phase: water (0.05% ammonia v/v)-acetonitrile; B is acetonitrile, B%: 55%- 78%, 9 minutes) to obtain the title compound (4.1 mg).

MS m/z (ESI): 576.2 [M+H] ⁺ .

¹ H NMR (400MHz, Methanol-d ₄ ): δ8.17 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.90 (s, 1H), 7.70-7.63 (m, 1H), 7.60 -7.55(m,1H),7.45-7.32(m,4H), 6.96(t,J=74.4Hz,1H), 6.71(d,J=8.5Hz,1H),4.45-4.34(m,1H), 4.03(q,J=7.0Hz,2H),3.87(s,3H),3.27-3.16(m,2H),3.10-3.05(m,2H),2.99-2.89(m,2H),2.76-2.66( m,2H),2.25-2.16(m,1H),1.82-1.77(m,1H),1.17(t,J=7.0Hz,3H).

Example 61, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1 -Methyl-1H-benzo[d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 091)

Step 1: 1-(2-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo Synthesis of [d]imidazol-2-yl)ethyl)pyrrolidin-3-ol (Intermediate 91-1)

Intermediate 86-3 (300mg, 925.31μmol) and double pinacol borate (352.46mg, 1.39mmol) were dissolved in 1,4-dioxane (7mL), and Pd( dppf) Cl ₂ (67.71 mg, 92.53 μmol) and potassium acetate (272.44 mg, 2.78 mmol), and the reaction solution was stirred at 100° C. for 16 h under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was extracted with ethyl acetate (20mL) and water (40mL), the organic phase was washed twice with water (20mL*2), and after removing excess water with anhydrous sodium sulfate, it was concentrated under reduced pressure to dryness, and was subjected to preparative thin-layer chromatography. (Ethyl acetate: methanol = 20:1) to obtain the title compound (60 mg).

MS m/z (ESI): 372.2 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-(3-hydroxypyrrolidin-1-yl)ethyl)-1- Synthesis of methyl-1H-benzo[d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 091)

Intermediate 91-1 (45mg, 121.20μmol) and intermediate 32-1 (37.14mg, 101.00μmol) were dissolved in 1,4-dioxane (2mL) and water (0.5mL), and added to the mixture Pd(dtbpf)Cl ₂ (6.58mg, 10.10μmol) and cesium carbonate (65.82mg, 202.00μmol), the reaction solution was stirred at 90°C for 16 hours under the protection of nitrogen. LC-MS detects that the reaction is complete. After the reaction was cooled to room temperature and concentrated under reduced pressure to remove dioxane, it was extracted with ethyl acetate (5 mL) and water (15 mL), and the organic phase was washed three times with water (5 mL*3). Purified by HPLC (column: Gemini-NX 150*30mm*5μm; mobile phase: water (0.225% formic acid)-acetonitrile; B is acetonitrile, B%: 35%-55%, retention time: 9min) to obtain the title compound ( 2.2mg).

MS m/z (ESI): 577.2 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ ):δ8.89(s,1H),8.54(s,0.65H, H COOH), 8.18(s,1H),7.90(s,1H),7.71-7.64( m,1H),7.61-7.55(m,1H),7.45-7.40(m,2H),7.39-7.34(m,2H),6.98(t,J=74Hz,1H),4.18(q,J=7.0 Hz, 2H), 3.85 (s, 3H), 3.55-3.47 (m, 2H), 3.46-3.39 (m, 1H), 3.39-3.33 (m, 2H), 3.32-3.16 (m, 4H), 2.32 2.25(m,1H),2.06-1.94(m,1H), 1.26(t,J=7.1Hz,3H).

Example 62, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-hydroxy-1-methyl-1H-benzo[d]imidazol-6-yl )Pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 067)

Step 1: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-hydroxy-1-methyl-1H-benzo[d]imidazol-6-yl) Synthesis of pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 067)

Dissolve reactant 67-1 (55.91mg, 203.95μmol) and reactant 32-1 (50mg, 135.97μmol) in 1,4-dioxane (0.8mL) and water (0.2mL), add cesium carbonate (88.60mg, 271.94μmol) and Pd(dtbpf)Cl ₂ (8.86mg, 13.60μmol). Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by preparative liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [A: water (0.05% ammonia v/v), B: acetonitrile]; B is acetonitrile, B% : 42%-62%, 11 minutes). The title compound (14.8 mg) was obtained.

MS m/z (ESI): = 480 [M+H] ⁺ .

¹ H NMR (400MHz, METHANOL-d ₄ ) δppm 8.93 (s, 1H), 8.17 (s, 1H), 7.52 (s, 1H), 7.47-7.41 (m, 3H), 7.40-7.35 (m, 2H) ,7.17-7.14(m,1H),6.97(t,J=72Hz,1H),4.18(q,J=7.0Hz,2H),3.44(s,3H),1.26(t,J=7.2Hz,3H )

Example 63, 8-(4-(Difluoromethoxy)phenyl)-2-methoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrido[ 2,3-d)pyrimidin-7(8H)-one (Compound 068)

Step 1: 6-Chloro-8-(4-(difluoromethoxy)phenyl)-2-methoxypyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate 63- 1) Synthesis

The reactant 3-1 (480 mg, 1.197 mmol) was dissolved in methanol (5 ml), and a methanol solution of sodium methoxide (0.44 mL, 2.40 mmol) was slowly dropped into it. The reaction was stirred at 25°C for 30 min. LCMS monitoring showed that the reaction was complete. After concentration under reduced pressure, it was diluted with water (10ml) and extracted with ethyl acetate (5ml*3). The obtained organic phase was dried and concentrated under reduced pressure to obtain the crude title compound (380 mg). Used directly in the next reaction.

MS m/z (ESI): = 354 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-methoxy-6-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrido[2 Synthesis of ,3-d]pyrimidine-7(8H)-one (Compound 063)

Intermediate 63-1 (100 mg, 0.283 mmol) and intermediate 63-2 (87.8 mg, 0.34 mmol) were dissolved in dioxane (2ml) and water (1ml). Cesium carbonate (277.0 mg, 0.849 mmol) was added thereto under the protection of nitrogen, and then Pd(dtbpf)Cl ₂ (18.44 mg, 0.028 mmol) was added. The reaction solution was heated to 90°C and reacted for 15 hours. After the reaction was completed, it was cooled to room temperature, water (2 ml) was added thereto, and extracted with ethyl acetate (5 mL*3). The obtained organic phase was spin-dried under reduced pressure to obtain a yellow oil. Pass HPLC-PREP [YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH ₄ HCO ₃ ) and a mixture of decreasing polarity of acetonitrile as eluent; gradient ratio of acetonitrile 60% -72%, elution time 12 minutes] to obtain the title compound (41 mg).

MS m/z (ESI): = 450.1 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ9.06(s,1H),8.33(s,1H),8.27(s,1H),7.99-7.98(m,1H),7.74-7.72(m,1H) ), 7.60-7.21 (m, 6H), 3.88 (s, 3H), 3.80 (s, 3H).

Example 64, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(6-methoxypyridin-3-yl)-1,8-naphthalene- 2(1H)-ketone (Compound 071)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(6-methoxypyridin-3-yl)-1,8-naphthalene-2 Synthesis of (1H)-ketone (Compound 071)

Under a nitrogen atmosphere, intermediate 38-4 (50 mg, 121.95 μmol) and reactant 71-1 (42.9 mg, 182.92 μmol) were dissolved in dioxane (0.8 mL) and water (0.4 mL). Cesium carbonate (118.9 mg, 365.85 μmol) was added thereto, followed by Pd(dtbpf)Cl ₂ (10 mg, 12.36 μmol). The reaction solution was stirred at 90°C for 15 hours. TLC monitors the completion of the reaction. The reaction solution is cooled to room temperature, filtered, and the filtrate is passed through HPLC-PREP [YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH ₄ HCO ₃ ) and acetonitrile The mixture of decreasing polarity was used as the eluent; the gradient ratio of acetonitrile was 60%-72%, and the elution time was 12 minutes] to obtain the title compound (7.2 mg).

MS m/z (ESI): = 440.2 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.55(d,J=2.4Hz,1H), 8.26(s,1H), 8.16(d,J=8.4Hz,1H), 8.09(dd,J= 8.7,2.5Hz,1H),7.49–7.40(m,2H),7.36(d,J=8.4Hz,3H), 6.91(d,J=8.6Hz,1H), 6.75(d,J=8.4Hz, 1H), 4.05-3.97 (m, 2H), 3.92 (s, 3H), 1.11 (t, J = 7.0Hz, 3H).

Example 65, 3-(benzo[d]oxazol-6-yl)-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-1,8-naphthalene -2(1H)-ketone (Compound 073)

Step 1: 3-(Benzo[d]oxazol-6-yl)-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-1,8-naphthalene- Synthesis of 2(1H)-one (Compound 073)

Under a nitrogen atmosphere, reactant 73-1 (89.5 mg, 0.37 mmol) and intermediate 38-4 (100 mg, 0.24 mmol) were dissolved in dioxane solution (5 mL), water (1 mL), carbonic acid Cesium (158.6mg, 0.48mmol) and Pd(dtbpf)Cl ₂ (15mg, 0.02mmol) were added and heated to 100°C and stirred for 12h. LCMS showed that the reaction was over. The reaction system was filtered. After the filtrate was concentrated under reduced pressure, the residue was dissolved in MeCN (2mL) and filtered, and purified by high-pressure preparation [YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water A mixture of decreasing polarity (containing 0.05% NH ₄ HCO ₃ ) and acetonitrile was used as the eluent; the gradient ratio of acetonitrile was 50%-82%, and the elution time was 14 minutes] to obtain the title compound (7 mg).

MS m/z (ESI): = 450.1 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.23-8.03(m,1H),7.92(s,1H),7.83(dd,J=11.4,8.4Hz,1H),7.72(d,J=1.6 Hz, 1H), 7.32 (q, J = 9.0 Hz, 3H), 6.77-6.40 (m, 3H), 4.00 (q, J = 7.1 Hz, 2H), 1.18 (t, J = 7.0 Hz, 3H).

Example 66, 6-(1-(2-aminoethyl)-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethyl Oxypyrido[2,3-d]pyrimidin-7(8H)-one (Compound 074)

Step 1: (2-(6-(8-(4-(difluoromethoxy)phenyl)-2-ethoxy-7-carbonyl-7,8-dihydropyrido[2,3-d ]Pyrimidine-6-yl)-1H-benzo[d]imidazol-1-yl)ethyl)benzyl carbamate (Intermediate 74-2)

Reactant 74-1 (171.85mg, 407.90μmol, can be synthesized according to the similar method of patent WO 2010027500) and intermediate 32-1 (100mg, 271.94μmol) were dissolved in 1,4-dioxane (2mL) and water ( 0.5 mL), cesium carbonate (177.20 mg, 543.87 μmol) and Pd(dtbpf)Cl ₂ (17.72 mg, 27.19 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative thin layer chromatography (silica, ethyl acetate: methanol = 30:1) to obtain the title compound (100 mg).

MS m/z (ESI): = 627 [M+H] ⁺ .

Step 2: 6-(1-(2-Aminoethyl)-1H-benzo[d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxy Synthesis of pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 074)

The reactant 74-2 (90mg, 140.93μmol) was dissolved in tetrahydrofuran (1.5mL), wet palladium carbon (200.00mg, 187.93μmol, 10% purity) was added, and hydrogen (15psi) was added to the reaction system at room temperature. The reaction solution The reaction was stirred at 25°C for 48 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: Phenomenex Gemini C18 250*50mm*10μm; mobile phase: [A: water (0.05% ammonia v/v), B: acetonitrile]; B is acetonitrile, B%: 38%- 58%, 9 minutes), to obtain the title compound (5.9 mg).

MS m/z (ESI): = 493 [M+H] ⁺ .

¹ H NMR(400MHz, _{METHANOL-d 4} )δ8.95(s,1H), 8.26(d,J=5.5Hz,2H), 8.05(s,1H), 7.77(d,J=8.5Hz,1H) ,7.65(dd,J=1.6,8.4Hz,1H),7.47-7.42(m,2H),7.41-7.35(m,2H),6.98(t,J=73.8Hz,1H), 4.40(t,J ＝6.3Hz,2H), 4.20(q,J＝7.0Hz,2H), 3.15(t,J＝6.3Hz,2H), 1.27(t,J＝7.2Hz,3H)

Example 67, 1-(4-(difluoromethoxy)phenyl)-7-ethoxy-3-(4-(2-(methylamino)ethoxy)phenyl)-1,8 -Naphthalene-2(1H)-one (Compound 078)

Step 1: (2-(4-(1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-2-carbonyl-1,2-dihydro-1,8-diazepine Synthesis of tert-butyl (naphth-3-yl)phenoxy)ethyl)(methyl)carbamate (Intermediate 76-2)

Under a nitrogen atmosphere, reactant 38-4 (110mg, 0.26mmol), reactant 78-1 (140mg, 0.37mmol, can be prepared and synthesized according to the patent WO2013183578 report method), Pd(dtbpf)Cl2 (20mg, 0.03mmoL) And Cs ₂ CO ₃ (240 mg, 0.78 mmol) were added to dioxane (1 mL) and H ₂ O (0.2 mL). The reaction solution was stirred at 100°C for 1 h. TLC detects the completion of the reaction. The reaction solution was diluted with water (10mL), extracted with ethyl acetate (20mL*3), the organic phases were combined, dried, and purified by column chromatography (petroleum ether: ethyl acetate=1:1), the product was collected, and concentrated under reduced pressure The title compound (100 mg) was obtained.

MS m/z (ESI): = 582 [M+H] ⁺ .

Step 2: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(4-(2-(methylamino)ethoxy)phenyl)-1,8- Synthesis of naphthalene-2(1H)-one (Compound 078)

Reactant 78-2 (100 mg, 0.17 mmol) was dissolved in TFA (0.5 mL) and DCM (0.5 mL). Stir at room temperature for 1 hour, and TLC detects that the reaction is complete. The reaction solution was concentrated under reduced pressure, and the residue was passed through HPLC-PREP (YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH ₄ HCO ₃ ) and a mixture of decreasing polarity of acetonitrile as Eluent; acetonitrile gradient ratio 60%-75%, elution time 12 minutes) to obtain the title compound (13.2mg).

MS m/z (ESI): = 482 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.17--8.10 (m, 2H), 7.73-7.65 (m, 2H), 7.45-7.31 (m, 5H), 7.04-6.96 (m, 2H), 6.72 (d,J=8.4Hz,1H),4.07(t,J=5.6Hz,2H), 4.00–3.89(m,2H), 2.87(t,J=5.6Hz,2H), 2.37(s,3H) ,1.09(t,J=7.0Hz,3H).

Example 68, 1-(4-(Difluoromethoxy)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)-7-ethoxy-1,8 -Naphthalene-2(1H)-one (Compound 079)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-3-(4-(2-(dimethylamino)ethoxy)phenyl)-7-ethoxy-1,8- Synthesis of Naphthyridine-2(1H)-one (Compound 079)

Intermediate 38-4 (60 mg, 0.146 mmol) and reactant 79-1 (51.1 mg, 0.176 mmol) were dissolved in dioxane (1 ml) and water (0.5 ml). Cesium carbonate (144.0 mg, 0.442 mmol) was added thereto under the protection of nitrogen, and then Pd(dtbpf)Cl ₂ (12.0 mg, 0.018 mmol) was added. The reaction solution was heated to 90°C and stirred for 15 hours. After the reaction was completed, it was cooled to room temperature, water (2 ml) was added thereto, and extracted with ethyl acetate (5 mL*3). The combined organic phases were concentrated under reduced pressure, and the residue was passed through HPLC-PREP [YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH ₄ HCO ₃ ) and the polarity of acetonitrile The decreasing mixture was used as the eluent; the gradient ratio of acetonitrile was 60%-72%, and the elution time was 12 minutes] to obtain the title compound (25 mg).

MS m/z (ESI): =496 [M+H] ⁺ .

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.16-8.15 (m, 2H), 7.71-7.69 (m, 2H), 7.56-7.19 (m, 5H), 7.03-7.00 (m, 2H), 6.73 (d,J=8.4Hz,1H), 4.11(t,J=5.8Hz,2H),3.96-3.95(m,2H),2.66(t,J=5.8Hz,2H),2.25(s,6H) ,1.10(t,J=7.0Hz,3H).

Example 69, 1-(4-(difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-2-((methyl(oxbutan-3-ylmethyl )Amino)methyl)-1H-benzo(d)imidazol-6-yl)-1,8-naphthalene-2(1H)-one (Compound 089)

Step 1: Synthesis of ((6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)methoxy)ethylsulfonate (Intermediate 89-2)

Reactant 89-1 (100 mg, 0.415 mmol) was dissolved in tetrahydrofuran solution (5 mL), and triethylamine (62.9 mg, 0.622 mmol) was added. Under ice-water bath, add ethyl sulfonyl chloride (79.99 mg, 3.79 mmol) to the above reaction solution, and stir at 20°C for 4 hours. LCMS showed that the reaction was over, the reaction solution was poured into water (10mL), extracted with EA (15mL*2), the organic phase was washed with saturated brine (20mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound (137.8mg), directly used in the next reaction.

MS m/z (ESI): =330 [M+H] ⁺ .

Step 2: 1-(6-Bromo-1-methyl-1H-benzo[d]imidazol-2-yl)-N-methyl-N-(oxbutacyclo-3-ylmethyl)methylamine ( Intermediate 89-4) Synthesis

Reactant 89-2 (137.8 mg, crude product), potassium carbonate (114.7 mg, 0.83 mmol) and reactant 89-3 (63 mg, 0.623 mmol) were dissolved in acetonitrile solution (2 mL). After the addition, stir at 25°C for 4h. LCMS showed that the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title compound (134.5 mg).

MS m/z (ESI): = 324 [M+H] ⁺ .

Step 3: N-methyl-1-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- Synthesis of Benzo[d]imidazol-2-yl)-N-(oxbutan-3-ylmethyl)methylamine (Intermediate 89-5)

Under a nitrogen atmosphere, reactant 89-4 (134.5mg, crude product) was dissolved in dioxane solution (2mL), and double pinacol borate (158mg, 0.623mmol), potassium acetate (122.2mg) were added , 1.245mmol) and Pd(dppf)Cl ₂ (45.36mg, 0.062mmol), after the addition, the temperature was raised to 100°C and stirred for 4h. TLC showed that the reaction was complete, the reaction solution was filtered, the filtrate was spin-dried, and column chromatography (DCM/MeOH=20/1-10/1) was performed. The filtrate was concentrated under reduced pressure to obtain the title compound (30 mg).

Step 4: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-2-((methyl(oxbutacyclo-3-ylmethyl) (Amino)methyl)-1H-benzo(d]imidazol-6-yl)-1,8-naphthalene-2(1H)-one (Compound 089)

Under a nitrogen atmosphere, reactant 89-5 (28.0 mg, 0.075 mmol) was dissolved in dioxane solution (0.4 mL), and reactant 38-4 (35.0 mg, 0.083 mmol), cesium carbonate (48.87 mg, 0.15mmol), water (0.1mL) and Pd(dtbpf)Cl ₂ (7.33mg, 0.011mmol), after the addition, the temperature was raised to 100°C and stirred for 2h. LCMS showed that the reaction was over, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was prepared and purified by high pressure [YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH ₄ HCO ₃ ) and A mixture of acetonitrile with decreasing polarity was used as the eluent; the gradient ratio of acetonitrile was 45%-72%, and the elution time was 12 minutes] to obtain the title compound (10mg)

MS m/z (ESI): = 576.2 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δ8.17(s,1H), 8.07(d,J＝8.5Hz,1H), 7.93(d,J＝1.5Hz,1H), 7.68(d,J＝ 8.4Hz, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.49-7.21 (m, 4H), 6.94 (t, J = 73.8 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H) ,4.77(dd,J=7.8,6.0Hz,2H),4.78(s,1H), 4.34(t,J=6.1Hz,2H),4.01(q,J=7.0Hz,2H), 3.89(d, J = 6.2Hz, 5H), 2.85 (d, J = 7.6Hz, 2H), 2.26 (s, 3H), 1.15 (t, J = 7.0Hz, 3H).

Example 70, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-2-(((tetrahydrofuran-3-yl)oxo)methyl )-1H-Benzo[d]imidazol-6-yl)-1,8-naphthalazine-2(1H)-one (Compound 090)

Step 1: Synthesis of 6-bromo-2-(chloromethyl)-1-methyl-1H-benzo[d]imidazole (Intermediate 90-2)

Reactant 90-1 (500 mg, 2.07 mmol) was dissolved in tetrahydrofuran solution (5 mL). Under an ice-water bath, triethylamine (418.9 mg, 4.14 mmol) and ethylsulfonyl chloride (399.9 mg, 3.11 mmol) were added to the above reaction solution in sequence. Then, move to 20 degrees and continue to stir for 4 hours. LCMS indicated the end of the reaction, the reaction solution was poured into water (15 mL), and extracted with EA (20 mL*2). The combined organic phase was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound (200.0 mg).

MS m/z (ESI): = 259 [M+H] ⁺ .

Step 2: Synthesis of 6-bromo-1-methyl-2-(((tetrahydrofuran-3-yl)oxo)methyl)-1H-benzo[d]imidazole (Intermediate 90-4)

Dissolve reactant 90-2 (200.0mg, crude product) in toluene solution (2mL), add NaH (46.5mg, 60%wt, 1.16mmol) at 0-10 degrees, stir for 0.5h after addition, add reactant 90 -3 (81.96mg, 0.93mmol). Subsequently, the temperature was raised to 100 degrees and stirred for 4 hours. LCMS indicated the end of the reaction, the reaction solution was poured into saturated ammonium chloride (100 mL), and extracted with EA (100 mL*2). The combined organic phase was washed with saturated brine (200 mL*2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude title compound (240.0 mg).

MS m/z (ESI): = 311 [M+H] ⁺ .

Step 3: 1-methyl-2-(((tetrahydrofuran-3-yl)oxo)methyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Synthesis of pentyl-2-yl)-1H-benzo[d]imidazole (Intermediate 90-5)

Under a nitrogen atmosphere, the reactant 90-4 (240.0 mg, crude product) was dissolved in dioxane solution (3 mL), and double pinacol borate (295.3 mg, 1.163 mmol), potassium acetate (152 mg) were added , 1.55mmol) and Pd(dppf)Cl ₂ (84.85mg, 0.116mmol). After the addition, the temperature was raised to 100 degrees and stirred for 4 hours. TLC monitoring showed that the reaction was complete, the reaction solution was filtered, the filtrate was spin-dried, and the concentrated residue was purified by column chromatography (DCM/MeOH=20/1-10/1) and concentrated under reduced pressure to obtain the title compound (250 mg).

Step 4: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-methyl-2-(((tetrahydrofuran-3-yl)oxo)methyl) Synthesis of -1H-benzo[d]imidazol-6-yl)-1,8-naphthalazine-2(1H)-one (Compound 090)

Under a nitrogen atmosphere, reactant 90-5 (100.0 mg, 0.279 mmol) was dissolved in dioxane (2 mL). Subsequently, reactant 38-4 (126.3 mg, 0.307 mmol), cesium carbonate (181.8 mg, 0.558 mmol), water (0.5 mL) and Pd(dtbpf)Cl ₂ (27.3 mg, 0.042 mmol) were added. After the addition, the temperature was raised to 100 degrees and stirred for 2 hours. LCMS showed that the reaction was complete, the reaction solution was filtered, and after concentration under reduced pressure, the residue was purified by high pressure preparation to obtain the title compound (12 mg).

MS m/z (ESI): =563 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δ8.16(s,1H), 8.06(d,J＝8.5Hz,1H), 7.93(dd,J＝1.6,0.7Hz,1H), 7.68(dd, J = 8.5, 0.7 Hz, 1H), 7.61 (dd, J = 8.5, 1.6 Hz, 1H), 7.42–7.30 (m, 4H), 6.93 (t, J = 73.9 Hz, 1H), 6.68 (d, J =8.4Hz,1H), 4.93–4.82(m,2H), 4.32(dd,J=4.2,1.7Hz,1H),4.01(q,J=7.0Hz,2H), 3.89–3.73(m,7H) ,2.06–2.04(m,2H),1.15(t,J=7.1Hz,3H).

Example 71, 1-(4-(Difluoromethoxy)phenyl)-3-(2-(2-((2R,6S)-2,6-dimethylmorpholino)ethyl)- 2H-indazol-5-yl)-7-ethoxy-1,8-naphthalazine-2(1H)-one (Compound 092)

Step 1: Synthesis of 2-((2S,6R)-2,6-dimethylmorpholino)acetonitrile (Intermediate 92-2)

The reactant 92-1 (5g, 43.41mmol) and potassium carbonate (6.60g, 47.75mmol) were dissolved in acetonitrile (150mL), and 2-bromoacetonitrile (5.21g, 43.41mmol) was added dropwise under the protection of nitrogen at 0°C. The reaction was stirred at 0°C for 30 minutes. The temperature of the reaction system was raised to 25°C and the reaction was stirred at 25°C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (150 mL), extracted three times with 450 mL of ethyl acetate (150 mL*3), the organic phase was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude title compound (5.95 g) was obtained.

MS m/z (ESI): = 155.0 [M+H] ⁺ .

Step 2: Synthesis of 2-((2S,6R)-2,6-dimethylmorpholino)ethylamine (Intermediate 92-3)

Intermediate 92-2 (1g, 6.48mmol) was dissolved in tetrahydrofuran (30mL), tetrahydrolithium aluminum (738.37mg, 19.45mmol) was added under nitrogen protection at 0℃～5℃, and the reaction was stirred at 0℃ for 1 hour. The temperature of the reaction system was raised to 25°C, and the reaction was stirred for 3 hours. LC-MS showed that the reaction was complete. The reaction solution was quenched with water (1mL) at 0°C and stirred for 20 minutes, then 20% aqueous sodium hydroxide solution (2mL) and water (1mL) were added, stirred at 0°C for 20 minutes, filtered, and concentrated to dryness under reduced pressure to obtain Crude title compound (1.09 g).

¹ H NMR(400MHz,METHANOL-d ₄ )δ=3.62-3.51(m,2H),2.71-2.60(m,4H), 2.32(t,J=6.6Hz,2H),1.62(t,J=10.9 Hz, 2H), 1.04 (s, 3H), 1.02 (s, 3H).

Step 3: Synthesis of (2S,6R)-4-(2-(5-bromo-2H-indazol-2-yl)ethyl)-2,6-dimethylmorpholine (Intermediate 92-4)

Intermediate 92-3 (1.09g, 6.89mmol) and 5-bromo-2-nitrobenzaldehyde (1.74g, 7.58mmol) were dissolved in isopropanol (25mL), the temperature of the reaction system was raised to 80°C and The reaction was stirred at 80°C for 4 hours. Tributylphosphine (4.18g, 20.66mmol, 5.10mL) was added dropwise at 25°C, and the reaction was stirred at 80°C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was decompressed to remove isopropanol and separated by column chromatography (

40g

Fast silica gel column, eluent 0-28% ethyl acetate/petroleum ether, gradient @50ml/min) to obtain the title compound (2.33g).

MS m/z (ESI): = 340.0 [M+H] ⁺ .

Step 4: (2S,6R)-2,6-dimethyl-4-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Synthesis of 2-yl)-2H-indazol-2-yl)ethyl)morpholine (Intermediate 92-5)

Intermediate 92-4 (200mg, 591.29μmol) and B ₂ Pin ₂ (180.18mg, 709.55μmol) were dissolved in dioxane (6mL), and Pd(dppf)Cl ₂ (43.27mg) was added under nitrogen protection at 25℃. , 59.13μmol) and KOAc (174.09mg, 1.77mmol), the temperature of the system was raised to 100°C and the reaction was stirred at 100°C for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (20mL), extracted three times with ethyl acetate 60mL (20mL*3), the organic phase was dried over sodium sulfate, filtered, concentrated under reduced pressure to dryness, and separated by column chromatography (

12g

Fast silica gel, eluent 0-6% ethyl acetate/petroleum ether, gradient @40 ml/min) to obtain the title compound (227 mg).

MS m/z (ESI): = 386.2 [M+H] ⁺ .

Step 5: 1-(4-(Difluoromethoxy)phenyl)-3-(2-(2-((2R,6S)-2,6-dimethylmorpholino)ethyl)-2H -Indazol-5-yl)-7-ethoxy-1,8-naphthalene-2(1H)-one (Compound 092) Synthesis

Intermediate 38-4 (50mg, 121.60μmol) and intermediate 92-5 (124.94mg, 243.19μmol, 75% purity) were dissolved in dioxane (1mL), and Pd(dtbpf)Cl _{2 was added under nitrogen protection} (7.92mg, 12.16umol) and cesium carbonate (79.24mg, 243.19μmol) were dissolved in water (0.25mL). The temperature of the system was raised to 90℃ and the reaction was stirred at 90℃ for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (10mL) and extracted three times with 30mL of ethyl acetate (10mL*3). The organic phase was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The concentrate was purified by high performance liquid chromatography (column: Boston Prime C18 150*30mm*5μm; mobile phase: water (0.05% ammonia v/v)-acetonitrile; B is acetonitrile, B%: 53%-73%, 9 minutes) to obtain the title compound (20.8 mg).

¹ H NMR(400MHz,METHANOL-d ₄ )δ=8.32(s,1H),8.11(s,1H), 8.08(s,1H), 8.05(d,J=8.5Hz,1H), 7.64(s, 2H), 7.41-7.33 (m, 4H), 6.95 (t, J = 73.6 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 4.59 (t, J = 6.4 Hz, 2H), 4.01 ( q, J = 7.0Hz, 2H), 3.69-3.58 (m, 2H), 2.94 (t, J = 6.5 Hz, 2H), 2.80 (d, J = 10.5 Hz, 2H), 1.83 (t, J = 10.8 Hz, 2H), 1.16 (t, J = 7.0 Hz, 3H), 1.13 (s, 3H), 1.11 (s, 3H).

MS m/z (ESI): =590.2 [M+H] ⁺ .

Example 72, 1-(4-(Difluoromethoxy)phenyl)-3-(2-(2-((2S,6S)-2,6-dimethylmorpholino)ethyl)- 2H-indazol-5-yl)-7-ethoxy-1,8-naphthalene-2(1H)-one (Compound 093)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-3-(2-(2-((2S,6S)-2,6-dimethylmorpholino)ethyl)-2H -Indazol-5-yl)-7-ethoxy-1,8-naphthalazine-2(1H)-one (Compound 093) Synthesis

Intermediate 93-1 (70.28mg, 182.39μmol, can be prepared according to the synthesis method of intermediate 92-5) and intermediate 38-4 (50mg, 121.60μmol) were dissolved in 1,4-dioxane (2mL) and In water (0.5 mL), cesium carbonate (79.24 mg, 243.19 μmol) and Pd(dtbpf)Cl ₂ (8.86 mg, 13.60 μmol) were added. Under the protection of nitrogen, the reaction solution was stirred and reacted at 100°C for 16 hours. LCMS detects the completion of the reaction. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated to dryness under reduced pressure. Purified by preparative liquid chromatography (column: Phenomenex Gemini-NX150*30mm*5μm; mobile phase: [water (0.04% ammonia + 10mM ammonium bicarbonate)-methanol]) ; B is acetonitrile, B%: 70%-90%, 9 minutes). The title compound (16.2mg) was obtained.

MS m/z (ESI): =590 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δppm 8.34(s,1H), 8.15(s,1H), 8.12-8.06(m,2H), 7.66(s,2H),7.43-7.34(m,4H) , 6.96 (t, J = 74Hz 1H), 6.71 (d, J = 8.5Hz, 1H), 4.59 (t, J = 6.1Hz, 2H), 4.03 (q, J = 7.0Hz, 2H), 3.95 (dt ,J=3.1,6.2Hz,2H),3.04-2.77(m,2H),2.55(dd,J=3.1,10.9Hz,2H),2.23(dd,J=5.6,10.9Hz,2H),1.20- 1.13 (m, 9H).

Example 73, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-isobutyl-6-carbonyl-1,6-dihydropyridin-3-yl )-1,8-naphthalene-2(1H)-one (Compound 094)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-isobutyl-6-carbonyl-1,6-dihydropyridin-3-yl) Synthesis of -1,8-naphthalene-2(1H)-one (Compound 094)

Under a nitrogen atmosphere, reactant 94-1 (678.0mg, can be synthesized according to the method reported in WO 2019102256) was dissolved in dioxane solution (8mL), and intermediate 38-4 (1.0g, 2.45mmol) was added, carbonic acid Cesium (1.6g, 4.9mmol), water (2mL) and Pd(dtbpf)Cl ₂ (240mg, 0.37mmol) were added and heated to 90°C and stirred for 12h. LCMS monitoring showed that the reaction was over, the reaction solution was filtered, the filtrate was spin-dried, and purified by high-pressure preparation [YMC-Actus Triart C18 column 5μm silica, 30mm diameter, 150mm length; water (containing 0.05% NH4HCO3) and acetonitrile have decreasing polarity As the eluent; acetonitrile gradient ratio 55%-80%, elution time 13 minutes] to obtain the title compound (80mg).

MS m/z (ESI): = 482 [M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δ8.24(d,J=2.6Hz,1H), 8.12(s,1H), 8.04(d,J=8.5Hz,1H), 7.94(dd,J= 9.4, 2.6 Hz, 1H), 7.34 (s, 4H), 6.93 (t, J = 73.8 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 6.61 (d, J = 9.4 Hz, 1H) ,3.99(d,J=7.0Hz,2H),3.86(d,J=7.4Hz,2H), 2.19(dt,J=13.7,6.8Hz,1H),1.13(t,J=7.0Hz,3H) ,0.96(d,J=6.7Hz,6H).

Example 74, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(6-oxylidene-1-((tetrahydrofuran-3-yl)methyl)-1 ,6-Dihydropyridin-3-yl)-1,8-naphthyridin-2(1H)-one (Compound 095)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(6-oxyylidene-1,6-dihydropyridin-3-yl)-1,8 -Synthesis of Naphthyridin-2(1H)-one (Intermediate 95-2)

The reactant 95-1 (100mg, 243.19μmol) and intermediate 98-4 (107.52mg, 486.38μmol) were dissolved in 1,4-dioxane and water, and then cesium carbonate (158.47mg, 486.38μmol) and Pd(dtbpf)Cl ₂ (15.85mg, 24.32μmol). The reaction solution was stirred and reacted at 100°C for 15 hours under the protection of nitrogen. LC-MS monitors all reactions of the raw materials. The reaction solution was extracted three times with ethyl acetate, the organic layer was washed with saturated brine, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by TLC preparation (silica, ethyl acetate/ethanol/petroleum ether=3/1/4) , The title compound (21.5 mg) was obtained.

MS m/z (ESI): = 426.2 [M+H] ⁺ .

Step 2: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(6-oxylidene-1-((tetrahydrofuran-3-yl)methyl)-1, Synthesis of 6-dihydropyridin-3-yl)-1,8-naphthyridin-2(1H)-one (Compound 095)

Intermediate 95-2 (20mg, 47.02μmol) and Intermediate 95-3 (23.2mg, 141.06μmol) were dissolved in DMF, and sodium hydrogen (60% purity, 9.40mg, 235.10μmol) was added when the temperature was lowered to 20°C, The reaction solution was stirred and reacted at 40°C for 16 hours under the protection of nitrogen. LC-MS monitors that all the raw materials have reacted completely, and the target product is formed. The reaction solution was quenched with water at 0°C, extracted three times with ethyl acetate, the organic layer was concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [ Water (0.05% ammonia v/v)-acetonitrile]; B is acetonitrile, B%: 53%-73%, 11 minutes) to obtain the title compound (9.9mg)

¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.31 (d, J = 2.5 Hz, 1H), 8.17 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.97 (dd, J = 2.5, 9.3 Hz, 1H), 7.37 (s, 4H), 7.17-6.76 (m, 1H), 6.71 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 9.3 Hz, 1H), 4.17- 4.05(m,2H),4.02(q,J=7.0Hz,2H),3.95(dt,J=5.5,8.2Hz,1H),3.85-3.74(m,2H), 3.65(dd,J=5.8, 8.8 Hz, 1H), 2.85 (td, J=6.8, 14.1 Hz, 1H), 2.12-1.98 (m, 1H), 1.87-1.73 (m, 1H), 1.16 (t, J=7.2 Hz, 3H).

MS m/z(ESI): = 510.3[M+H] ⁺

Example 75, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(6-carbonyl-1-(2-(tetrahydrofuran-2-yl)ethyl)-1 ,6-Dihydropyridin-3-yl)-1,8-naphthalene-2(1H)-one (Compound 097)

Step 1: Synthesis of 5-bromo-1-(2-(tetrahydrofuran-2-yl)ethyl)pyridine-2(1H)-one (Intermediate 97-3)

The reactant 97-2 (1.46g, 8.38mmol) was dissolved in DMF (35mL), sodium hydrogen (670.34mg, 16.76mmol, 60% effective content) was added under nitrogen protection at 0℃～5℃, and the reaction was stirred at 0℃. After 30 minutes, reactant 97-1 (1.5 g, 8.38 mmol) was added under the protection of nitrogen, the temperature of the reaction system was raised to 25° C. and the reaction was stirred at 25° C. for 16 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (50mL), extracted three times with 150mL (50mL*3) of ethyl acetate, and the organic phase was washed three times with 450mL (150mL*3) of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Column chromatography separation (

25g

Fast silica gel column, eluent gradient 11-100% ethyl acetate/petroleum ether, flow rate 50mL/min) to obtain the title compound (1g).

MS m/z (ESI):=271.8 [M+H] ⁺ .

Step 2: 1-(2-(Tetrahydrofuran-2-yl)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Synthesis of Pyridine-2(1H)-one (Intermediate 97-4)

Intermediate 97-3 (200mg, 734.92μmol) and double pinacol borate (279.94mg, 1.10mmol) were dissolved in dioxane (5mL), and Pd(dppf)Cl was added under nitrogen protection at 25℃ ₂ (53.77mg, 73.49μmol) and potassium acetate (216.38mg, 2.20mmol), the temperature of the system was raised to 90°C and the reaction was stirred at 90°C for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (10mL), extracted with 30mL of ethyl acetate (10mL*3) three times, the organic phase was dried over sodium sulfate, filtered, concentrated to dryness under reduced pressure, and separated by thin layer chromatography (silica, petroleum ether/ethyl acetate) Ester = 2/1) to obtain the title compound (76 mg).

¹ H NMR (400MHz, _{METHANOL-d 4} ) δ8.01-7.89 (m, 1H), 7.77 (d, J = 7.9Hz, 1H), 7.72-7.61 (m, 1H), 4.23-4.14 (m, 1H) ),4.07-3.98(m,1H),3.93-3.80(m,2H),3.78-3.70(m,1H),2.10-1.83(m,5H),1.61-1.51(m,1H),1.22(s ,12H).

Step 3: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(6-carbonyl-1-(2-(tetrahydrofuran-2-yl)ethyl)-1, Synthesis of 6-dihydropyridin-3-yl)-1,8-naphthalene-2(1H)-one (Compound 097)

Intermediate 97-4 (69.86mg, 218.87μmol) and intermediate 38-4 (45mg, 109.44μmol) were dissolved in dioxane (4mL), and Pd(dtbpf)Cl ₂ (7.13mg, 10.94μmol) and cesium carbonate (71.31mg, 218.87μmol) were dissolved in water (1mL). The temperature of the system was raised to 90℃ and the reaction was stirred at 90℃ for 2 hours. LC-MS showed that the reaction was complete. The reaction solution was diluted with water (10mL) and extracted three times with 30mL of ethyl acetate (10mL*3). The organic phase was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The concentrate was purified by high performance liquid chromatography (0.05% ammonia v/v). )-Acetonitrile; B is acetonitrile, B%: 50%-70%, 11 minutes) to obtain the title compound (15 mg).

¹ H NMR(400MHz,METHANOL-d ₄ )δ=8.28(d,J=2.4Hz,1H), 8.15(s,1H), 8.07(d,J=8.4Hz,1H), 7.96(dd,J= 2.6, 9.4 Hz, 1H), 7.37 (s, 4H), 6.96 (t, J = 74 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 9.4 Hz, 1H), 4.28-4.2(m,1H),4.13-4.05(m,1H),4.02(q,J=7.0Hz,2H),3.94-3.85(m,2H),3.77-3.71(m,1H),2.12- 2.00 (m, 2H), 2.00-1.86 (m, 3H), 1.63-1.51 (m, 1H), 1.16 (t, J=7.0 Hz, 3H).

MS m/z (ESI): = 524.1 [M+H] ⁺ .

Example 76, 6-(2-(2-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl)ethyl)-1-methyl-1H-benzo[ d]imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d]pyrimidin-7(8H)-one (compound 098 )

Step 1: 6-(2-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)ethyl)-1-methyl-1H-benzo[d ]Imidazol-6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d]pyrimidin-7(8H)-one (Compound 098) Synthesis

The reactant 98-1 (108.04mg, 271.94μmol, can be synthesized according to the similar method of intermediate 84-1, replacing morpholine with 8-oxa-3-azabicyclo[3.2.1]octane) , Intermediate 38-4 (50mg, 135.97μmol), cesium carbonate (88.6mg, 271.94μmol) and Pd(dtbpf)Cl ₂ (8.86mg, 13.6μmol) are dissolved in water and 1,4-dioxane, The reaction solution was heated to 90°C under the protection of nitrogen and stirred for 16 hours. LC-MS monitors that all the raw materials have reacted completely and the target product is formed. The reaction solution was extracted three times with ethyl acetate, the organic layer was concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid v/v) )-Acetonitrile]; B is acetonitrile, B%: 35%-55%, 11 minutes) to obtain the title compound (11.4 mg).

¹ H NMR (400MHz, METHANOL-d4) δ = 8.91 (s, 1H), 8.48 (s, 0.398H, HCO ₂ H), 8.20 (s, 1H), 7.91-7.87 (m, 1H), 7.68-7.56 (m,2H),7.46-7.34(m,4H),7.17-6.76(m,1H),4.18(q,J=7.1Hz,2H),3.85(s,3H),3.21-3.14(m,2H) ), 2.93 (t, J = 7.2 Hz, 2H), 2.83 (d, J = 11.0 Hz, 2H), 2.49 (d, J = 10.3 Hz, 2H), 1.92-1.77 (m, 4H), 1.26 (t , J=7.1Hz, 3H).

MS m/z (ESI): = 603.0 [M+H] ⁺ .

Example 77, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-((pyridine-3-oxy)methyl)-1H -Benzo[d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 099)

Step 1: Synthesis of 6-bromo-1-methyl-2-((pyridine-3-oxy)methyl)-1H-benzo[d]imidazole (Intermediate 99-2)

The reactant 99-1 (500mg, 2.07mmol) and 3-hydroxypyridine (197.23mg, 2.07mmol) were dissolved in tetrahydrofuran (2mL), and tri-tert-butylphosphine (419.60mg, 2.07mmol) was added at 0°C, DIAD (419.38 mg, 2.07 mmol). The reaction solution was heated to 50°C and stirred for 12 hours. LC-MS detects that the reaction is complete. It was extracted with ethyl acetate 30mL (10mL*3). After the organic phase was dried with anhydrous sodium sulfate, it was evaporated to dryness under reduced pressure and column chromatography was prepared (

25g

Fast silica gel column, eluent: ethyl acetate and petroleum ether @45mL/min) to obtain the title compound (120mg).

MS m/z (ESI): = 317.9 [M+H] ⁺ .

Step 2: 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxoboronate-2-yl)-2-(2,2,2-trifluoro Synthesis of ethyl)-1H-benzo[d]imidazole (Intermediate 99-3)

Intermediate 99-2 (120mg, 377.16μmol), double pinacol borate (143.66mg, 565.74μmol) were dissolved in dioxane (3mL). Add potassium acetate (111.04mg, 1.13mmol), Pd(dppf)Cl ₂ (13.80mg, 18.86μmol). Under the protection of nitrogen, the reaction was stirred at 90°C for 12 hours, and the reaction was completed by LC-MS. The reaction solution was filtered and extracted with 30 mL of ethyl acetate (10 mL*3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and purified by preparative thin layer chromatography (silica, dichloromethane: methanol = 10:1) to obtain the title compound (61 mg).

MS m/z (ESI): = 366.0 [M+H] ⁺ .

Step 3: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-((pyridine-3-oxy)methyl)-1H- Synthesis of Benzo[d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Compound 099)

Intermediate 99-3 ((30mg, 82.14μmol), intermediate 38-4 (30.21mg, 82.14μmol), cesium carbonate (53.53mg, 164.28μmol), Pd(dtbpf)Cl ₂ (5.35mg, 8.21μmol) Dissolved in dioxane/water (4:1) (1mL). The reaction was stirred at 90°C for 12 hours under a nitrogen atmosphere. LC-MS detected the completion of the reaction. After the reaction solution was evaporated to dryness under reduced pressure, high performance liquid chromatography was prepared. (Column: YMC-Actus Triart C18150*30mm*5μm; mobile phase: [water (0.05% ammonia v/v)-acetonitrile]; B is acetonitrile, B%: 48%-68%, 11 minutes) to obtain the title compound (4.8mg).

MS m/z (ESI): = 571.1 [M+H] ⁺ .

¹ H NMR (400MHz, METHANOL-d4) δ = 8.95 (s, 1H), 8.43 (d, J = 2.9 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J = 4.8 Hz, 1H), 7.99(s,1H),7.80-7.73(m,1H),7.69-7.65(m,2H),7.47-7.45(m,1H),7.45-7.41(m,2H),7.40-7.36(m,2H) ), 6.97(t,J=74Hz,1H),5.56(s,2H), 4.20(q,J=7.1Hz,2H),3.99(s,3H),1.27(t,J=7.1Hz,3H) .

Example 78, 6-(2-(2-(8-oxa-2-azaspiro[4.5]decane-2-yl)ethyl)-1-methyl-1H-benzo[d]imidazole -6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d]pyrimidin-7(8H)-one (Compound 101)

Step 1: 2-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d] Synthesis of Imidazol-2-yl)ethanol (Intermediate 101-2)

The reactant 101-1 (300mg, 1.18mmol), double pinacol borate (447.93mg, 1.76mmol), Pd(dppf)Cl ₂ (43.02mg, 58.8μmol) and potassium acetate (346.23mg, 3.53 mmol) is soluble in 1,4-dioxane. Under the protection of nitrogen, the reaction solution was heated to 90° C. and stirred for 0.5 hours. LC-MS monitors that all reactions are complete and the target product is formed. The reaction solution was extracted three times with ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure to obtain the crude title compound (326.53 mg).

MS m/z (ESI): = 303.2 [M+H] ⁺ .

Step 2: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(2-(2-hydroxyethyl)-1-methyl-1H-benzo[d] Synthesis of Imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (Intermediate 101-3)

Intermediate 101-2 (82.17mg, 271.94μmol), intermediate 32-1 (50mg, 135.97μmol), cesium carbonate (88.6mg, 271.94μmol) and Pd(dtbpf)Cl ₂ (8.86mg, 13.6μmol) were dissolved In water and 1,4-dioxane. The reaction solution was heated to 90° C. under the protection of nitrogen, and the reaction was stirred for 5 hours. LC-MS monitors that all the raw materials have reacted completely and the target product is formed. The reaction solution was extracted three times with ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure to obtain the crude title compound (69 mg).

MS m/z (ESI): =508.1 [M+H] ⁺ .

Step 3: 2-(6-(8-(4-(difluoromethoxy)phenyl)-2-ethoxy-7-oxyylidene-7,8-dihydropyrido[2,3- Synthesis of d]pyrimidin-6-yl)-1-methyl-1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate (Intermediate 101-4)

Intermediate 101-3 (69 mg, 135.96 μmol) was added to dichloromethane, triethylamine (27.52 mg, 271.93 μmol) was added, and methylsulfonyl chloride (17.13 mg, 149.56 μmol) was added at 0°C. The reaction solution was stirred and reacted at 25°C for 2 hours under the protection of nitrogen. LC-MS monitors the partial reaction of the raw materials and the formation of the target product. The reaction solution was quenched with saturated sodium bicarbonate solution at 0°C, extracted with ethyl acetate three times, and the organic layer was concentrated to dryness under reduced pressure to obtain the crude title compound (69 mg).

MS m/z (ESI): = 398.0 [M+H] ⁺ .

Step 4: 6-(2-(2-(8-oxa-2-azaspiro[4.5]decane-2-yl)ethyl)-1-methyl-1H-benzo[d]imidazole- Synthesis of 6-yl)-8-(4-(difluoromethoxy)phenyl)-2-ethoxypyrido[2,3-d]pyrimidin-7(8H)-one (compound 101)

Intermediate 101-4 (69 mg, 117.83 μmol), intermediate 101-5 (19.05 mg, 134.91 μmol) and triethylamine (40.95 mg, 404.73 μmol) were dissolved in acetonitrile, and the reaction solution was heated to 40 under the protection of nitrogen. The reaction was stirred at °C for 16 hours. LC-MS monitors that all the raw materials have reacted completely, and the target product is formed. The reaction solution was extracted three times with ethyl acetate, the organic layer was dried with sodium sulfate and concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [水(0.05) % Ammonia v/v)-acetonitrile]; B is acetonitrile, B%: 60%-80%, 11 minutes) to obtain the title compound (3.7 mg).

¹ H NMR(400MHz,METHANOL-d ₄ )δ=8.94(s,1H),8.23(s,1H),7.94(s,1H),7.73-7.67(m,1H),7.65-7.60(m,1H) ),7.46-7.42(m,2H),7.40-7.37(m,2H),7.18-6.77(m,1H),4.19(q,J=7.1Hz,2H),3.89(s,3H),3.72- 3.69 (m, 4H), 3.62-3.51 (m, 2H), 3.40 (s, 4H), 3.22 (s, 2H), 2.08-2.00 (m, 2H), 1.75-1.66 (m, 4H), 1.26 ( t,J=7.0Hz,3H)

MS m/z (ESI): = 631.5 [M+H] ⁺ .

Example 79, 3-(6-(8-(4-(difluoromethoxy)phenyl)-2-ethoxy-7-carbonyl-7,8-dihydropyrido[2,3-d ]Pyrimidin-6-yl)-1-methyl-1H-benzo[d]imidazol-2-yl)propionitrile (Compound 102)

Step 1: Synthesis of 2-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethyl methanesulfonate (Intermediate 102-2)

The reactant 102-1 (500mg, 1.96mmol) was dissolved in dichloromethane (8mL), and triethylamine (396.65mg, 3.92mmol) was added to the mixed solution. After the temperature of the reaction solution was reduced to 0°C, the reaction solution Slowly add methanesulfonyl chloride (269.41mg, 2.35mmol) to the reaction solution and stir for 1 hour at 25°C under nitrogen protection. LC-MS detects that the reaction is complete. The reaction solution was extracted with dichloromethane and water, and the organic phase was washed three times with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to dryness to obtain the title compound (650 mg).

MS m/z (ESI): = 333.0 [M+H] ⁺ .

Step 2: Synthesis of 3-(6-bromo-1-methyl-1H-benzo[d]imidazol-2-yl)propionitrile (Intermediate 102-3)

Intermediate 102-2 (650 mg, 1.95 mmol) and sodium cyanide (114.72 mg, 2.34 mmol) were dissolved in methanol (10 mL), triethylamine (394.79 mg, 3.90 mmol) was added to the mixture, and the reaction solution was placed under nitrogen. Stir at 40°C for 16 hours under protection. LC-MS detects that the reaction is complete. After the reaction was cooled to room temperature and concentrated under reduced pressure to remove methanol, it was extracted with ethyl acetate (30 mL) and water (60 mL), and the organic phase was washed three times with water (20 mL X 3). The title compound (270 mg) was obtained by preparative column chromatography (petroleum ether: ethyl acetate = 8:1 to 0:1).

MS m/z (ESI): = 264.0 [M+H] ⁺ .

Step 3: 3-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d] Synthesis of imidazol-2-yl)propionitrile (Intermediate 102-4)

Intermediate 102-3 (150mg, 567.92μmol) and double pinacol borate (216.32mg, 851.88μmol) were dissolved in anhydrous 1,4-dioxane (3mL), and Pd was added to the mixture (dppf) Cl ₂ (20.78 mg, 28.40 μmol) and potassium acetate (167.21 mg, 1.70 mmol), the reaction solution was stirred at 100°C for 16 hours under nitrogen protection. LC-MS detects that the reaction is complete. After the reaction was cooled to room temperature, it was extracted with water (60 mL) and ethyl acetate (20 mL), the organic phase was washed with water (20 mL*2), the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The title compound (98 mg) was obtained by preparative thin layer chromatography (silica, dichloromethane: methanol = 10:1).

MS m/z (ESI): = 312.1 [M+H] ⁺ .

Step 4: 3-(6-(8-(4-(difluoromethoxy)phenyl)-2-ethoxy-7-carbonyl-7,8-dihydropyrido[2,3-d] Synthesis of pyrimidin-6-yl)-1-methyl-1H-benzo[d]imidazol-2-yl)propionitrile (Compound 102)

Intermediate 102-4 (98mg, 314.92μmol) and Intermediate 32-1 (77.21mg, 209.95μmol) were dissolved in anhydrous dioxane (2mL) and water (0.5mL), and cesium carbonate was added to the mixture (136.81mg, 419.90μmol) and Pd(dtbpf)Cl ₂ (6.84mg, 10.50μmol), the reaction solution was stirred at 90°C for 16 hours under the protection of nitrogen. LC-MS detects that the reaction is complete. After the reaction was cooled to room temperature, water (20 mL) and ethyl acetate (10 mL) were sequentially added, the organic phase was washed with water (20 mL*2), and the washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Purified by preparative HPLC (column: Boston Prime C18 150*30mm*5μm; mobile phase: water (0.05% ammonia v/v)-ammonia; B is acetonitrile, B%: 55%-78%, 9 minutes) to obtain the title Compound (42.2 mg).

¹ H NMR: (400MHz,Methanol-d ₄ )δ=9.02(s,1H),8.29(s,1H),7.99(s,1H),7.79-7.73(m,1H),7.69-7.64(m, 1H), 7.57-7.50 (m, 2H), 7.48-7.40 (m, 2H), 7.18 (t, J = 74Hz, 1H), 4.26 (s, 2H), 3.91 (s, 3H), 3.46-3.38 ( m,2H),3.17-3.10(m,2H),1.32(t,J=7.0Hz,3H).

MS m/z (ESI): = 517.3 [M+H] ⁺ .

Example 80, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(pyridin-3-ylmethyl)-1H-benzo [d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (compound 105)

Step 1: Synthesis of 6-bromo-1-methyl-2-(pyridin-3-ylmethyl)-1H-benzo[d]imidazole (Intermediate 105-2)

The reactants 105-1 (500 mg, 2.49 mmol) and 2-(pyridin-3-yl)acetic acid (1.02 g, 7.46 mmol) were dissolved in aqueous hydrochloric acid. The reaction solution was heated to 100°C under the protection of nitrogen, and the reaction was stirred for 16 hours. LC-MS monitors that all the raw materials have reacted completely. The reaction solution was adjusted to pH=8 with saturated sodium hydroxide solution, extracted three times with ethyl acetate, the organic layer was dried over sodium sulfate, and the organic layer was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (silica, methanol/dichloromethane=0/1 to 1/10) to obtain the title compound (400 mg).

MS m/z(ESI):=304.0[M+H] ⁺

Step 2: Methyl-2-(pyridin-3-ylmethyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- Synthesis of 1H-Benzo[d]imidazole (Intermediate 105-3)

Intermediate 105-2 (230mg, 761.16μmol), double pinacol borate (289.93mg, 1.14mmol), Pd(dppf)Cl ₂ (289.93mg, 1.14mmol) and potassium acetate (98.14mg, 2.28 mmol) is soluble in 1,4-dioxane. Under the protection of nitrogen, the reaction solution was heated to 100°C and stirred for 16 hours. LC-MS monitored all the reactions to be complete. The reaction solution was extracted three times with ethyl acetate, the organic layer was dried over sodium sulfate, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (silica, methanol/dichloromethane=0/1 to 1/10 ) To obtain the title compound (211.9 mg).

MS m/z(ESI):=350.0[M+H] ⁺

Step 3: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(pyridin-3-ylmethyl)-1H-benzo[ Synthesis of d]imidazol-6-yl)pyrido[2,3-d]pyrimidin-7(8H)-one (compound 103)

Intermediate 105-3 (94.9mg, 271.94μmol), intermediate 32-1 (50mg, 135.97μmol), cesium carbonate (88.6mg, 271.94μmol) and Pd(dtbpf)Cl ₂ (8.86mg, 13.6μmol) were dissolved In water and 1,4-dioxane, the reaction solution was heated to 90°C under the protection of nitrogen and stirred for 16 hours. LC-MS monitors that all the raw materials have reacted completely and the target product is formed. The reaction solution was extracted three times with ethyl acetate, the organic layer was concentrated to dryness under reduced pressure, and purified by high performance liquid chromatography (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water (0.05% ammonia v/v) )-Acetonitrile]; B is acetonitrile, B%: 46%-66%, 11 minutes) to obtain the title compound (8.1 mg).

¹ H NMR (400MHz, METHANOL-d4) δ = 8.94 (s, 1H), 8.56 (d, J = 1.6 Hz, 1H), 8.51-8.45 (m, 1H), 8.22 (s, 1H), 7.91 (d ,J=1.0Hz,1H),7.78(d,J=7.9Hz,1H),7.73-7.66(m,1H),7.64-7.58(m,1H),7.47-7.34(m,5H),7.21- 6.75 (m, 1H), 4.46 (s, 2H), 4.19 (d, J=7.1 Hz, 2H), 3.82 (s, 3H), 1.29-1.25 (m, 3H).

MS m/z(ESI): =555.4[M+H] ⁺

Example 81, 2-(5-(1-(4-(difluoromethoxy)phenyl)-7-ethoxy-2-carbonyl-1,2-dihydro-1,8-diazepine Naphth-3-yl)-2H-indazol-2-yl)ethyl acetate (Compound 107)

Step 1: 2-(5-(1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-2-carbonyl-1,2-dihydro-1,8-naphthalene Synthesis of -3-yl)-2H-indazol-2-yl)ethyl acetate (compound 107)

Compound 065 (50mg, 101.53μmol) was dissolved in acetonitrile (3mL), cooled to 0℃, DMAP (1.24mg, 10.15μmol), TEA (20.55mg, 203.06μmol, 28.26μL), acetic anhydride (15.55mg, 152.29μmol, 14.26μL), stirred at room temperature for 16 hours. LCMS detects the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [0.05% ammonia (v/v)-acetonitrile]; B is acetonitrile, B% : 55%-75%, 11 minutes) to obtain the title compound (14.5mg).

MS m/z (ESI): = 535 [M+H] ⁺ .

¹ H NMR (400MHz, METHANOL-d ₄ ) δppm 8.34(s,1H), 8.15(s,1H), 8.13-8.05(m,2H), 7.67(s,2H),7.43-7.33(m,4H) ,6.96(s,J=73.8Hz,1H),6.71(d,J=8.3Hz,1H),4.76-4.71(m,2H),4.61-4.57(m,2H),4.03(q,J=7.0 Hz,2H),2.01(s,3H),1.17(t,J=7.0Hz,3H)

Example 82, 2-(5-(1-(4-(difluoromethoxy)phenyl)-7-ethoxy-2-carbonyl-1,2-dihydro-1,8-diazepine Naphth-3-yl)-2H-indazol-2-yl)ethyl isopropyl carbamate (Compound 108)

Step 1: 2-(5-(1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-2-carbonyl-1,2-dihydro-1,8-naphthalene Synthesis of -3-yl)-2H-indazol-2-yl)ethyl isopropyl carbamate (Compound 108)

Compound 065 (50 mg, 101.53 μmol) was dissolved in acetonitrile (3 mL), 2-isocyanatopropane (12.96 mg, 152.29 μmol) was added, and the mixture was stirred at room temperature for 16 hours. LCMS detects the completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative liquid chromatography (column: Gemini NX C18 5μm*10*150mm; mobile phase: [water (0.05% ammonia v/v)-acetonitrile]; B is acetonitrile, B% : 55%-75%, 11 minutes) to obtain the title compound (18.4mg).

MS m/z (ESI): = 578 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δppm 8.32(s,1H), 8.15(s,1H), 8.12-8.05(m,2H), 7.66(d,J=1.0Hz,2H),7.46-7.32 (m, 4H), 6.96 (s, J = 74 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 4.74-4.68 (m, 2H), 4.61 (s, 1H), 4.54 (d, J = 4.5 Hz, 2H), 4.03 (q, J = 7.0 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H), 1.10 (d, J = 6.5 Hz, 6H).

Example 83, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(((1-methylcyclopropyl)methoxy )Methyl)-1H-benzo[d]imidazol-6-yl)pyridine[2,3-d]pyrimidin-7(8H)one (Compound 109)

Step 1: Synthesis of 6-bromo-1-methyl-2-(((1-methylcyclopropyl)methoxy)methyl)-1H-benzo[d]imidazole (Intermediate 109-2)

Dissolve (1-methylcyclopropyl)methanol (100mg, 1.16mmo) in DMF, add NaH (92.79mg, 2.32mmol at 0°C, stir and react for 30 minutes, add the DMF solution of reactant 109-1 dropwise The reaction was stirred at room temperature for 12 hours. The reaction was detected by LCMS. After quenching the reaction with water at 0°C, it was extracted with 6 mL of ethyl acetate (2 mL*3). After the organic phase was dried over anhydrous sodium sulfate, it was evaporated to dryness under reduced pressure Preparative thin layer chromatography (silica, dichloromethane/methanol = 10/1) to obtain the title compound (50mg)

MS m/z (ESI): = 309.1 [M+H] ⁺ .

Step 2: 1-methyl-2-(((1-methylcyclopropyl)methoxy)methyl)-6-(4,4,5,5-4methyl-1,3,2- Synthesis of dioxoboronate-2-yl)-1H-benzo[d]imidazole (Intermediate 109-3)

Intermediate 109-2 (50mg, 161.71μmol) was dissolved in dioxane, and double pinacol borate ((61.60mg, 242.56μmol), potassium acetate (47.61mg, 485.12μmo), Pd( dppf)Cl ₂ (5.92mg, 8.09μmol). The reaction solution was stirred at 90°C for 1 hour under the protection of nitrogen. LC-MS monitored that all the raw materials had reacted completely and the target product was formed. The reaction solution was concentrated to dryness under reduced pressure. After evaporation to dryness, thin layer chromatography (silica, petroleum ether/ethyl acetate = 1/1) was prepared to obtain the title compound (30 mg)

MS m/z (ESI): = 357.2 [M+H] ⁺ .

Step 3: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(((1-methylcyclopropyl)methoxy) Synthesis of methyl)-1H-benzo[d]imidazol-6-yl)pyridine[2,3-d]pyrimidin-7(8H)one (Compound 109)

Intermediate 109-3 (30mg, 84.21μmol) was dissolved in dioxane/water, and intermediate 32-1 (30mg, 81.58μmol), cesium carbonate (53.16mg, 163.16μmol), Pd(dtpf)Cl _{2 were added} (5.32mg, 8.16μmol). The reaction solution was stirred and reacted at 90°C for 12 hours under the protection of nitrogen. LC-MS monitors that all the raw materials have reacted completely and the target product is formed. The reaction solution was concentrated to dryness under reduced pressure, and then evaporated to dryness under reduced pressure to prepare a high performance liquid chromatography column (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [A: water (0.05% ammonia v/v), B: Acetonitrile]; B is acetonitrile, B%: 56%-76%, 11 minutes). The title compound (1.8mg) was obtained.

¹ H NMR(400MHz,METHANOL-d ₄ )δ=8.96(s,1H),8.25(s,1H),7.96(s,1H),7.76-7.69(m,1H),7.66-7.62(m,1H) ),7.48-7.43(m,2H),7.41-7.36(m,2H),6.98(t,J=74Hz,1H), 4.85(s,2H), 4.20(q,J=7.1Hz,2H), 3.97(s, 3H), 3.37(s, 2H), 1.27(t, J = 7.1Hz, 3H), 1.15(s, 3H), 0.47-0.40(m, 2H), 0.35(m, 2H)

MS m/z (ESI): = 562.1 [M+H] ⁺ .

Example 84, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(6-((tetrahydrofuran-3-yl)methoxy)pyridin-3-yl)- 1,8-naphthyridin-2(1H)-one (Compound 111)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(6-((tetrahydrofuran-3-yl)methoxy)pyridin-3-yl)-1 Synthesis of ,8-naphthyridin-2(1H)-one (Compound 111)

¹ H NMR(400MHz,METHANOL-d ₄ )δ=8.48(d,J=2.3Hz,1H), 8.14(s,1H), 8.08(d,J=8.5Hz,2H), 7.41-7.33(m, 4H), 6.96 (s, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.71 (d, J = 8.5 Hz, 1H), 4.37-4.21 (m, 2H), 4.02 (q, J = 7.0 Hz,2H),3.96-3.88(m,2H),3.84-3.68(m,2H),2.80(td,J=6.5,13.2Hz,1H),2.20-2.10(m,1H),1.80(dt, J=7.2, 13.1 Hz, 1H), 1.16 (t, J=7.2 Hz, 3H).

MS m/z(ESI):=510.4[M+H] ⁺

Example 85, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-isopropyl-6-carbonyl-1,6-dihydropyridin-3-yl )-1,8-naphthalene-2(1H)-one (Compound 112)

Step 1: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(1-isopropyl-6-carbonyl-1,6-dihydropyridin-3-yl) Synthesis of -1,8-naphthalene-2(1H)-one (Compound 112)

Under a nitrogen atmosphere, Intermediate 38-4 (50 mg, 121.95 μmol) and Intermediate 112-1 (45.22 mg, 182.92 μmol) were dissolved in dioxane (0.8 mL) and water (0.4 mL). Cesium carbonate (119.9 mg, 368.92 μmol) was added thereto, followed by Pd(dtbpf)Cl ₂ (10 mg, 12.36 μmol). The reaction solution was stirred at 90°C for 15 hours. TLC monitoring completion of the reaction, the reaction solution was cooled to room temperature, filtered, the filtrate by HPLC-PREP (YMC-Actus Triart C18 column 5μm, 30mm diameter silica, 150mm length; washed with water (containing 0.05% NH ₄ HCO ₃₎ and acetonitrile The mixture of decreasing polarity was used as the eluent; acetonitrile gradient ratio 60%-82%, elution time 12 minutes) was purified, the title compound (25.5mg).

MS m/z (ESI): =468 [M+H] ⁺ .

¹ H NMR(400MHz,DMSO-d ₆ )δ8.39(d,J=2.6Hz,1H), 8.25(s,1H), 8.11(d,J=8.4Hz,1H), 7.87–7.78(m, 1H),7.44–7.31(m,5H), 6.73(d,J=8.4Hz,1H), 6.47(d,J=9.5Hz,1H), 5.16–5.04(m,1H),3.99–3.89(m ,2H),1.32(d,J=6.8Hz,6H),1.08(t,J=7.0Hz,3H).

Example 86, 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-(2-oxopyridine-1(2H) -Yl)ethyl)-1H-benzo[d]imidazol-6-yl)pyrrole[2,3-d]pyrimidin-7(8H)-one (compound 116)

Step 1: 1-(2-(6-Bromo-1-methyl-1H-benzo[d]imidazol-2-yl)ethyl)pyridine-2(1H)-one (Intermediate 116-2) synthesis

The reactants 116-1 (500mg, 1.96mmol) and 2-hydroxypyridine (186.39mg, 1.96mmol) were dissolved in tetrahydrofuran, and tributylphosphine (396.53mg, 1.96mmol) and azodicarboxylate were added at 0°C. Isopropyl ester (396.32 mg, 1.96 mmol). The reaction solution was stirred and reacted at 90°C for 15 hours under the protection of nitrogen. LC-MS monitors that part of the raw material remains and the target product is formed. The reaction solution was extracted three times with ethyl acetate, the organic layer was washed with saturated brine, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (silica, dichloromethane/methanol=7/1 to obtain the title compound (240mg ).

MS m/z (ESI): = 333.9 [M+H] ⁺ .

Step 2: 1-(2-(1-methyl-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo Synthesis of [d]imidazol-2-yl)ethyl)pyridine-2(1H)-one (Intermediate 116-3)

Intermediate 116-2 (50mg, 150.51μmol) was dissolved in dioxane, and double pinacol borate (57.33mg, 225.77μmol), potassium acetate (44.31mg, 451.54μmol), Pd(dppf) were added ) With Cl ₂ (5.51 mg, 7.53 μmol), the reaction solution was raised to 90° C., and the reaction was stirred for 12 hours. LC-MS monitors that all the raw materials have reacted completely and the target product is formed. After the reaction liquid was evaporated to dryness under reduced pressure, it was extracted with 30 mL of ethyl acetate (10 mL*3). The organic phase was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, and column chromatography (silica, petroleum ether/ethyl acetate = 1/1) was prepared to obtain the title compound (28 mg)

MS m/z (ESI): = 380.1 [M+H] ⁺ .

Step 3: 8-(4-(Difluoromethoxy)phenyl)-2-ethoxy-6-(1-methyl-2-(2-(2-oxopyridine-1(2H)- (Yl)ethyl)-1H-benzo[d]imidazol-6-yl)pyrrole[2,3-d]pyrimidin-7(8H)-one (Compound 116)

Intermediate 116-3 (28mg, 73.83μmol) was dissolved in dioxane/water, and intermediate 32-1 (27.15mg, 73.83μmol), cesium carbonate (48.11mg, 147.66μmol), Pd(dtbpf)Cl was added ₂ ((4.81mg, 7.38μmol). The reaction solution was stirred at 90°C for 12 hours under the protection of nitrogen. LC-MS monitored that all the raw materials had reacted completely and the target product was formed. The reaction solution was concentrated to dryness under reduced pressure to prepare a high-performance liquid phase Chromatographic column (chromatographic column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: [A: water (0.05% ammonia v/v), B: acetonitrile]; B is acetonitrile, B%: 45%-65%, 11 minutes) to obtain the title compound (5.5 mg).

¹ H NMR(400MHz,METHANOL-d ₄ )δ=8.95(s,1H),8.22(s,1H),7.89(s,1H),7.69-7.64(m,1H),7.63-7.59(m,1H) ),7.56-7.49(m,2H),7.47-7.41(m,2H),7.41-7.36(m,2H),7.17-6.77(t,J=74Hz,1H),6.59-6.54(m,1H) ,6.35-6.28(m,1H),4.49(t,J=7.2Hz,2H), 4.19(d,J=7.0Hz,2H), 3.81(s,3H), 3.46(t,J=7.0Hz, 2H), 1.26 (t, J=7.0 Hz, 3H).

MS m/z (ESI): = 585.1 [M+H] ⁺ .

Example 87, 8-(4-(Difluoromethyl)phenyl)-2-ethoxy-6-(1-methyl-2-(2,2,2-trifluoroethyl)-1H- Benzo[d]imidazol-1-yl)pyridine[2,3-d]pyrimidin-7(8H)-one (compound 117)

Step 1: Synthesis of 6-bromo-1-methyl-2-(2,2,2-trifluoromethyl)-1H-benzo[d]imidazole (Intermediate 117-2)

The reactant 117-1 (2g, 9.95mmol) was dissolved in water (30mL), and 3,3,3-trifluoroacetic acid (2.55g, 19.89mmol) and hydrochloric acid (6M, 20mL) were added dropwise. The temperature was raised to 100°C and the reaction was stirred for 12 hours. LC-MS detects that the reaction is complete. Sodium hydroxide solution was added dropwise to the reaction solution at 0°C until the pH was 8, and it was extracted with 600 mL of ethyl acetate (200 mL*3). After the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure, the title compound (620 mg) was obtained.

MS m/z (ESI): = 319.9 [M+H] ⁺ .

Step 2: 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxboronate-2-yl)-2-(2,2,2-trifluoro Synthesis of ethyl)-1H-benzo[d]imidazole (Intermediate 117-3)

Intermediate 117-2 (220 mg, 750.64 μmol), double pinacol borate (381.23 mg, 1.50 mmol) was dissolved in dioxane (5 mL). Add potassium acetate (221.00 mg, 2.25 mmol), Pd(dppf)Cl ₂ (27.46 mg, 37.53 μmol). Under nitrogen protection, the reaction was stirred at 100°C for 12 hours, and the reaction was completed by LC-MS. The reaction solution was filtered and extracted with 30 mL of ethyl acetate (10 mL*3). After the organic phase was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure, thin layer chromatography (silica, dichloromethane: methanol = 9:1) was prepared to obtain the title compound (44 mg).

MS m/z (ESI): = 341.0 [M+H] ⁺ .

Step 3: 8-(4-(Difluoromethyl)phenyl)-2-ethoxy-6-(1-methyl-2-(2,2,2-trifluoroethyl)-1H-benzene Synthesis of and [d]imidazol-1-yl)pyridine[2,3-d]pyrimidin-7(8H)-one (compound 117)

Intermediate 117-3 (20mg, 58.80μmol), intermediate 32-1 (21.62mg, 58.80μmol), potassium phosphate (24.96mg, 117.60μmol), Pd(dtbpf)Cl ₂ (3.83mg, 5.88μmol) were dissolved In dioxane/water (4:1) (1mL). The reaction was stirred at 90°C for 1 hour under a nitrogen atmosphere. LC-MS detects that the reaction is complete. After the reaction solution was evaporated to dryness under reduced pressure, high performance liquid chromatography was prepared (column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water (0.05% ammonia v/v)-acetonitrile]; B is acetonitrile, B%: 50%-70%, 11 minutes) to obtain the title compound (4.1 mg).

MS m/z (ESI): = 546.1 [M+H] ⁺ .

¹ H NMR(400MHz,METHANOL-d ₄ )δ=8.96(s,1H),8.26(s,1H),7.98(s,1H),7.81-7.72(m,1H),7.69-7.63(m,1H) ),7.47-7.42(m,2H),7.42-7.36(m,2H),7.19-6.75(t,J=74Hz,1H), 4.19(q,J=7.1Hz,2H),4.08(q,J = 10.3 Hz, 2H), 3.94 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H).

Example 88. 8-[4-(Difluoromethoxy)phenyl]-2-ethoxy-6-2-[2-[(3R)-3-methoxypyrrolidin-1-yl] Ethyl]-3-methyl-benzimidazol-5-yl]pyrido[2,3-d]pyrimidin-7-one (Compound 118)

Step 1: 8-[4-(Difluoromethoxy)phenyl]-2-ethoxy-6-2-[2-[(3R)-3-methoxypyrrolidin-1-yl]ethyl Synthesis of yl]-3-methyl-benzimidazol-5-yl]pyrido[2,3-d]pyrimidin-7-one (Compound 118)

Under the protection of nitrogen, at 20℃, to intermediate 32-1 (20mg, 54.39μmol) and intermediate 118-1 (31.43mg, 81.58μmol), according to the synthetic route of intermediate 91-1, to (R)-3 -Methoxypyrrolidine as raw material for synthesis) mixed solution of water (0.5mL) and dioxane (2mL) was added cesium carbonate (35.44mg, 108.77μmol) and catalyst Pd(dtbpf)Cl ₂ (3.54mg, 5.44μmol), react at 90°C for 16 hours. LC-MS showed that the reaction was complete and the target product was formed. After the reaction, the reactant was concentrated under reduced pressure to remove the solvent. The residue was purified by high performance liquid chromatography (basic conditions, column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid v/v)-acetonitrile]; B is acetonitrile, B %: 25%-45%, 11 minutes), title compound (3.5 mg).

¹ H NMR(400MHz,METHANOL-d)δ=8.93(s,1H), 8.56(s,0.44H, H COOH), 8.24-8.20(m,1H), 7.95-7.89(m,1H), 7.64 7.63(m,1H),7.72-7.63(m,1H),7.48-7.41(m,2H),7.40-7.34(m,2H),6.98(t,J=73.8Hz,1H),4.19(q, J=7.0Hz,2H),4.06(s,1H),3.93-3.83(m,3H),3.36(s,2H), 3.24(d,J=5.3Hz,4H),3.13-3.02(m,2H) ), 3.00 (d, J = 4.5 Hz, 1H), 2.84 (d, J = 8.3 Hz, 1H), 2.19 (m, J = 6.4, 13.9 Hz, 1H), 1.98 (s, 1H), 1.28-1.25 (m,3H).

MS m/z (ESI): =591.5 [M+H] ⁺ .

Example 89. 8-[4-(Difluoromethoxy)phenyl]-2-ethoxy-6-2-[2-[(3S)-3-methoxypyrrolidin-1-yl] Ethyl]-3-methyl-benzimidazol-5-yl]pyrido[2,3-d]pyrimidin-7-one (Compound 119)

Step 1: 8-[4-(Difluoromethoxy)phenyl]-2-ethoxy-6-2-[2-[(3S)-3-methoxypyrrolidin-1-yl]ethyl Synthesis of yl]-3-methyl-benzimidazol-5-yl]pyrido[2,3-d]pyrimidin-7-one (Compound 119)

At 90℃, add to the mixed solution (water (0.5mL) and dioxane (2mL)) of Intermediate 119-1 (41.91mg, 108.77μmol) and Intermediate 32-1 (20mg, 54.39μmol) Cesium carbonate (35.44mg, 108.77μmol) and catalyst Pd(dtbpf)Cl ₂ (3.54mg, 5.44μmol), under the protection of nitrogen, the reaction solution was stirred and reacted at 90°C for 16 hours. LC-MS showed that Intermediate 4 had reacted completely and the target product was formed. After the completion of the reaction, the reactant was concentrated under reduced pressure to remove the solvent. The residue was purified by high performance liquid chromatography (basic conditions, column: YMC-Actus Triart C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid v/v)-acetonitrile]; B is acetonitrile, B %: 25%-45%, 11 minutes) to obtain the title compound (3mg).

¹ H NMR (400MHz, METHANOL-d) δ = 8.94 (s, 1H), 8.55 (s, 0.275H, H COOH), 8.22 (s, 1H), 7.91 (s, 1H), 7.72-7.64 (m, 1H),7.63-7.56(m,1H),7.47-7.42(m,2H),7.41-7.34(m,2H),6.98(t,J=73.8Hz,1H),4.19(q,J=7.0Hz ,2H),4.05(s,1H),3.88(s,3H),3.38-3.34(m,2H),3.24(s,4H),3.03(d,J=16.6Hz,3H),2.81(s, 1H), 2.19 (s, 1H), 1.95 (s, 1H), 1.26 (t, J = 7.0 Hz, 3H).

MS m/z (ESI): =591.5 [M+H] ⁺ .

Example 90, 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-(2-(3-hydroxyazetidine-1-yl)ethyl)- 1-Methyl-1H-benzo[d]imidazol-6-yl)-1,8-naphthalene-2(1H)-one (Compound 120)

Step 1: 3-(2-(2-(3-((tert-butyldiphenylsilyl)oxo)azetidin-1-yl)ethyl)-1-methyl-1H-benzene And [d]imidazol-6-yl)-1-(4-(difluoromethoxy)phenyl)-7-ethoxy-1,8-naphthalene-2(1H)-one (middle Body 120-2) synthesis

The reactant 120-1 (86.91mg, 145.92μmol, can be replaced by 3-((tert-butyldiphenylsilyl)oxo)azetidine instead of morpholine according to the similar method of intermediate 84-1 To synthesize the reactants) and intermediate 38-4 (30mg, 72.96μmol) were dissolved in anhydrous dioxane (2mL) and water (0.5mL), and cesium carbonate (47.54mg, 145.92μmol) was added to the mixture And Pd(dtbpf)Cl ₂ (4.75 mg, 7.30 μmol), and the reaction solution was stirred at 90° C. for 16 hours under the protection of nitrogen. LC-MS detects that the reaction is complete. After the reaction was cooled to room temperature, water (40 mL) and ethyl acetate (20 mL) were sequentially added, and the organic phase was washed with water (20 mL*2). The washed organic phase was dried with an appropriate amount of anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The title compound (22 mg) was obtained by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate=0:1).

MS m/z (ESI): = 800.3 [M+H] ⁺ .

Step 2: 1-(4-(Difluoromethoxy)phenyl)-7-ethoxy-3-(2-(2-(3-hydroxyazetidin-1-yl)ethyl)-1 Synthesis of -Methyl-1H-benzo[d]imidazol-6-yl)-1,8-naphthalazine-2(1H)-one (Compound 120)

Intermediate 120-2 (22mg, 27.50μmol) was added to methanol (5mL) potassium fluoride (15.98mg, 275.01μmol, 6.44μL), and the reaction solution was stirred at 25°C for 16 hours under the protection of nitrogen. LC-MS detects that the reaction is complete. The reaction solution was concentrated to dryness under reduced pressure, and purified by preparative HPLC (column: Phenomenex Gemini-NX 150*30mm*5μm; mobile phase: 0.05% ammonia (v/v)-acetonitrile; B is acetonitrile, B%: 45%- 65%, 11 minutes) to obtain the title compound (1.9 mg).

¹ H NMR: (400MHz,Methanol-d ₄ )δppm 8.18(s,1H), 8.09(d,J=8.5Hz,1H),7.91(s,1H),7.71-7.64(m,1H),7.61- 7.53(m,1H),7.43-7.40(m,2H),7.39-7.35(m,2H),7.15-6.77(m,1H),6.71(d,J=8.5Hz,1H),4.41-4.32( m,1H),4.03(q,J=7.2Hz,2H),3.86(s,3H),3.80-3.68(m,2H),3.05(s,4H),3.04-2.97(m,2H),1.17 (t, J=7.0 Hz, 3H).

MS m/z (ESI): = 562.2 [M+H] ⁺ .

Test examples of biological activity and related properties

Test case 1. Biochemical test

Introduction to the test principle: L-methionine and ATP can be converted into SAM, inorganic phosphate and inorganic diphosphate under MAT2A enzyme catalysis. By adding a color developing agent, such as ammonium molybdate, to the enzymatic reaction mixture, the content of inorganic phosphate in the sample can be quantitatively detected, and then the enzyme activity of MAT2A can be reflected.

Materials: MAT2A screening kit was purchased from BPS Bioscience (U.S.); 384-well plate was purchased from Corning (U.S.).

1. MAT2a protein (Kanglong Chemical (Beijing) New Drug Technology Co., Ltd.);

2.L-methionine (Sigma#M9625-5G)

3.ATP(Sigma#A7699-1G)

4.KCL(Sigma#60142-500ML-F)

5.Tris(Sigma#T2663-1L)

6.MgCl ₂ (Sigma#M1028)

7.EDTA(Invitrogen#AM9260G)

8.BSA(Sangon Biotech#A500023-0100)

9.PiColorLock(abcam#ab270004)

Detection method:

Dissolve the compound in DMSO, use Echo to dilute the compound to a final concentration of 10 μM, 3 times dilution, and transfer 80 nL to a 384-well plate.

Configure experiment buffer (50mM Tris, 50mM KCl, 15mM MgCl ₂ , 100μM EDTA, 0.005% BSA). Dilute MAT2a protein with experimental buffer (final concentration is 4ug/mL). Add 40 μL of 2X MAT2a solution to the 384-well plate, centrifuge at 1000 rpm for 1 minute, and reincubate for 120 minutes.

Dilute L-methionine and ATP with experimental buffer (final concentration of L-methionine is 200 μM and final concentration of ATP is 400 μM). Add 40 μL of 2X L-methionine and ATP solution to start the reaction, centrifuge at 1000 rpm for 1 minute, and re-incubate for 90 minutes.

According to the instructions with the catalyst PiColorLock ^TM PiColorLock ^TM buffer 1: 100 mix added to each well shaken for 30 seconds 20μL. Add 8μL of stabilizing reagent and shake for 30 seconds. The signal value was detected after 30 minutes of incubation at room temperature.

data analysis:

Calculate %Compound inhibition and fit the IC ₅₀ Compound inhibition=(100-100*(Signal-Bottom)/(Top-Bottom))%

Experimental results:

Under the experimental conditions, the inhibitory effect of test compound on MAT2A enzymatic reaction may be expressed during the reaction to produce the level of inhibition IC ₅₀ values. The MAT2A inhibitory activity of the tested compound is shown in Table 1.

Table 1

Test Example 2: Detection of SAM level in cells

Introduction to the test principle: After the MAT2A inhibitor to be tested is incubated with the cancer cells for a period of time, the cell is lysed with a stop reagent to quench the MAT2A enzyme activity. The MAT2A catalytic product SAM in the cell lysate was quantitatively determined by LC-MS/MS, and then the activity of MAT2A in the cell was reflected.

Materials and cells: HCT116 MTAP ^-/- cells were purchased from Kangyuan Bochuang; fetal bovine serum, McCoy's 5a medium and penicillin-streptomycin were purchased from Gibco (U.S.), and 96-well plates were purchased from Corning (U.S.).

Cell culture: HCT116 MTAP ^-/- cells were cultured in McCoy's 5a medium containing 10% fetal bovine serum + 1% penicillin-streptomycin at 37°C and 5% CO ₂ . Cells in the logarithmic growth phase can be used in experiments.

LC-MS/MS detection: Use LC-MS/MS to detect the effect of compounds on the level of SAM production in the ^{HCT116 MTAP -/- cell line.} Adjust the cell concentration to 50,000 cells per well, inoculate a 96-well plate, and culture overnight at 37°C and 5% CO2. The compound was dissolved in DMSO, and the compound was diluted with DMSO and medium in turn and transferred to the cell plate. The final concentration was 10uM, and the compound was diluted 3 times. Place them at 37°C and 5% CO2 and continue to incubate for 6 hours. Aspirate the supernatant, wash with PBS, add glacial acetic acid to lyse the cells. After the lysate is processed, it is analyzed by LC-MS/MS sample injection to determine the SAM concentration. data analysis:

Calculate %Compound inhibition and fit to get the IC _{50 of the} compound ％Compound inhibition=1-100%*(Signal-Bottom)/(Top-Bottom)

Experimental results:

Under the experimental conditions, the inhibitory activity of the test compound on the MAT2A enzyme in ^{the HCT116 MTAP -/-} _{cell line is expressed as the IC 50} value of the test compound's inhibition of intracellular SAM production. See Table 2 for the inhibitory activity of the tested compounds on intracellular SAM production.

Table 2

Test Example 3. Human colon cancer HCT116 cell proliferation inhibition test

Introduction to the test principle: After the test MAT2A inhibitor is incubated with cancer cells for a period of time, the cell proliferation counting method based on ATP content is used to measure the effect of the test compound on cell proliferation.

Materials and cells: HCT116 MTAP ^+/+ cells and HCT116 MTAP ^-/- cells were purchased from Kangyuan Bochuang; fetal bovine serum, McCoy's 5a medium and penicillin-streptomycin were purchased from Gibco (USA), 96-well plates From Corning (USA), Cell-Titer Glo reagent was purchased from Promega (USA).

Cell culture: ^{Both HCT116 MTAP +/+} cells and HCT116 MTAP ^-/- cells were cultured in McCoy's 5a medium containing 10% fetal bovine serum + 1% penicillin-streptomycin at 37°C and 5% CO ₂ . Cells in the logarithmic growth phase can be used in experiments.

Cell proliferation activity detection: Cell-Titer Glo reagent was used to detect the compound's inhibitory activity on the proliferation of ^{HCT116 MTAP +/+} and HCT116 MTAP ^{-/- cell lines.} Adjust the cell concentration to 400 cells per well, inoculate a 96-well plate, and incubate overnight at 37°C and 5% CO2. The compound was dissolved in DMSO, and the compound was diluted with DMSO and medium in turn and transferred to the cell plate. The final concentration was 10uM, and the compound was diluted 3 times. Placed at 37°C and 5% CO2 for another 6 days. Add Cell-Titer Glo reagent to detect cell viability.

data analysis:

Experimental results:

Under the experimental conditions, the test compound showed a strong proliferation inhibitory activity ^{on HCT116 MTAP -/-} cells, and showed a certain selectivity ^{compared to HCT116 MTAP +/+ cells.} The corresponding anti-cell proliferation activities of the tested compounds are shown in Table 3.

table 3

In the above table, the symbols used to indicate binding activity have the following meanings:

_{-Indicates that the IC 50} range of the anti-proliferative activity of the test compound on cells is >10000nmol/L or the maximum inhibition rate is <50%;

N/A means it has not been tested yet.

Test Example 4. Inhibition test of human UGT1A1 enzyme activity

The inhibition of the enzyme activity of human UGT1A1 by the compound of the present invention was determined by the following test method.

1. Test materials and instruments

1.Tris (Shanghai Test 30188206)

2. UGT1A1 Recombinase (SPMED SBU01A010)

3.UDPGA (Sigma U6751)

4. UGT probe substrate β-estradiol (J&K 228703) and positive control compound silybin (Sigma S0417)

5. Promethicin (J&K 622045)

6.MgCl ₂ (Shanghai test 10012817)

7.AB Sciex API5000 LC/MS instrument

Second, the test steps

1. Use Tris-MgCl ₂ buffer to dilute UGT1A1, the compound of the present invention, probe substrate and UDPGA to a working solution concentration of 5× concentration.

2. Take 20μL of 1.25mg/mL UGT1A1 working solution, 20μL of 125μg/ml propamycin working solution and 20μL of the compound working solution of the present invention, pre-incubate on ice for 15 minutes, and then transfer to 37°C for pre-incubation for 15 minutes. After 15 minutes, add 20 μL of 50 μM probe substrate β-estradiol working solution and 20 μL of 25 mM UDPGA working solution to start the reaction. In the negative control group, 20 μL of buffer containing the same amount of solvent was used instead of the compound of the present invention.

3. After incubating for 30 minutes, add 400 μL of pre-cooled methanol containing internal standard to terminate the reaction, vortex to mix and centrifuge at 12000 rpm for 5 minutes, and take the supernatant for LC-MS/MS analysis.

The inhibitory rate of the compound of the present invention on UGT1A1 enzyme activity calculated by Microsoft Excel software and the IC ₅₀ value of the compound of the present invention on UGT1A1 enzyme activity calculated by Graphpad Prism are shown in Table 8.

_{Table 4 Inhibition rate or IC 50} value of the compounds of the present invention on UGT1A1 enzyme activity

化合物Compound	IC ₅₀(μM) IC ₅₀ (μM)	％抑制率(at 3μM)% Inhibition rate (at 3μM)
化合物011Compound 011	NANA	92.492.4
化合物024Compound 024	NANA	91.891.8
化合物042Compound 042	NANA	81.581.5
化合物045Compound 045	NANA	56.556.5
化合物054Compound 054	NANA	33.933.9
化合物058Compound 058	NANA	87.987.9
化合物064Compound 064	4.574.57	——
化合物066Compound 066	NANA	68.368.3
化合物071Compound 071	NANA	42.542.5

化合物072Compound 072	5.365.36	32.932.9
化合物077Compound 077	NANA	74.474.4
化合物081Compound 081	NANA	61.161.1

Claims

A compound represented by general formula (A) or a pharmaceutically acceptable salt thereof:

Ring Q is a 5-6 membered heterocyclic group, a C 6 -C 10 aryl group or a 5-10 membered heteroaryl group, the 5-6 membered heterocyclic group, a C 6 -C 10 aryl group or a 5-10 membered heterocyclic group aryl optionally substituted with R a, R a is selected from a F, Cl, Br, I, OH, CN or an optionally substituted group consisting of R b: C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl, C 1 -C 10 alkoxy;

R b is selected from F, Cl, Br, I, OH or CN;

Ring W is a phenyl group, a pyridyl group, a pyridonyl group or a 9-10 membered heteroaryl group, and the phenyl group, a pyridyl group, a pyridonyl group or a 9-10 membered heteroaryl group is optionally substituted by R c , and the R c is selected from OH or the following groups optionally substituted by R c1 : C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 3 -C 10 cycloalkyl, P(O)(C 1- C 3 alkyl) 2 , 4-6 membered heterocycloalkyl;

R c1 is selected from F, Cl, Br, I, CN, OH, NH 2 or the following groups optionally substituted by R c2 : C 1 -C 3 alkyl, C 1 -C 3 alkoxy, NHC(O ) O (C 1 -C 6 alkyl), (C 1 -C 6 alkyl) NHC(O)O, NH (C 1 -C 3 alkyl), N (C 1 -C 3 alkyl) 2 , S(O) 2 (C 1 -C 3 alkyl), 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, (C 3 -C 10 cycloalkyl) CH 2 O, 5-6 Membered heteroaryl, 5-6 membered heteroaryloxy;

R c2 is selected from 4-6 membered heterocycloalkyl, =0, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogenated C 1 -C 3 alkyl, F, Cl, Br, I , CN, OH, CH 2 OH or NH 2 ;

R 1 is selected from H, C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl, said C 1 -C 10 alkyl or C 3 -C 10 cycloalkyl is optionally substituted by R d , said R d is selected from F, Cl, Br, I, OH, CN or C 1 -C 3 alkyl;

X is selected from N or CH;

L is selected from O or NH;

requirement is,

When W is a phenyl ring optionally substituted by R c, ring Q is substituted with one or more R a phenyl or pyridyl, said R a is C 1 -C 10 alkoxy group, a C 1 -C 10 alkoxy optionally substituted with a R b, and when ring Q is phenyl substituted with one or more of R a, wherein R a 4 is connected with a phenyl group;

When ring Q is a 5-6 membered heterocyclic group, L is selected from O.
The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the ring W is a phenyl group, a pyridyl group, a 2-pyridonyl group or a 9-10 membered heterocyclic group. Aryl, the phenyl, 2-pyridonyl, pyridyl or 9-10 membered heteroaryl group is optionally substituted by R c.
The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein when ring W is a phenyl group optionally substituted by R c , and ring Q is one or more When R a is substituted with a phenyl group, and one of R a is connected to the 4-position of the phenyl group, the R a is a C 1 -C 6 alkoxy group optionally substituted by R b , and the R b is selected from F, Cl, Br, I, OH or CN.
The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R c is selected from OH or the following groups optionally substituted by R c1 : C 1 -C 6 Alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, P(O)(C 1 -C 3 alkyl) 2 , 4-6 membered heterocycloalkyl.
The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R c1 is selected from F, CN, OH, NH 2 or the following groups optionally substituted by R c2 Group: C 1 -C 3 alkyl, C 1 -C 3 alkoxy, NHC(O)OC(CH 3 ) 3 , (CH 3 ) 2 CHNHC(O)O, NH(C 1 -C 3 alkyl ), N(C 1 -C 3 alkyl) 2 , S(O) 2 (C 1 -C 3 alkyl), 4-10 membered heterocyclyl, 4-10 membered heterocyclyloxy, (C 3 -C 6 cycloalkyl) -CH 2 -O, 6-membered heteroaryl, 6-membered heteroaryloxy.
The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R c2 is selected from the group consisting of oxetanyl, =0, methyl, methoxy, OH, CH 2 CH 2 CH 2 F, CH 2 OH.
The compound represented by the general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the ring W is selected from
The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring Q is piperidinyl, phenyl or pyridyl, and said piperidinyl, phenyl or pyridyl optionally substituted with R a.
The compound represented by general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein Ra is F, Cl, Br, I, C 1 -C 6 alkyl, C 3- C 6 cycloalkyl or C 1 -C 6 alkoxy optionally substituted by F.
The compound represented by the general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the ring Q is selected from
The compound represented by the general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is H, C 3 -C 6 optionally substituted by C 1 -C 3 alkyl Cycloalkyl or C 1 -C 6 alkyl optionally substituted with F.
The compound of general formula (A) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from one of the following structures:
A pharmaceutical composition comprising the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.
Use of the compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 13 in the preparation of a medicament for preventing or treating MTAP-deficient tumors.