CN116406271A - Bicyclic compounds - Google Patents

Abstract

The invention provides a compound shown in a formula (I) or pharmaceutically acceptable salt thereof, a pharmaceutical composition, a preparation method thereof and application of the compound serving as an MAT2A inhibitor.

Description

Bicyclic compounds

The invention requires three prior applications of patent application number CN202010676114.3, the invention name of the double-ring compound and application number CN202110054406.8, the invention name of the double-ring compound and application number CN202110174940.2, and the invention name of the double-ring compound are filed in China national intellectual property office on 7 and 14 days of 2020 and are filed in China national intellectual property office on 1 and 15 days of 2021. The entire contents of the above-mentioned prior application are incorporated by reference into the present invention.

Technical Field

The invention relates to a novel bicyclic compound or pharmaceutically acceptable salt, a pharmaceutical composition containing the same and application of the novel bicyclic compound or pharmaceutically acceptable salt as an MAT2A inhibitor.

Background

Methionine adenosyltransferase (methionine adenosyltransferase, MAT), also known as S-adenosylmethionine synthetase, is a class of enzymes capable of catalyzing the reaction of methionine (Met) with ATP to produce S-adenosylmethionine (SAM). SAM can be used as a main methyl donor of in vivo methyltransferase, and controls the expression, transcription and translation of genes through a transmethylation reaction, thereby having important influence on the growth, death and differentiation of cells. Protein arginine methyltransferase 5 (protein arginine N-methyltransgerase 5, PRMT5) is methyltransferase using SAM as substrate, which plays an important role in regulating and controlling proliferation of tumor cells.

MAT enzymes are mainly of three subtypes, MAT1A, MAT A and MAT2B. MAT1A is mainly present in normal hepatocytes, while MAT2A is widely distributed in extrahepatic cells. These two subtypes differ in catalytic efficiency and in the manner of regulation. MAT2B does not have the ability to catalyze the synthesis of SAM, but rather acts as a regulatory subunit of MAT2A, modulating the catalytic activity of MAT2A after formation of a complex with MAT 2A.

The study found that the cancer Cell line deleted for methylthioadenosine phosphorylase (methylthioadenosine phosphorylase, MTAP) was sensitive to MAT2A inhibition (Cell Reports 15 (3) (2016) 574-587). MTAP is widely expressed in normal tissue cells. The enzyme is capable of catalyzing the conversion of 5' Methylthioadenosine (MTA) to 5-methylthioribose-1-phosphate and adenine. This process is also an important compensatory pathway for methionine in humans. When MTAP is deleted, the metabolic pathway of MTA is inhibited, resulting in a large accumulation of MTA in the body. The massive accumulation of MTA will partially inhibit PRMT5 activity, resulting in increased sensitivity of PRMT5 to changes in SAM levels in vivo; thus, in MTAP-deleted tumors, by inhibiting MAT2A, lowering SAM levels in vivo will further inhibit PRMT5 activity, producing a synthetic lethal effect.

The gene encoding human MTAP is located in the chromosome 9p21 region (chr 9p 21), and the frequency of homozygous deletions in all tumors is about 15% and varies from tumor to tumor. The tumor with high deletion frequency comprises glioma, mesothelioma, melanoma, gastric cancer, esophageal cancer, bladder cancer, pancreatic cancer, non-small cell lung cancer, astrocytoma, osteosarcoma, head and neck cancer, myxocartilage sarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, etc.

The human chromosome 9p21 region contains not only the gene encoding MTAP, but also tumor suppressor genes p16.sup.INK4A (also called CDKN 2A) and p15.sup.INK4B. In 80% -90% of CDKN 2A-deficient tumors, MTAP is also in a deleted state.

Whereas the expression level of MAT2A is abnormally elevated in various kinds of tumors, including gastric cancer, colon cancer, liver cancer, pancreatic cancer, etc., and selective inhibition of MAT2A can reduce the proliferative activity of MTAP-deficient cancer cells. Therefore, selective inhibition of MAT2A can be an effective tumor treatment.

WO2018039972, WO2018045071, WO2019191470 and WO2020123395 disclose MAT2A inhibitor heterocyclic compounds for the treatment of tumors.

Disclosure of Invention

The invention provides a compound shown in a general formula (I) or pharmaceutically acceptable salt thereof:

wherein,

L ₁ selected from N or O;

when L ₁ When selected from N, R ¹ Selected from H or optionally R ^1a The substituted following groups: c (C) ₁ -C ₁₀ Alkyl, C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, R ² Selected from optionally R ^2a The substituted following groups: c (C) ₁ -C ₁₀ Alkyl, C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, or R ¹ 、R ² Together with the N atoms to which they are attached form a 4-7 membered heterocyclic group, said 4-7 membered heterocyclic group optionally being R ^1a Substitution;

when L ₁ When selected from O, R ² Is absent and R ¹ Selected from optionally R ^1a The substituted following groups: c (C) ₁ -C ₁₀ Alkyl, C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl;

L ₂ selected from a bond, NH, or O;

R ³ selected from halogen or optionally R ^3a Substituted following groupsAnd (3) ball: c (C) ₁ -C ₁₀ Alkyl, C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl;

X ₁ 、X ₃ selected from N or CH;

X ₂ selected from N or CR ⁴ ；

Y is selected from O or S, and when X ₂ When N, Y is selected from S only;

R ⁴ selected from H, halogen, OH, CN, COOH or optionally R ^4a The substituted following groups: c (C) ₁ -C ₁₀ Alkyl, C (=o) -O- (C) ₁ -C ₆ Alkyl), C (=O) -NH (C) ₁ -C ₆ Alkyl), C (=O) -N (C) ₁ -C ₆ Alkyl group ₂ 、C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₁ -C ₁₀ Alkoxy, C ₃ -C ₁₀ Cycloalkyloxy, 3-to 10-membered heterocyclyloxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ Aryloxy, 5-to 10-membered heteroaryloxy, C ₂ -C ₁₀ Alkenyl, C ₂ -C ₁₀ Alkynyl;

ring Q is selected from C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl, said C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl optionally substituted with R ⁵ Substitution;

R ⁵ selected from halogen, =o, OH, CN or optionally R ^5a Substituted with the following groups: NH (NH) ₂ 、C ₁ -C ₁₀ Alkyl, C ₃ -C ₁₀ Cycloalkyl, C ₁ -C ₁₀ Alkoxy, C ₃ -C ₁₀ Cycloalkyloxy, 3-10 membered heterocyclyloxy;

each R is ^1a 、R ^2a 、R ^3a 、R ^4a 、R ^5a Independently selected from deuterium, F, cl, br, I, OH, CN, =o or optionally R ^b Substituted with the following groups: NH (NH) ₂ 、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyloxy, 4-7 membered heterocyclyloxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy;

each R is ^b Independently selected from F, cl, br, I, OH, CN, = O, NH ₂ 、SH、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl;

with the proviso that the compound of formula (I) does not comprise

In some embodiments, each R ^1a 、R ^2a 、R ^3a 、R ^4a 、R ^5a Independently selected from F, cl, br, I, OH, CN, =o or optionally R ^b Substituted with the following groups: NH (NH) ₂ 、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyloxy, 4-7 membered heterocyclyloxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy.

In some embodiments, R ⁴ Selected from H, halogen, OH, CN or optionally R ^4a The substituted following groups: c (C) ₁ -C ₁₀ Alkyl, C (=o) -O- (C) ₁ -C ₆ Alkyl), C (=O) -NH (C) ₁ -C ₆ Alkyl), C (=O) -N (C) ₁ -C ₆ Alkyl group ₂ 、C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₁ -C ₁₀ Alkoxy, C ₃ -C ₁₀ Cycloalkyloxy, 3-to 10-membered heterocyclyloxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ Aryloxy, 5-to 10-membered heteroaryloxy, C ₂ -C ₁₀ Alkenyl, C ₂ -C ₁₀ Alkynyl groups.

In some embodiments, L ₁ Selected from N, R ¹ Selected from H or optionally R ^1a Substituted C ₁ -C ₆ Alkyl, R ² Selected from optionally R ^2a The substituted following groups: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl.

In some embodiments, L ₁ Selected from N, R ¹ Selected from H or methyl, R ² Selected from optionally R ^2a The substituted following groups: methyl, cyclopropyl, cyclobutyl, oxetanyl.

In some embodiments, L ₁ Selected from N, R ¹ 、R ² Together with the N atoms to which they are attached form a 4-5 membered heterocyclic group, said 4-5 membered heterocyclic group optionally being R ^1a And (3) substitution.

In some embodiments, L ₁ Selected from N, R ¹ 、R ² Together with the N atom to which they are attached form an azetidinyl or pyrrolidinyl group, which is optionally substituted with R ^1a And (3) substitution.

In some embodiments, each R ^1a 、R ^2a Independently selected from deuterium, F, cl, br, I, OH, CN, =o or optionally R ^b Substituted with the following groups: NH (NH) ₂ 、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^1a 、R ^2a Independently selected from F, cl, br, I, OH, CN, =o or optionally R ^b Substituted with the following groups: NH (NH) ₂ 、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^1a 、R ^2a Independently selected from deuterium, F, cl, br, I, OH, CN, =o or optionally R ^b Substituted with the following groups: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl groups.

In some embodiments, each R ^1a 、R ^2a Independently selected from F, cl, br, I, OH, CN, =o or optionally R ^b Substituted with the following groups: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl groups.

In some embodiments, each R ^1a 、R ^2a Independently selected from OH or the following groups optionally substituted with OH: c (C) ₁ -C ₃ Alkyl, cyclopropyl.

In some embodiments, each R ^1a Independently selected from OH or CH ₂ OH。

In some embodiments, each R ^2a Independently selected from deuterium, OH or cyclopropyl.

In some implementationsIn embodiments, each R ^2a Independently selected from OH or cyclopropyl.

In some embodiments, L ₁ Selected from N, R ¹ Selected from H or methyl, R ² Selected from methyl, CD ₃ 、

Cyclopropyl group,

Or R is ¹ 、R ² And the N atoms to which they are attached together form

In some embodiments, L ₁ Selected from N, R ¹ Selected from H or methyl, R ² Selected from methyl group,

Cyclopropyl group,

Or R is ¹ 、R ² And the N atoms to which they are attached together form

In some embodiments, the building block

Selected from the group consisting of

In some embodiments, L ₂ Selected from chemical bonds.

In some embodiments, L ₂ Selected from O.

In some embodiments, R ³ Selected from halogen or optionally R ^3a The substituted following groups: c (C) ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl.

In some embodiments, R ³ Selected from halogen or optionally R ^3a Substituted C ₁ -C ₃ An alkyl group.

In some embodiments, R ³ Selected from F, cl, br, I or optionally R ^3a The substituted following groups: methyl, ethyl.

In some embodiments, each R ^3a Independently selected from F, cl, br, I, OH, CN, =o or optionally R ^b Substituted with the following groups: NH (NH) ₂ 、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₁ -C ₆ An alkoxy group.

In some embodiments, each R ^3a Independently selected from F, cl, br, I.

In some embodiments, each R ^3a Independently selected from F.

In some embodiments, R ³ Selected from Cl, CF ₃ Or B (B)A base.

In some embodiments, the building block

Selected from Cl, CF ₃ Or OCH (optical wavelength) ₂ CH ₃ 。

In some embodiments, X ₃ Selected from CH.

In some embodiments, X ₂ Selected from N, Y is selected from S.

In some embodiments, X ₂ Selected from CR ⁴ Y is selected from O.

In some embodiments, when X ₂ When selected from N, Y is selected from S, when X ₂ Selected from CR ⁴ When Y is selected from O.

In some embodiments, R ⁴ Selected from H, halogen, CN, COOH or optionally R ^4a The substituted following groups: c (C) ₁ -C ₆ Alkyl, C (=o) -O- (C) ₁ -C ₆ Alkyl), C (=O) -NH (C) ₁ -C ₃ Alkyl group, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyloxy, 5-10 membered heteroaryl.

In some embodiments, R ⁴ Selected from H, halogen, CN or optionally R ^4a The substituted following groups: c (C) ₁ -C ₆ Alkyl, C (=o) -O- (C) ₁ -C ₃ Alkyl), C (=O) -NH (C) ₁ -C ₃ Alkyl group, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyloxy, 5-10 membered heteroaryl.

In some embodiments, R ⁴ Selected from H, F, cl, br, I, CN, COOH or optionally quiltR ^4a The substituted following groups: c (C) ₁ -C ₃ Alkyl, C (=o) -O- (C) ₁ -C ₄ Alkyl), CONHMe, cyclopropyl, 4-6 membered heterocyclyl, C ₁ -C ₃ Alkoxy, cyclopropyloxy, 5-6 membered heteroaryl, 9 membered heteroaryl.

In some embodiments, R ⁴ Selected from H, F, cl, br, I, CN or optionally R ^4a The substituted following groups: c (C) ₁ -C ₃ Alkyl, COOMe, CONHMe, cyclopropyl, 4-6 membered heterocyclyl, C ₁ -C ₃ Alkoxy, cyclopropyloxy, 5-6 membered heteroaryl, 9 membered heteroaryl.

In some embodiments, each R ^4a Independently selected from F, cl, br, I, CN, OH, = O, C ₁ -C ₃ Alkyl or C ₁ -C ₃ An alkoxy group.

In some embodiments, each R ^4a Independently selected from OH, = O, C ₁ -C ₃ Alkyl or C ₁ -C ₃ An alkoxy group.

In some embodiments, each R ^4a Independently selected from = O, C ₁ -C ₃ Alkyl or C ₁ -C ₃ An alkoxy group.

In some embodiments, R ⁴ Selected from H, F, br, CN, COOMe, CONHMe,

Cyclopropyl, methoxy, cyclopropyloxy,

In some embodiments, R ⁴ Selected from H, F, br, CN, COOMe, CONHMe,

Cyclopropyl, methoxy, cyclopropyloxy,

In some embodiments, ring Q is selected from phenyl or pyridinyl, optionally substituted with R ⁵ And (3) substitution.

In some embodiments, ring Q is selected from phenyl, optionally substituted with R ⁵ And (3) substitution.

In some embodiments, R ⁵ Selected from halogen, CN or optionally R ^5a Substituted with the following groups: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyloxy, 4-7 membered heterocyclyloxy.

In some embodiments, R ⁵ Selected from halogen, C ₁ -C ₆ Alkyl, C ₁ -C ₆ Alkoxy or C ₃ -C ₆ Cycloalkyl group, the C ₁ -C ₆ Alkyl or C ₁ -C ₆ Alkoxy is optionally substituted with F.

In some embodiments, R ⁵ Selected from halogen or methoxy optionally substituted by F.

In some embodiments, R ⁵ Selected from F, cl, methyl, OCHF ₂ 、CF ₃ Or cyclopropyl.

In some embodiments, R ⁵ Selected from Cl or OCHF ₂ 。

In some embodiments, ring Q is selected from

In some embodiments, ring Q is selected from

In some embodiments, ring Q is selected from

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (II):

wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、X ₁ 、L ₂ And ring Q is as defined above.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (III):

wherein,

R ¹ selected from H;

R ² selected from C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl, said C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl optionally substituted with R ^2a Substitution;

or R is ¹ 、R ² And the N atoms to which they are attached together form a 4-6 membered heterocyclic group, said 4-6 membered heterocyclic group optionally being R ^2a Substitution;

R ^2a selected from halogen, CN, OH or optionally R ^b The substituted following groups: c (C) ₁ -C ₃ Alkyl, C ₃ -C ₆ Cycloalkyl or 5-6 membered heteroaryl;

R ^b selected from C ₁ -C ₃ Alkyl, halogen, CN or OH;

R ³ selected from halogen, C ₁ -C ₃ Alkyl or C ₃ -C ₆ Cycloalkyl group, the C ₁ -C ₃ Alkyl or C ₃ -C ₆ Cycloalkyl is optionally substituted with halogen, CN or OH;

R ⁵ selected from H, halogen or C ₁ -C ₃ An alkyl group;

X ₁ 、X ₂ selected from N or CH;

y is selected from O or S;

provided that when X ₂ When selected from N, Y is selected from S.

In some embodiments, R ² Selected from methyl groups.

In some embodiments, R ³ Selected from halogen or halomethyl.

In some embodiments, R ³ Selected from Cl or CF ₃ 。

In some embodiments，R ⁵ Selected from H, halogen or methyl.

In some embodiments, R ⁵ Selected from H or Cl.

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt is selected from the following compounds or pharmaceutically acceptable salts:

the invention also provides a pharmaceutical composition which comprises the compound shown in the formula (I) or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.

Further, the invention relates to application of a compound shown in the general formula (I) or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for preventing or treating MTAP-deleted tumors.

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

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

Further, the present invention provides a method of treating a MTAP-deficient tumor in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Definition and description of terms

Unless otherwise indicated, the radical and term definitions recited in the specification and claims of this application, including as examples, exemplary definitions, preferred definitions, definitions recited in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and coupled with each other. Such combinations and combined group definitions and structures of compounds should fall within the scope of the description herein. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.

Herein, a method of manufacturing a semiconductor device

Representing the ligation site.

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

The term "stereoisomer" refers to an isomer produced by the spatial arrangement of atoms in a molecule, and includes cis-trans isomers, enantiomers, non-corresponding isomers and conformational isomers.

The compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present invention.

The graphic representation of racemates or enantiomerically pure compounds herein is from Maehr, J.chem. Ed.1985, 62:114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by the wedge-shaped key and the dashed key. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomers unless specified otherwise. Likewise, all tautomeric forms are included within the scope of the invention.

The compounds of the invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-) -and (+) -pairs of enantiomers, (R) -and (S) -enantiomers, diastereomers, (D) -isomers, (L) -isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.

The term "tautomer" refers to a functional group isomer that results from the rapid movement of an atom in a molecule at two positions. The compounds of the present invention may exhibit tautomerism. Tautomeric compounds may exist in two or more interconvertible species. Proton-mobile tautomers result from the migration of a hydrogen atom covalently bonded between two atoms. Tautomers generally exist in equilibrium and attempts to isolate individual tautomers often result in a mixture whose physicochemical properties are consistent with the mixture of compounds. The location of the equilibrium depends on the chemical nature of the molecule. For example, among many aliphatic aldehydes and ketones such as acetaldehyde, the ketone type predominates; whereas, among phenols, the enol form is dominant. The present invention encompasses all tautomeric forms of the compounds.

The term "pharmaceutical composition" means a mixture of one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof with 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 particular atom is substituted with a substituent, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =o), meaning that two hydrogen atoms are substituted, oxo does not occur on the aromatic group.

The term "optional"Or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl "optionally" substituted with halogen means that ethyl may be unsubstituted (CH ₂ CH ₃ ) Monosubstituted (e.g. CH ₂ CH ₂ F) Polysubstituted (e.g. CHFCH ₂ F、CH ₂ CHF ₂ Etc.) or fully substituted (CF) ₂ CF ₃ ). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or pattern of substitution is introduced that is sterically impossible and/or synthetic.

When any variable (e.g. R ^a 、R ^b ) Where the composition or structure of a compound occurs more than once, its definition is independent in each case. For example, if a group is substituted with 2R ^b Substituted, each R ^b There are independent options.

When the number of one linking group is 0, such as- (CH) ₂ ) ₀ -, indicating that the linking group is a bond.

When one of the variables is selected from the group consisting of a chemical bond or is absent, the two groups representing its attachment are directly linked, e.g., when L in A-L-Z represents a bond, it is meant that the structure is actually A-Z.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

The term "C ₁ -C ₁₀ Alkyl "is understood to mean a straight-chain or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkyl group includes, but is not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl,2, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 2-dimethylbutyl, or the like; "C ₁ -C ₆ Alkyl "is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4, 5, 6 carbon atoms; "C ₁ -C ₄ Alkyl "is understood to mean a straight or branched saturated monovalent hydrocarbon radical having 1,2, 3, 4 carbon atoms; "C ₁ -C ₃ Alkyl "is understood to mean methyl, ethyl, n-propyl or isopropyl.

The term "C ₃ -C ₁₀ Cycloalkyl "is understood to mean a saturated monovalent mono-or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring. The term "C ₃ -C ₆ Cycloalkyl "is understood to mean a saturated monovalent mono-or bicyclic hydrocarbon ring having 3, 4, 5, 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "alkoxy" is understood to mean "alkyloxy" or "alkyl-O", preferably "C ₁ -C ₁₀ Alkoxy "may contain" C ₁ -C ₆ Alkoxy "and" C ₁ -C ₃ An alkoxy group.

The term "C ₂ -C ₁₀ Alkenyl "is understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The alkenyl groups can be classified into "cis" and "trans" orientations (or "E" and "Z" orientations). "C ₂ -C ₆ Alkenyl "is understood to be a straight-chain or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5 or 6 carbon atoms. "C ₂ -C ₁₀ Examples of alkenyl groups include, but are not limited to, vinyl (-ch=ch) ₂ ) Prop-1-enyl (-ch=chch) ₃ ) C, C-2-alkenyl (-CH) ₂ CH＝CH ₂ ) 2-methylpropan-1-enyl, but-2-enyl, but-3-enyl, but-1, 3-dienyl, 2-methyl-1, 3-butadienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl or hex-4-enyl.

The term "C ₂ -C ₁₀ Alkynyl "is understood to mean preferably a straight-chain or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C ₂ -C ₁₀ Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), prop-1-ynyl (1-propynyl, -C.ident.CCH) ₃ ) Prop-2-ynyl (propargyl), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C ₂ -C ₃ Examples of alkynyl groups include ethynyl (-C.ident.CH), prop-1-ynyl (1-propynyl, -C.ident.CCH) ₃ ) Prop-2-ynyl (propargyl).

The term "C ₃ -C ₁₀ Cycloalkyl "is understood to mean a saturated monovalent monocyclic, parallel, spiro or bridged ring having 3, 4, 5, 6, 7, 8, 9, 10 carbon atoms. Such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or a bicyclic hydrocarbon group such as a decalin ring; the term "C ₃ -C ₆ Cycloalkyl "is understood to mean a saturated monovalent monocyclic, fused, spiro or bridged ring having 3, 4, 5, 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term "cycloalkyloxy" is understood as "cycloalkyl-O-".

The term "3-10 membered heterocyclyl" means a saturated or partially saturated monovalent monocyclic, fused, spiro or bridged ring comprising 1 to 5, preferably 1 to 3, groups selected from N, O, S, S (O), S (O) ₂ Or a heteroatom group of (b). In particular, "3-10 membered heterocyclic group" includes "4-7 membered heterocyclic group" and the like. The term "4-7 membered heterocyclyl" means a saturated or partially saturated monovalent monocyclic, spiro or bridged ring comprising 1 to 4, preferably 1 to 2, groups selected from N, O, S, S (O), S (O) ₂ Or a heteroatom group of (b). In particular, the heterocyclic groups may include, but are not limited to: 4-membered rings such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6 membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl, or a partially saturated 6 membered ring such as tetrahydropyridinyl; or a 7-membered ring such as diazepanyl. Preferably, "4-7 membered heterocyclic group" includes "4-6 membered heterocyclic group", "4-5 membered heterocyclic group" and the like; optionally, the "3-10 membered heterocyclyl" also includes fused ring groups in which some heterocyclyl groups are fused to an aryl or heteroaryl group.

The term "heterocyclyloxy" is understood to mean "heterocyclyl-O-".

The term "5-10 membered heteroaryl" is understood to mean such monovalent monocyclic or bicyclic aromatic ring systems: having 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and which contain 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S; and, additionally, may be benzo-fused in each case. In particular, "5-10 membered heteroaryl" is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and their benzo derivatives, such as benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazole, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and their benzo derivatives, such as quinolinyl, quinazolinyl, isoquinolinyl, and the like. Preferably, "5-10 membered heteroaryl" includes "5-6 membered heteroaryl", "9 membered heteroaryl" and the like.

The term "heteroaryloxy" may be understood as "heteroaryl-O-".

The term "5-6 membered heteroaryl" is understood to be a monovalent aromatic ring system having 5 or 6 ring atoms and comprising 1 to 3 heteroatoms independently selected from N, O and S. In particular from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like.

The term "C ₆ -C ₁₀ Aryl "is understood to mean preferably a mono-or bicyclic ring of monovalent aromatic or partly aromatic nature having 6 to 10 carbon atoms. In particular having 6 carbon atoms ("C) ₆ Aryl "), such as phenyl; or a ring having 9 carbon atoms ("C) ₉ Aryl "), e.g. indanyl or indenyl, or a ring having 10 carbon atoms (" C " ₁₀ Aryl "), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl.

The term "aryloxy" may be understood as "aryl-O-".

The term "adjuvant" refers to a pharmaceutically acceptable inert ingredient. Examples of the category of the term "excipient" include, without limitation, binders, disintegrants, lubricants, glidants, stabilizers, fillers, diluents, and the like. Excipients can enhance the handling characteristics of the pharmaceutical formulation, i.e., by increasing flowability and/or tackiness, making the formulation more suitable for direct compression. Typical examples of "pharmaceutically acceptable carriers" suitable for use in the above formulations are: saccharides, starches, cellulose and derivatives thereof, and the like.

The term "treating" means administering a compound or formulation described herein 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 a mammal, particularly when such mammal is susceptible to the disease state, but has not been diagnosed as having the disease state;

(ii) Inhibiting a disease or disease state, i.e., inhibiting its progression;

(iii) The disease or condition is alleviated, even if the disease or condition subsides.

The term "therapeutically effective amount" means an amount of a compound of the invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays 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" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one of ordinary skill in the art based on his own knowledge and disclosure.

The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person 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", "comprising" or "includes" and variations thereof such as include or comprise are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to".

The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.

The present application also includes isotopically-labeled compounds identical to those recited herein, but for the replacement of one or more atoms by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as, respectively 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, and the like.

Certain isotopically-labeled compounds of the present application (e.g., with ³ H is H ¹⁴ C-labeled) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e ³ H) And carbon-14 (i.e ¹⁴ C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as ¹⁵ O、 ¹³ N、 ¹¹ C and C ¹⁸ F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present application can generally be prepared by following procedures analogous to those disclosed in the schemes and/or examples below by substituting an isotopically-labeled reagent for an non-isotopically-labeled reagent.

In addition, the use of heavier isotopes (such as deuterium (i.e. ² H) Substitution may provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, where deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium.

The pharmaceutical compositions of the present application may be prepared by combining the compounds of the present application with suitable pharmaceutically acceptable excipients, for example, in solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols, and the like.

Typical routes of administration of the compounds of the present application or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.

The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

In all methods of administration of the compounds of formula I described herein, the dosage administered is from 0.01 to 100mg/kg body weight, preferably from 0.05 to 50mg/kg body weight, more preferably from 0.1 to 30mg/kg body weight, either alone or in divided doses.

The chemical reactions of the embodiments of the present invention are accomplished in a suitable solvent that is compatible with the chemical changes of the present invention and the reagents and materials required therefor. In order to obtain the compounds of the present invention, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already present.

Detailed Description

The following examples illustrate the technical aspects of the invention in detail, but the scope of the invention is not limited thereto. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the invention without departing from the spirit and scope of the invention. All reagents used in the present invention are commercially available and can be used without further purification.

Unless otherwise indicated, the ratio of the mixed solvent is a volume mixing ratio.

Unless otherwise indicated,% refers to wt%.

The compounds being obtained by hand or by hand

Software naming, commercial compounds are referred to by vendor catalog names.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS). The unit of NMR shift is 10 ^-6 (ppm). The solvent for NMR measurement is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is Tetramethylsilane (TMS); IC (integrated circuit) ₅₀ "means half inhibition concentration, means concentration at which half of the maximum inhibition effect is achieved; "DCM" refers to dichloromethane; the following eluent can be a mixed eluent formed by two or more solvents, the ratio of which is the volume ratio of each solvent, for example, 0-10% methanol/methylene dichloride represents methanol in the mixed eluent in the gradient elution process: the volume usage of the dichloromethane is 0:100-10:100.

Example 1, 1- (2-chlorophenyl) -4- (methylamino) -7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 1)

Step 1: synthesis of 2- ((2-chlorophenyl) amino) -4- (trifluoromethyl) benzonitrile (intermediate 1-2)

2-Chloroaniline (674.59 mg,5.29 mmol) was dissolved in DMF (10 mL) and sodium hydrogen (528.74 m) was added at 0deg.C g,13.22 mmol), for 15 min, a solution of reactant 1-1 (1 g,5.29 mmol) in DMF (3 mL) was added, stirred at 0deg.C for 30 min, then at 25deg.C for 16 h. LCMS indicated product formation, the reaction was quenched with ammonium chloride solution (15 mL), extracted with ethyl acetate (15 mL x 2), washed with saturated brine (20 mL) and concentrated. Purifying the obtained product by flash column chromatography

20g

Quick silica gel column, gradient elution with 4-10% ethyl acetate/petroleum ether, flow rate 60 mL/min). The title compound (1.04 g) was obtained.

MS m/z(ESI):297.0[M+H] ⁺ 。

Step 2: synthesis of methyl 4-amino-1- (2-chlorophenyl) -2-carbonyl-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (intermediate 1-3)

Dimethyl malonate (1.25 g,9.44 mmol) was added to a toluene solution (4 mL) of intermediate 1-2 (700 mg,2.36 mmol) and tin tetrachloride (2.46 g,9.44 mmol) under nitrogen. Heated to 120℃and stirred for 20 hours. LCMS indicated product formation. The reaction was poured into water (10 mL), pH was adjusted to 7 with saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 2), and concentrated. Purifying the residue by flash column chromatography

12g

Quick silica gel column, 0-50% ethyl acetate/dichloromethane gradient elution, flow rate 80 mL/min). The title compound (300 mg) was obtained.

MS m/z(ESI):396.9[M+H] ⁺ 。

Step 3: synthesis of 4-amino-1- (2-chlorophenyl) -7- (trifluoromethyl) quinolin-2 (1H) -one (intermediate 1-4)

Intermediate 1-3 (200 mg, 504.10. Mu. Mol) was dissolved in methanol (6 mL) and water (2 mL), sodium hydroxide (403.28 mg,10.08 mmol) was added and the reaction was stirred at 50℃for 36 hours, LCMS indicated complete reaction of the starting material and product formation. Extracted with ethyl acetate (10 ml x 2), washed with brine, dried and concentrated. Crude title compound (150 mg) was obtained and used directly in the next reaction.

MS m/z(ESI):339.1[M+H] ⁺ 。

Step 4: synthesis of 1- (2-chlorophenyl) -4- (methylamino) -7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 1)

Intermediate 1-4 (40 mg, 100.38. Mu. Mol,85% purity) was dissolved in DMF (1.5 mL) and NaH (12.04 mg, 301.14. Mu. Mol,60% active content) was added at 0deg.C and reacted for 10 min with stirring at 0deg.C, methyl iodide (14.25 mg, 100.38. Mu. Mol) was added and reacted for 1h with stirring at 0deg.C, LCMS indicated product formation. The reaction mixture was poured into an ammonium chloride solution, extracted with ethyl acetate (10 ml×3), washed with brine, dried and concentrated. The solid obtained was purified by preparative high performance liquid chromatography (alkaline conditions, column: boston Prime C18. Times.30 mm. Times.5 μm; mobile phase: [ A:0.05% ammonia (v/v), B: acetonitrile ]; B%:39% -69%,9 min). The title compound (5.9 mg) was obtained.

m/z:ES ⁺ [M+H] ⁺ ＝MS m/z(ESI):353.0[M+H] ⁺ 。

¹ H NMR(400MHz,CD ₃ OD)δ＝8.17(d,J＝8.6Hz,1H),7.80-7.70(m,1H),7.65-7.58(m,2H),7.55(d,J＝9.2Hz,1H),7.46-7.37(m,1H),6.69(s,1H),5.72(s,1H),3.06-2.99(m,3H)。

Example 2, 7-chloro-1- (2-chlorophenyl) -4- (methylamino) quinolin-2 (1H) -one (Compound 2)

Step 1: synthesis of 4-chloro-2- ((2-chlorophenyl) amino) benzonitrile (intermediate 2-2)

2-Chloroaniline (82.01 mg, 642.85. Mu. Mol) was dissolved in DMF (2 mL), sodium hydrogen (51.42 mg,1.29mmol,60% active content) was added at 0deg.C, and after stirring for 15 min, a solution of reactant 2-1 in DMF (0.5 mL) was slowly added dropwise. After stirring the reaction at 0℃for 30 minutes, the reaction was stirred at room temperature for 16 hours. After completion of LCMS detection, saturated ammonium chloride solution (3 mL) was added dropwise and extracted with ethyl acetate (5 mL x 2). Drying the organic phase with anhydrous sodium sulfate, and evaporating under reduced pressure to obtain column chromatography

4g

Rapid silica gel column, eluent gradient: 0-5% ethyl acetate/Petroleum ether, flow rate 18 mL/min) to give the title compound (150 mg).

MS m/z(ESI):＝263.1[M+H] ⁺ .

Step 2: synthesis of methyl 4-amino-7-chloro-1- (2-chlorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylate (intermediate 2-3)

Intermediate 2-2 (50 mg, 190.03. Mu. Mol) was dissolved in 1, 2-Dichloroethane (DCE) (5 mL) and tin tetrachloride (99.01 mg, 380.05. Mu. Mol) and dimethyl malonate (75.32 mg, 570.08. Mu. Mol) were added. The reaction mixture was heated to 70℃and stirred for reaction for 12 hours. LC-MS detection reaction was completed. The reaction mixture was extracted with 15mL (5 mL. Times.3) of ethyl acetate by adding water. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (silica, petroleum ether: ethyl acetate=1:1) to give the title compound (53 mg).

MS m/z(ESI):＝363.0[M+H] ⁺ .

Step 3: synthesis of 4-amino-7-chloro-1- (2-chlorophenyl) quinolin-2 (1H) -one (intermediate 2-4)

Intermediate 2-3 (90 mg, 247.80. Mu. Mol) was dissolved in water/methanol (1 mL), an aqueous solution of sodium hydroxide (10M, 991.20. Mu.L) was added, and the reaction mixture was stirred at 50℃for 96 hours. LC-MS detection reaction was completed. The reaction solution was evaporated to dryness under reduced pressure and extracted with 15mL (5 ml×3) of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to give the title compound (27 mg).

MS m/z(ESI):＝304.9[M+H] ⁺ .

Step 4: synthesis of 7-chloro-1- (2-chlorophenyl) -4- (methylamino) quinolin-2 (1H) -one (Compound 2)

Intermediate 2-4 (27 mg,1.38 mmol) was dissolved in tetrahydrofuran (3 mL), sodium hydrogen (10.62 mg, 265.44. Mu. Mol) was added at 0℃and then the mixture was stirred for 2 hours, methyl iodide (6.28 mg, 44.24. Mu. Mol) was added, and the reaction mixture was heated to 40℃and then stirred for 12 hours. LC-MS detection reaction was completed. The reaction solution was evaporated to dryness under reduced pressure to give a high performance liquid chromatography (column: YMC-acts Triart C18 150 x 30mm x 5 μm; mobile phase: [ A:0.05% aqueous ammonia (v/v), B: acetonitrile ]; B%:40% -60%,11 min) to give the title compound (0.6 mg).

¹ H NMR(400MHz,CD ₃ OD)δ＝7.96(d,J＝8.8Hz,1H),7.73(d,J＝5.0Hz,1H),7.63-7.58(m,2H),7.45-7.40(m,2H),7.27(d,J＝1.8Hz,1H),5.63(s,1H),3.01(s,3H)。

MS m/z(ESI):＝319.0[M+H] ⁺ .

Example 3, 4-methylamino-1- (2-chlorophenyl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 3)

Step 1: synthesis of 2- ((2-chlorophenyl) amino) -6- (trifluoromethyl) -3-cyanopyridine (intermediate 3-2)

O-chloroaniline (7.20 g,56.46 mmol) was dissolved in DMF (100 mL), sodium hydride (9.68 g,242.07 mmol) was hydrogenated under nitrogen at 0deg.C, maintained at 0deg.C for 1 hour, a solution of reactant 3-1 (10 g,48.41 mmol) in DMF (20 mL) was added dropwise to the reaction system at 0deg.C and reacted at 25deg.C for 16 hours with stirring. LCMS detected reaction completion. The reaction mixture was quenched with 200mL of water at 0 ℃, followed by dilution with 200mL of ethyl acetate, three extractions with 600mL of ethyl acetate (200 mL x 3), three aqueous washes with saturated brine (400 mL x 3) and anhydrous sulfuric acidSodium drying, filtering and concentrating under reduced pressure. Separating the concentrated solution by column chromatography

120g

Quick silica gel column, eluent: 0-2% ethyl acetate/petroleum ether, gradient @100 ml/min) to give the title compound (5.16 g).

MS m/z(ESI):297.9[M+H] ⁺ 。

Step 2: synthesis of methyl 4-amino-1- (2-chlorophenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 3-3)

Intermediate 3-2 (5.16 g,17.34 mmol) and tin tetrachloride (18.06 g,69.34 mmol) were dissolved in 1, 2-dichloroethane (100 mL), dimethyl malonate (6.87 g,52.01 mmol) was added under nitrogen at 25℃and the reaction solution was warmed to 70℃and stirred at 70℃for 16 hours. Tin tetrachloride (2.23 g,8.56 mmol) and dimethyl malonate (1.15 g,8.70 mmol) were then added under nitrogen at 25℃and the reaction was warmed to 70℃and stirred at 70℃for 4 hours. LC-MS was shown to be complete. The reaction was quenched with water (150 mL), diluted with ethyl acetate (150 mL) and extracted three times with ethyl acetate (150 mL x 3). The organic phase was dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. Separating the concentrated solution by column chromatography

120g

Quick silica gel column, eluent: 0-100% ethyl acetate/petroleum ether, gradient @100 ml/min; eluent: 0-20% ethyl acetate/methanol, gradient @100 ml/min) to give crude title compound (11.64 g), which was used directly in the next reaction.

MS m/z(ESI):389.0[M+H] ⁺ 。

Step 3: synthesis of 4-amino-1- (2-chlorophenyl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (intermediate 3-4)

Intermediate 3-3 (11.64 g,29.27 mmol) was dissolved in methanol (115 mL) and aqueous sodium hydroxide (10M, 87.80 mL) was added dropwise at 0deg.C. The temperature of the reaction system was raised to 25℃and the reaction was stirred at 25℃for 16 hours. Next, the temperature of the reaction system was raised to 50℃and the reaction was stirred at 50℃for 70 hours. LC-MS showed the reaction was complete. The reaction was concentrated under reduced pressure to remove methanol, the concentrate was diluted with water (150 mL), extracted four times with ethyl acetate (200 mL x 4), the organic phase was dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure. Separating by column chromatography

80g

Quick silica gel column, eluent: 0-4% dichloromethane/methanol gradient @100 ml/min) to give the title compound (4.5 g).

MS m/z(ESI):340.1[M+H] ⁺ 。

Step 4: synthesis of 4-methylamino-1- (2-chlorophenyl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 3)

Intermediate 3-4 (14 mg, 41.21. Mu. Mol) was dissolved in THF (0.5 mL), sodium hydrogen (4.94 mg, 123.63. Mu. Mol,60% active content) was added under nitrogen at 0deg.C and the reaction was stirred at 0deg.C for 10 minutes. Methyl iodide (5.85 mg, 41.21. Mu. Mol) was added at 0℃and the reaction was stirred at 0℃for 1 hour. LC-MS showed product formation. The reaction mixture was quenched with water (0.5 mL) at 0deg.C and tetrahydrofuran was removed under reduced pressure. The title compound (0.7 mg) was obtained by HPLC (basic conditions) (column: YMC-acts Triart C18. Times.30 mm. Times.5 μm; A:0.05% aqueous ammonia (v/v), B: acetonitrile; B%:46% -66%,11 min).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.60(d,J＝8.3Hz,1H),7.68(d,J＝8.3Hz,1H),7.64-7.60(m,1H),7.51(td,J＝2.4,4.6Hz,2H),7.37-7.32(m,1H),5.74(s,1H),3.04(s,3H)

MS m/z(ESI):353.9[M+H] ⁺ 。

Example 4, 4-dimethylamino-1- (2-chlorophenyl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 4)

Step 1: synthesis of 4-dimethylamino-1- (2-chlorophenyl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 4)

Intermediate 3-4 (14 mg, 41.21. Mu. Mol) was dissolved in THF (0.5 mL), sodium hydrogen (4.94 mg, 123.63. Mu. Mol,60% active content) was added under nitrogen at 0deg.C and the reaction was stirred at 0deg.C for 10 minutes. Methyl iodide (5.85 mg, 41.21. Mu. Mol) was added at 0℃and the reaction was stirred at 0℃for 1 hour. LC-MS showed product formation. The reaction mixture was quenched with water (0.5 mL) at 0deg.C and tetrahydrofuran was removed under reduced pressure. The title compound (1.6 mg) was obtained by HPLC (basic conditions) (column: YMC-acts Triart C18: 150: 30 mm: 5 μm; mobile phase: A:0.05% aqueous ammonia (v/v), B: acetonitrile; B%:46% -66%,11 min).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.62(d,J＝8.3Hz,1H),7.69(d,J＝8.3Hz,1H),7.66-7.62(m,1H),7.55-7.49(m,2H),7.38-7.33(m,1H),6.14(s,1H),3.13(s,6H)。

MS m/z(ESI):368.0[M+H] ⁺ 。

Example 5, 1- (2-chlorophenyl) -4- (methylamino) -7- (trifluoromethyl) pyrido [2,3-d ] pyrimidine-2 (1H) -thione (Compound 5)

Step 1: synthesis of 2-chloro-6- (trifluoromethyl) pyridine-3-carbonyl chloride (intermediate 5-2)

Reaction 5-1 (500 mg,2.22 mmol) was dissolved in dichloromethane (10 mL) and dimethylformamide (48.68 mg, 666.00. Mu. Mol) was added and cooled to 0deg.C. Oxalyl chloride (422.68 mg,3.33 mmol) was added dropwise to the reaction solution at 0℃and the mixture was stirred at 25℃for 1 hour. And (5) detecting the completion of the reaction by thin layer chromatography. The reaction solution was concentrated to dryness under reduced pressure to give crude title compound (500 mg), which was used in the next reaction without purification.

Step 2: synthesis of 2-chloro-6- (trifluoromethyl) pyridine-3-carboxamide (intermediate 5-3)

Intermediate 5-2 (500 mg,2.05 mmol) was dissolved in dichloromethane (10 mL) and cooled to 0deg.C. Ammonia water (1.01 g,7.17mmol,1.10mL,25% active content) was added dropwise to the reaction solution at 0deg.C. After the dripping, the mixture is heated to 25 ℃ and stirred for reaction for 2 hours. LCMS detected reaction completion. The reaction solution was concentrated under reduced pressure to remove methylene chloride, ethyl acetate (20 mL) was added to dilute the solution, and the organic layer was washed with saturated brine, and concentrated to dryness under reduced pressure to give the crude title compound (450 mg) which was used in the next reaction without purification.

MS m/z(ESI):224.9[M+H] ⁺ 。

Step 3: synthesis of 1- (2-chlorophenyl) -2-thio-7- (trifluoromethyl) -2, 3-dihydropyrido [2,3-d ] pyrimidin-4 (1H) -one (intermediate 5-5)

Intermediate 5-3 (350 mg,1.56 mmol) was dissolved in dimethylformamide (6 mL) and cooled to 0deg.C. Sodium hydrogen (156 mg,3.9mmol,60% active content) was added to the reaction solution at 0℃and the reaction was stirred at 0℃for 0.5h. Intermediate 5-4 (264.38 mg,1.56 mmol) was added dropwise to the reaction solution at 0deg.C, and the reaction solution was stirred at 25deg.C for 1.5h. LCMS detected reaction completion. Water (1 mL) was added dropwise to the reaction solution at 0deg.C, extraction was performed with ethyl acetate (20 mL. Times.3), and the organic layer was concentrated to dryness under reduced pressure to give the crude title compound (500 mg) which was used directly in the next reaction without purification.

MS m/z(ESI):357.9[M+H] ⁺ 。

Step 4: synthesis of 4-chloro-1- (2-chlorophenyl) -7- (trifluoromethyl) pyrido [2,3-d ] pyrimidine-2 (1H) -thione (intermediate 5-6)

Intermediate 5-5 (50 mg, 139.77. Mu. Mol) was dissolved in acetonitrile (1 mL), diisopropylethylamine (90.32 mg, 698.84. Mu. Mol) and phosphorus oxychloride (107.15 mg, 698.84. Mu. Mol) was added. The reaction mixture was heated to 80℃and stirred for 2 hours. LCMS detected reaction completion. Concentrated to dryness under reduced pressure to give crude title compound (50 mg) which was used directly in the next reaction without purification.

MS m/z(ESI):376.0[M+H] ⁺ 。

Step 5: synthesis of 1- (2-chlorophenyl) -4- (methylamino) -7- (trifluoromethyl) pyrido [2,3-d ] pyrimidine-2 (1H) -thione (Compound 5)

Intermediate 5-6 (50 mg, 132.91. Mu. Mol) was added to an ethanol solution of methylamine (137.60 mg,1.33mmol,30% active content) at 0℃and the reaction mixture was stirred at 25℃for 2h. LCMS detected reaction completion. Ethyl acetate (20 mL x 3) and the organic layer concentrated to dryness under reduced pressure, the crude product was purified by preparing a liquid phase (column: YMC-acts three 18 x 30mm x 5 μm; mobile phase: 0.05% aqueous ammonia (v/v), B: acetonitrile; B%:40% -60%,11 min) to give the title compound (4.4 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δppm 8.66(d,J＝8.3Hz,1H),7.73(d,J＝8.3Hz,1H),7.62-7.57(m,1H),7.51-7.44(m,2H),7.40-7.31(m,1H),3.25(s,3H).

MS m/z(ESI):370.9[M+H] ⁺ 。

Example 6, 4- (methylamino) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 6)

Step 1: synthesis of 4-chloro-7- (trifluoromethyl) quinoline N-oxide (intermediate 6-2)

The starting material 6-1 (3.1 g,13.39 mmol) was dissolved in methylene chloride (55 mL), and m-chloroperoxybenzoic acid (5.43 g,26.77mmol, content 85%) was added and reacted at room temperature for 4 hours at 25 ℃. TLC showed the reaction was complete. The reaction mixture was quenched with saturated sodium bicarbonate (25 mL) at 25℃and the layers separated, and the organic phase was washed again with sodium bicarbonate (15 mL. Times.2), dried over anhydrous sodium sulfate, and quenchedThe organic phase was concentrated after filtration. The crude product was purified by column chromatography (SiO) ₂ Petroleum ether/ethyl acetate=7/1 to 1/1) to give the title compound (2.94 g).

MS m/z(ESI):248.1[M+H] ⁺ 。

Step 2: synthesis of 4-chloro-7- (trifluoromethyl) quinolin-2 (1H) -one (intermediate 6-3)

Intermediate 6-2 was dissolved in a mixed solvent of chloroform (30 mL) and water (4 mL), p-toluenesulfonyl chloride (1.79 g,9.40 mmol) was added, and the reaction was stirred at 25℃for 16 hours under nitrogen protection of potassium carbonate (3.25 g,23.51 mmol). TLC showed the reaction was complete. The reaction mixture was extracted with 30ml of methylene chloride and 50ml of water, followed by washing. The organic phase was separated, washed with 20mL of water, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (SiO) ₂ Petroleum ether/ethyl acetate=7/1 to 1/1) to give the title compound (1.9 g).

MS m/z(ESI):248.0[M+H] ⁺ 。

Step 3: synthesis of 4-chloro-1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (intermediate 6-4)

Intermediate 6-3 was dissolved in methylene chloride (2 mL), followed by addition of phenylboronic acid (98.49 mg, 807.75. Mu. Mol), copper acetate (80.69 mg, 444.26. Mu. Mol), pyridine (95.84 mg,1.21 mmol), and the reaction was carried out at 40℃for 16 hours under an oxygen atmosphere. The reaction solution was filtered, concentrated and purified by thin layer preparative chromatography (SiO ₂ Petroleum ether/ethyl acetate=1/1) to give the title compound (71.5 mg).

MS m/z(ESI):324.1[M+H] ⁺ 。

Step 4: synthesis of 4- (methylamino) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 6)

Intermediate 6-4 (35 mg, 108.13. Mu. Mol) and a solution of methylamine in ethanol (508.80 mg,5.41mmol, content 33%) were dissolved in N-methylpyrrolidone (1 mL), and reacted at 100℃for 16 hours under nitrogen. LCMS showed complete reaction of the starting material, and the reaction mixture was concentrated under reduced pressure and purified by hplc (column: YMC-acts three C18 150 x 30mm x 5 μm; mobile phase: 0.05% aqueous ammonia (v/v), B: acetonitrile; B%:60% -80%,11 min) to give the title compound (2.1 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.14(d,J＝8.8Hz,1H),7.72-7.65(m,2H),7.62(d,J＝6.8Hz,1H),7.52(d,J＝8.0Hz,1H),7.31(d,J＝7.3Hz,2H),6.87(s,1H),5.72(s,1H),3.03(s,3H).

MS m/z(ESI):319.1[M+H] ⁺ 。

Example 7, 7-chloro-4- (methylamino) -1-phenylquinolin-2 (1H) -one (Compound 7)

Step 1: synthesis of 4, 7-dichloropquinoline N-oxide (intermediate 7-2)

The starting material 7-1 (1 g,5.05 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid (2.05 g,10.10mmol,85% active content) was added and reacted at room temperature for 4 hours at 25 ℃. The reaction was quenched with saturated sodium bicarbonate (25 mL) at 25 ℃, the layers separated and the organic phase was again washed with 30mL sodium bicarbonate (15 mL x 2), dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (SiO) ₂ Petroleum ether/ethyl acetate=8/1 to 1/1) to give the title compound (670 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.71(d,J＝2.0Hz,1H),8.65(d,J＝6.5Hz,1H),8.35(d,J＝9.0Hz,1H),7.91(dd,J＝2.0,9.0Hz,1H),7.72(d,J＝6.8Hz,1H).

MS m/z(ESI):214.1[M+H] ⁺ 。

Step 2: synthesis of 4, 7-dichloropquinolin-2 (1H) -one (intermediate 7-3)

Intermediate 7-2 was dissolved in a mixed solvent of chloroform (12 mL) and water (1.5 mL), p-toluenesulfonyl chloride (716.10 mg,3.76 mmol) was added, and the reaction was stirred at 25℃for 16 hours under nitrogen protection with potassium carbonate (1.30 g,9.39 mmol). The reaction was extracted with 30ml of ethyl acetate and 30ml of water and washed. The organic phase was separated, washed with 40mL (20 mL x 2) of water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO) ₂ StoneOily ether/ethyl acetate=8/1 to 1/1) to give the title compound (395 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ7.85(d,J＝8.8Hz,1H),7.33(d,J＝2.0Hz,1H),7.25(dd,J＝2.0,8.8Hz,1H),6.72(s,1H).

MS m/z(ESI):214.1[M+H] ⁺ 。

Step 3: synthesis of 4, 7-dichloro-1-phenylquinolin-2 (1H) -one (intermediate 7-4)

Intermediate 7-3 was dissolved in methylene chloride (5 mL), followed by addition of phenylboronic acid (113.93 mg, 934.37. Mu. Mol), copper acetate (93.34 mg, 513.90. Mu. Mol), pyridine (110.86 mg,1.40 mmol), and the reaction was carried out at 40℃for 16 hours under an oxygen atmosphere. The reaction solution was filtered, concentrated under reduced pressure, and purified by thin layer preparative chromatography (SiO ₂ Petroleum ether/ethyl acetate=1/1) to give the title compound (75 mg).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.03(d,J＝8.7Hz,1H),7.70-7.58(m,3H),7.49-7.38(m,3H),7.10(s,1H),6.49(d,J＝2.0Hz,1H).

MS m/z(ESI):290.1[M+H] ⁺ 。

Step 4: synthesis of 7-chloro-4- (methylamino) -1-phenylquinolin-2 (1H) -one (Compound 7)

Intermediate 7-4 (35 mg, 120.63. Mu. Mol) and a solution of methylamine in ethanol (567.63 mg,6.03mmol, content 33%) were dissolved in N-methylpyrrolidone (1 mL), and reacted at 100℃for 16 hours under nitrogen. The reaction solution was concentrated under reduced pressure and purified by high performance liquid chromatography (column: YMC-acts Triart C18 150X 30mm X5 μm; mobile phase: [ A:0.05% aqueous ammonia (v/v), B: acetonitrile ]; B%:38% -58%,11 min) to give the title compound (1.4 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ7.93(d,J＝8.3Hz,1H),7.73-7.64(m,2H),7.63-7.56(m,1H),7.35-7.22(m,3H),6.59(s,1H),5.64(s,1H),3.00(s,3H).

MS m/z(ESI):285.1[M+H] ⁺ 。

Example 8 Synthesis of 7-chloro-1- (2-chlorophenyl) -4- (methylamino) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (Compound 8)

Step 1: synthesis of 4-amino-7-chloro-1- (2-chlorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxylic acid (intermediate 8-1)

Intermediate 2-3 (1.1 g,3.03 mmol) was dissolved in methanol (30 mL) and aqueous sodium hydroxide solution (8M, 12.49 mL) was added dropwise at 25 ℃. The reaction system was stirred at 25℃for 2 hours. Next, the temperature of the reaction system was raised to 50℃and the reaction was stirred at 50℃for 70 hours. LC-MS showed the reaction was complete. The reaction was adjusted to ph=1 with hydrochloric acid (3.8 m,35 mL), filtered, the filtrate was concentrated under reduced pressure to remove methanol, the concentrate was diluted with water (50 mL), extracted three times with ethyl acetate 150mL (50 mL x 3), the organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to dryness to give the crude title compound (1 g).

MS m/z(ESI):348.9[M+H] ⁺ 。

Step 2: synthesis of 4-amino-7-chloro-1- (2-chlorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carboxamide (intermediate 8-2)

Intermediate 8-1 (1 g,2.86 mmol), 4-dimethylaminopyridine (349.89 mg,2.86 mmol) and diisopropylethylamine (444.16 mg,3.44 mmol) were dissolved in tetrahydrofuran (25 mL) and Boc was added dropwise at 25 ℃ ₂ O (1.25 g,5.73 mmol), the reaction was stirred at 25℃for 16 hours. Aqueous ammonia (32.26 g,257.76 mmol) was added dropwise at 25℃and the reaction stirred at 25℃for 16 hours. LC-MS showed the reaction was complete. The reaction mixture was diluted with water (50 mL), extracted three times with ethyl acetate (50 mL 3), the organic phase was dried over sodium sulfate and purified by column chromatography

12g

Quick silica gel column, eluent 0-67% ethyl acetate/petroleum ether, flow velocity 40 mL/min) The title compound (363 mg) was obtained.

MS m/z(ESI):348.1[M+H] ⁺ 。

Step 3: synthesis of 4-amino-7-chloro-1- (2-chlorophenyl) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (intermediate 8-3)

Intermediate 8-2 (300 mg, 861.62. Mu. Mol) and pyridine (272.61 mg,3.45 mmol) were dissolved in acetonitrile (12 mL), phosphorus oxychloride (1.06 g,6.89 mmol) was added dropwise under nitrogen protection at 0deg.C, the reaction system temperature was raised to 40deg.C and the reaction was stirred at 40deg.C for 48 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove acetonitrile and phosphorus oxychloride, washed three times with 60mL (20 mL x 3) of water, the organic phase was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude title compound (391 mg) which was directly used in the next reaction.

MS m/z(ESI):330.0[M+H] ⁺ 。

Step 4: synthesis of 7-chloro-1- (2-chlorophenyl) -4- (methylamino) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (Compound 8)

Intermediate 8-3 (50 mg, 151.44. Mu. Mol) was dissolved in THF (2 mL), sodium hydrogen (12.11 mg, 302.88. Mu. Mol,60% active content) was added at 0deg.C to react for 1 hour at 0deg.C, methyl iodide (10.75 mg, 75.72. Mu. Mol) was added at 0deg.C, and LCMS showed complete consumption of the reaction and product formation. The reaction solution was quenched with water (2 mL) at 0 ℃, diluted with 5mL of ethyl acetate, extracted three times with ethyl acetate (5 mL of 3), the organic phase was dried over sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the concentrated solution was purified by high performance liquid chromatography (basic conditions) (column: YMC-acts Triart C18: 150 x 30mm x 5 μm; mobile phase: a:0.05% aqueous ammonia (v/v), B: acetonitrile; B%:42% -62%,11 min) to give the title compound (2.8 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.07(d,J＝8.9Hz,1H),7.77-7.72(m,1H),7.66-7.57(m,2H),7.48-7.42(m,1H),7.34(dd,J＝1.9,8.8Hz,1H),6.46(d,J＝2.0Hz,1H),3.53(s,3H)。

MS m/z(ESI):343.9[M+H] ⁺ 。

Example 9, 4- (3-hydroxy azetidin-1-yl) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 9)

Step 1: synthesis of 4- (3-hydroxyazetidin-1-yl) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 9)

Intermediate 6-4 (70 mg, 216.25. Mu. Mol) and azetidin-3-ol (79.03 mg,1.08 mmol) were added to N-methylpyrrolidone (1.5 mL), and the reaction solution was stirred under nitrogen at 80℃for 16h. LC-MS detection reaction was completed. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative HPLC (column: YMC-acts Triart C18 150X 30mm X5 μm; mobile phase: [ A:0.05% aqueous ammonia (v/v), B: acetonitrile ]; B%:35% -57%,9 min) to give the title compound (23.6 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.11(d,J＝8.5Hz,1H),7.72-7.59(m,3H),7.51(d,J＝8.3Hz,1H),7.29(d,J＝7.5Hz,2H),6.87(s,1H),5.57(s,1H),4.83-4.78(m,1H),4.70(t,J＝7.8Hz,2H),4.21(dd,J＝3.6,9.2Hz,2H).

MS m/z(ESI):361.3[M+H] ⁺ 。

Example 10, 7-chloro-1- (2-chlorophenyl) -4- (dimethylamino) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (Compound 10)

Step 1: synthesis of 7-chloro-1- (2-chlorophenyl) -4- (dimethylamino) -2-oxo-1, 2-dihydroquinoline-3-carbonitrile (Compound 10)

Intermediate 8-3 (50 mg, 151.44. Mu. Mol) was dissolved in THF (2 mL) and reacted at 0deg.C with sodium hydrogen (12.11 mg, 302.88. Mu. Mol,60% active content) under nitrogen for 1 hour at 0deg.C with methyl iodide (10.75 mg, 75.72. Mu. Mol) at 0deg.C, LCMS showed complete consumption of the reaction and product formation. The reaction solution was quenched with water (2 mL) at 0 ℃, diluted with 5mL of ethyl acetate, extracted three times with ethyl acetate (5 mL of 3), the organic phase was dried over sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the concentrated solution was purified by high performance liquid chromatography (basic conditions) (column: YMC-acts Triart C18: 150 x 30mm x 5 μm; mobile phase: a:0.05% aqueous ammonia (v/v), B: acetonitrile; B%:42% -62%,11 min) to give the title compound (0.5 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.08(d,J＝9.0Hz,1H),7.79-7.74(m,1H),7.68-7.59(m,2H),7.49-7.43(m,1H),7.35(dd,J＝1.9,8.9Hz,1H),6.50(d,J＝1.8Hz,1H),3.49(s,6H)。

MS m/z(ESI):357.9[M+H] ⁺ 。

Example 11, 4- (3-hydroxypyrrolidin-1-yl) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 11)

Step 1: synthesis of 4- (3-hydroxypyrrolidin-1-yl) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 11)

Intermediate 6-4 (70 mg, 216.25. Mu. Mol) was dissolved in N-methylpyrrolidinone (NMP) (1 mL), 3-hydroxypyrrolidine (94.20 mg,1.08 mmol) was added dropwise at 25℃and the reaction solution was warmed to 80℃and stirred at 80℃for 16 hours. LC-MS detection reaction was completed. The reaction solution was diluted with acetonitrile (1 mL) and separated by column chromatography (basic conditions) (column: boston Prime C18 x 25mm x 5 μm; mobile phase: a:0.05% aqueous ammonia (v/v), B: acetonitrile; B%:40% -60%,9 min) to give the title compound (17.9 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.41(d,J＝8.5Hz,1H),7.72-7.65(m,2H),7.65-7.59(m,1H),7.53-7.49(m,1H),7.30(dd,J＝2.4,5.9Hz,2H),6.89(s,1H),5.90(s,1H),4.59(s,1H),4.04-3.95(m,2H),3.72-3.65(m,1H),3.57(d,J＝11.0Hz,1H),2.25-2.09(m,2H)；

MS m/z(ESI):375.1[M+H] ⁺ 。

Example 12 (R) -4- (2- (hydroxymethyl) pyrrolidin-1-yl) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 12)

Step 1: synthesis of (R) -4- (2- (hydroxymethyl) pyrrolidin-1-yl) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 12)

Intermediate 6-4 (70 mg, 216.25. Mu. Mol) was dissolved in N-methylpyrrolidone (NMP), D-prolyl (109.37 mg,1.08 mmol) was added dropwise at 25℃and the reaction mixture was warmed to 80℃and stirred at 80℃for 16 hours. LC-MS detection reaction was completed. The reaction solution was diluted with acetonitrile (1 mL) and separated by column chromatography (basic conditions) (column Boston Prime C18 150 x 25mm x 5 μm; mobile phase: 0.05% aqueous ammonia (v/v), B: acetonitrile; B%:43% -65%,9 min) to give the title compound (27.3 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.31(d,J＝8.6Hz,1H),7.71-7.65(m,2H),7.64-7.59(m,1H),7.50(dd,J＝1.4,8.6Hz,1H),7.36-7.27(m,2H),6.88(s,1H),6.12(s,1H),4.23-4.13(m, 1H),4.02(dt,J＝5.6,10.3Hz,1H),3.78-3.72(m,1H),3.71-3.62(m,2H),2.41-2.30(m,1H),2.15-2.03(m,2H),1.94-1.78(m,1H)；

MS m/z(ESI):389.1[M+H] ⁺ 。

Example 13, 4- ((cyclopropylmethyl) amino) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 13)

Step 1: synthesis of 4- ((cyclopropylmethyl) amino) -1-phenyl-7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 13)

Intermediate 6-4 (70 mg, 216.25. Mu. Mol) was dissolved in N-methylpyrrolidone (NMP) (1 mL), cyclopropylmethylamine (76.90 mg) was added dropwise at 25℃and the reaction mixture was warmed to 80℃and stirred at 80℃for 16 hours. LC-MS detection reaction was completed. The reaction solution was diluted with acetonitrile (1 mL) and separated by column chromatography (basic conditions) (column Boston Prime C18 150 x 25mm x 5 μm; mobile phase [ a:0.05% aqueous ammonia (v/v), B: acetonitrile ]; B%:50% -72%,9 min) to give the title compound (21.1 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.28(d,J＝8.4Hz,1H),7.72-7.65(m,2H),7.64-7.59(m,1H),7.53(d,J＝8.2Hz,1H),7.31(d,J＝7.3Hz,2H),6.87(s,1H),5.80(s,1H),3.24(d,J＝6.7Hz,2H),1.30(s,1H),0.66(br d,J＝6.8Hz,2H),0.39(br d,J＝5.1Hz,2H)；

MS m/z(ESI):359.1[M+H] ⁺ 。

Example 14, 1- (4- (difluoromethoxy) phenyl) -4- (methylamino) -7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 14)

Step 1: synthesis of 4-chloro-1- (4- (difluoromethoxy) phenyl) -7- (trifluoromethyl) quinolin-2 (1H) -one (intermediate 14-1) intermediate 7-3 (110 mg, 0.447 mmol) was dissolved in dichloromethane (2 mL) under an oxygen atmosphere followed by the sequential addition of p-difluoromethoxy phenylboronic acid (124.85 mg,0.664 mmol), copper acetate (160.6 mg), pyridine (110 mg,1.33 mmol). Subsequently, the reaction solution was reacted at 40℃for 16 hours. LCMS showed product formation. The reaction solution was filtered, concentrated and purified directly by thin layer preparative chromatography (SiO ₂ Petroleum ether/ethyl acetate=1/1) to give the crude title compound (105 mg) which was used directly in the next reaction.

Step 2: synthesis of 1- (4- (difluoromethoxy) phenyl) -4- (methylamino) -7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 14)

Intermediate 14-1 (100 mg, crude, 30% purity), et under nitrogen atmosphere ₃ N (780 mg,7.71 mmol) and methylamine hydrochloride (348 mg,5.14 mmol) were dissolved in N-methylpyrrolidone (3 mL) and reacted at 100℃for 16 hours. LCMS showed complete reaction of starting material. Concentrating the reaction solution under reduced pressure, purifying by high performance liquid chromatography (column: YMC-Actus Triart C18 150 x 30mm x 5 μm; mobile phase: [ A:0.05% ammonia water) (v/v), B: acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:60% -80%,11 min), the product was collected and lyophilized to give the title compound (14 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.15(d,J＝8.4Hz,1H),7.54(dd,J＝8.7,1.7Hz,1H),7.43(s,2H),7.36(d,J＝8.9Hz,2H),7.01(s,1H),6.90(s,1H),5.72(s,1H),3.03(s,3H).

MS m/z(ESI):385.1[M+H] ⁺ 。

Example 15, 1- (2-chlorophenyl) -4- ((cyclopropylmethyl) amino) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid methyl ester (Compound 15)

Step 1: synthesis of methyl 1- (2-chlorophenyl) -4- ((cyclopropylmethyl) amino) -2-oxo-7- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (Compound 15)

Intermediate 1-3 (80 mg, 201.64. Mu. Mol) and bromomethylcyclopropane (27.22 mg, 201.64. Mu. Mol) were dissolved in DMF (1 mL) at 25℃and potassium carbonate (69.67 mg, 504.10. Mu. Mol) was added thereto, and the reaction mixture was stirred at 80℃for 3 hours. LCMS indicated product formation. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL x 2), dried and concentrated under reduced pressure. The residue was purified by preparative high performance liquid chromatography (basic conditions, column: boston Prime C18. Times.30 mm. Times.5 μm; mobile phase: [ A:0.05% ammonia (v/v), B: acetonitrile ]; B%:40% -70%,9 min) to give the title compound (1.2 mg).

MS m/z(ESI):451.1[M+H] ⁺ 。

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.41(d,J＝8.6Hz,1H),7.77-7.69(m,1H),7.65-7.54(m,3H),7.47-7.36(m,1H),6.69(s,1H),3.86(s,3H),3.25(d,J＝7.1Hz,2H),1.29-1.22(m,1H),0.71-0.60(m,2H),0.34(m,2H)。

EXAMPLE 16, 1- (2-chlorophenyl) -4- (3-hydroxypyrrolidin-1-yl) -7- (trifluoromethyl) pyrido [2,3-d ] pyrimidine-2 (1H) -thione (Compound 16)

Step 1: synthesis of 1- (2-chlorophenyl) -4- (3-hydroxypyrrolidin-1-yl) -7- (trifluoromethyl) pyrido [2,3-d ] pyrimidine-2 (1H) -thione (Compound 16)

Intermediate 5-6 (50 mg, 132.91. Mu. Mol) was dissolved in acetonitrile (1 mL), 3-hydroxypyrrolidine (77.19 mg, 265.82. Mu. Mol) and diisopropylethylamine (51.53 mg, 398.73. Mu. Mol) were added, and the reaction mixture was stirred at 50℃for 15 hours. LCMS detected reaction completion. Ethyl acetate (20 mL x 3) and the organic layer concentrated to dryness under reduced pressure, the crude product was purified by preparative liquid phase (column: YMC-acts three 18.150.30 mm.5 μm; mobile phase: 0.05% ammonia (v/v), B: acetonitrile; B%:40% -60%,11 min) to give the title compound (1.5 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.98-8.92(m,1H),7.74-7.67(m,1H),7.63-7.54(m,1H),7.52-7.44(m,2H),7.39-7.30(m,1H),4.37-4.32(m,1H),4.20-4.15(m,2H),4.12-3.77(m,2H),2.34-2.02(m,2H)。

MS m/z(ESI):427.1[M+H] ⁺ 。

Example 17, 1- (2-chlorophenyl) -4- (3-hydroxypyrrolidin-1-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 17)

Step 1: synthesis of 4-chloro-1- (2-chlorophenyl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (intermediate 17-1)

Intermediate 1-4 (200 mg, 588.76. Mu. Mol) was dissolved in acetonitrile (40 mL) and tert-butyl nitrite (182.14 mg,1.77 mmol) was added dropwise under nitrogen at 0deg.C and maintained at 0deg.C for 10 minutes. Copper chloride (253.31 mg,1.88 mmol) was added at 0deg.C and held for 10 minutes, and the reaction was stirred at 25deg.C for 40 hours. LC-MS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove acetonitrile, the concentrate was diluted with water (20 mL), extracted three times with ethyl acetate (20 mL x 3), the organic phase was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give the crude title compound (211 mg) which was used directly in the next step.

MS m/z(ESI):358.9[M+H] ⁺ 。

Step 2: synthesis of 1- (2-chlorophenyl) -4- (3-hydroxypyrrolidin-1-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 17)

Intermediate 17-1 (211 mg, 587.53. Mu. Mol) and 3-hydroxypyrrolidine (102.37 mg,1.18 mmol) were dissolved in acetonitrile (5 mL), triethylamine (178.36 mg,1.76 mmol) was added at 25℃and the reaction system temperature was raised to 50℃and stirred at 50℃for 16 hours. LC-MS showed the reaction was complete. The reaction solution was concentrated under reduced pressure, the concentrated solution was diluted with methanol (3 mL), and the diluted solution was separated by high performance liquid chromatography (column: YMC-acts Triart C18 150X 30mm X7 μm; mobile phase: A:0.05% aqueous ammonia (v/v), B: acetonitrile; B%:45% -70%,9 minutes) to give the title compound (21.2 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.85(dd,J＝3.6,8.4Hz,1H),7.70-7.56(m,2H),7.60-7.46(m,2H),7.40-7.29(m,1H),5.85(s,1H),4.06-3.96(m,2H),3.79-3.69(m,1H),3.61(d,J＝10.8Hz,1H),3.33(s,1H),2.27-2.10(m,2H)。

MS m/z(ESI):409.9[M+H] ⁺ 。

Example 18, 1- (2-chlorophenyl) -4- (methylamino) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylic acid methyl ester (Compound 18)

Step 1: synthesis of methyl 1- (2-chlorophenyl) -4- (methylamino) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (Compound 18)

Intermediate 3-3 (30 mg, 75.43. Mu. Mol) was dissolved in THF (1 mL), sodium hydrogen (9.05 mg, 226.28. Mu. Mol,60% active content) was added under nitrogen at 0deg.C and the reaction was stirred at 0deg.C for 10 minutes. Methyl iodide (10.71 mg, 75.43. Mu. Mol) was added at 0℃and the reaction was stirred at 25℃for 1 hour. The reaction system temperature was raised to 40℃and the reaction was stirred at 40℃for 4 hours. LC-MS showed the reaction was complete. The reaction mixture was quenched with water (0.5 mL) and diluted with methanol (1 mL) at 0deg.C. The title compound (2.9 mg) was obtained by HPLC (basic conditions) (column: YMC-acts Triart C18. Times.30 mm. Times.5 μm; mobile phase: A:0.05% aqueous ammonia (v/v), B: acetonitrile; B%:40% -60%,11 min).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.69(d,J＝8.3Hz,1H),7.69(d,J＝8.3Hz,1H),7.65-7.59(m,1H),7.53-7.46(m,2H),7.40-7.35(m,1H),3.90(s,3H),3.07(s,3H).

MS m/z(ESI):412.0[M+H] ⁺ 。

Example 19, 1- (2-chlorophenyl) -4- (dimethylamino) -7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 19)

Step 1: synthesis of 1- (2-chlorophenyl) -4- (dimethylamino) -7- (trifluoromethyl) quinolin-2 (1H) -one (Compound 19)

Intermediate 1-4 (40 mg, 100.38. Mu. Mol,85% purity) was dissolved in DMF (1.5 mL) and NaH (12.04 mg, 301.14. Mu. Mol,60% active content) was added at 0deg.C and reacted for 10 min with stirring at 0deg.C, methyl iodide (14.25 mg, 100.38. Mu. Mol) was added and reacted for 1h with stirring at 0deg.C, LCMS indicated product formation. The reaction mixture was poured into an ammonium chloride solution, extracted with ethyl acetate (10 ml×3), washed with brine, dried and concentrated. The solid obtained was purified by preparative high performance liquid chromatography (alkaline conditions, column: boston Prime C18. Times.30 mm. Times.5 μm; mobile phase: [ A:0.05% ammonia (v/v), B: acetonitrile ]; B%:39% -69%,9 min). The title compound (3.5 mg) was obtained.

MS m/z(ESI):367.1[M+H] ⁺ 。

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.20(d,J＝8.6Hz,1H),7.81-7.70(m,1H),7.66-7.59(m,3H),7.56(d,J＝8.3Hz,1H),7.47-7.40(m,1H),6.74(s,1H),6.16(s,1H),3.08(s,6H)。

Example 20, 1- (2-chlorophenyl) -3- (1-methyl-1H-benzo [ d ] imidazol-6-yl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 20)

Step 1: synthesis of 4-amino-3-bromo-1- (2-chlorophenyl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (intermediate 20-1)

Intermediate 1-4 (400 mg,1.18 mmol) was dissolved in acetonitrile (8 mL), N-bromosuccinimide (209.58 mg,1.18 mmol) was added at 25℃and the reaction was stirred at 25℃for 0.1 hour. LC-MS monitored complete reaction of the starting materials and formation of the target product. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=48% to 100%) to give the title compound (492.9 mg).

MS m/z(ESI):420.1[M+H] ⁺ 。

Step 2: synthesis of 3-bromo-1- (2-chlorophenyl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (intermediate 20-2) and 3-bromo-1- (2-chlorophenyl) -4- (dimethylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (intermediate 20-3)

Intermediate 20-1 (492 mg,1.18 mmol) was dissolved in tetrahydrofuran (10 mL), sodium hydride (94.02 mg,2.35mmol,60% purity) was added under nitrogen at 0deg.C and the reaction was stirred at 0deg.C for 1 hour. Next, methyl iodide (133.46 mg, 940.29. Mu. Mol) was added dropwise to the reaction mixture at 0 ℃. The reaction mixture was stirred at 25℃for 16 hours. LC-MS monitored complete reaction of the starting materials and formation of the target product. The reaction solution was quenched with water (10 mL) at 0deg.C, extracted three times with ethyl acetate, and the organic layer was concentrated to dryness under reduced pressure to give crude title compound (mixture containing intermediate 20-2 and intermediate 20-3) which was used directly in the next reaction without purification.

MS m/z (ESI) (intermediate 20-2): 433.9[ M+H ]] ⁺ 。

MS m/z (ESI) (middleBody 20-3) 447.8[ M+H ]] ⁺ 。

Step 3: synthesis of 1- (2-chlorophenyl) -3- (1-methyl-1H-benzo [ d ] imidazol-6-yl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 20)

A mixture of intermediate 20-2 and intermediate 20-3 (100 mg, 231.15. Mu. Mol), intermediate 20-4 (89.50 mg, 346.73. Mu. Mol) was dissolved in dioxane (2 mL), and Pd (dppf) Cl was added ₂ (16.91 mg, 23.12. Mu. Mol), cesium carbonate (150.63 mg, 462.30. Mu. Mol) and water (0.5 mL). The reaction solution was stirred under nitrogen protection at 100℃for 16 hours. LC-MS monitored complete reaction of the starting materials and formation of the target product. The reaction solution was extracted three times with ethyl acetate, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by high performance liquid chromatography (column: YMC-Actuas Triart C18 150. Mu.m.30 mm. Mu.m 5 μm; mobile phase: 0.05% aqueous ammonia (v/v): B: acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B%:45% -65%,11 min)), to give the title compound (7.3 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.69(d,J＝8.3Hz,1H),8.16(s,1H),7.70(dd,J＝6.6,8.1Hz,2H),7.63-7.59(m,2H),7.51-7.45(m,2H),7.43-7.38(m,1H),7.35-7.30(m,1H),3.93(s,3H),2.47(s,3H)

MS m/z(ESI):484.2[M+H] ⁺ 。

Example 21, 1- (2-chlorophenyl) -4- (dimethylamino) -3- (1-methyl-1H-benzo [ d ] imidazol-6-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 21)

Step 1: synthesis of 1- (2-chlorophenyl) -4- (dimethylamino) -3- (1-methyl-1H-benzo [ d ] imidazol-6-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 21)

A mixture of intermediate 20-2 and intermediate 20-3 (100 mg, 231.15. Mu. Mol), intermediate 20-4 (89.50 mg, 346.73. Mu. Mol) was dissolved in dioxane (2 mL), and Pd (dppf) Cl was added ₂ (16.91 mg, 23.12. Mu. Mol), cesium carbonate (150.63 mg, 462.30. Mu. Mol) and water (0.5 mL). ReactionThe solution was stirred at 100deg.C under nitrogen for 16 hours. LC-MS monitored complete reaction of the starting materials and formation of the target product. The reaction solution was extracted three times with ethyl acetate, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by high performance liquid chromatography (column: YMC-Actuas Triart C18 150. Mu.m.30 mm. Mu.m 5 μm; mobile phase: 0.05% aqueous ammonia (v/v): B: acetonitrile) ]The method comprises the steps of carrying out a first treatment on the surface of the B%:45% -65%,11 min)), to give the title compound (3.8 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.65(d,J＝8.1Hz,1H),8.37(s,1H),7.79(d,J＝8.3Hz,1H),7.72(d,J＝8.3Hz,1H),7.67-7.61(m,2H),7.55-7.48(m,2H),7.45-7.39(m,1H),7.32(d,J＝8.0Hz,1H),3.98(s,3H),2.73(s,6H).

MS m/z(ESI):498.2[M+H] ⁺ 。

Example 22, 1- (2-chlorophenyl) -3- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 22)

Step 1: synthesis of 1- (2-chlorophenyl) -3- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 22)

Intermediate 20-2 and intermediate 20-3 (50 mg, 115.57. Mu. Mol), intermediate 22-1 (40.76 mg, 173.36. Mu. Mol) were dissolved in dioxane (1 mL), and Pd (dppf) Cl was added ₂ (8.46 mg, 11.56. Mu. Mol), cesium carbonate (75.31 mg, 231.15. Mu. Mol) and water (0.25 mL). The reaction solution was stirred under nitrogen protection at 100℃for 16 hours. LC-MS monitored complete reaction of the starting materials and formation of the target product. The reaction solution was extracted three times with ethyl acetate, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by high performance liquid chromatography (column: YMC-Actuas Triart C18 150. Mu.m.30 mm. Mu.m 5 μm; mobile phase: 0.05% aqueous ammonia (v/v): B: acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B%:45% -65%,11 min)), to give the title compound (3.3 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.69(d,J＝8.3Hz,1H),7.72-7.66(m,2H),7.65-7.55(m,2H),7.51-7.46(m,2H),7.40-7.34(m,1H),6.62(d,J＝9.3Hz,1H),3.64(s,3H),2.81(s,3H)

MS m/z(ESI):461.2[M+H] ⁺ 。

Example 23, 1- (2-chlorophenyl) -4- (dimethylamino) -3- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 23)

Step 1: synthesis of 1- (2-chlorophenyl) -4- (dimethylamino) -3- (1-methyl-6-oxo-1, 6-dihydropyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 22)

A mixture of intermediate 20-2 and intermediate 20-3 (50 mg, 115.57. Mu. Mol), intermediate 22-1 (40.76 mg, 173.36. Mu. Mol) was dissolved in dioxane (1 mL), and Pd (dppf) Cl was added ₂ (8.46 mg, 11.56. Mu. Mol), cesium carbonate (75.31 mg, 231.15. Mu. Mol) and water (0.25 mL). The reaction solution was stirred under nitrogen protection at 100℃for 16 hours. LC-MS monitored complete reaction of the starting materials and formation of the target product. The reaction solution was extracted three times with ethyl acetate, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by high performance liquid chromatography (column: YMC-Actuas Triart C18 150. Mu.m.30 mm. Mu.m 5 μm; mobile phase: 0.05% aqueous ammonia (v/v): B: acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B%:45% -65%,11 min)), to give the title compound (1 mg).

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.63(d,J＝8.3Hz,1H),7.74(d,J＝2.4Hz,1H),7.71(d,J＝8.3Hz,1H),7.66-7.61(m,1H),7.55-7.49(m,3H),7.41-7.36(m,1H),6.67(d,J＝9.3Hz,1H),3.66(s,3H),2.93(s,6H).

MS m/z(ESI):475.2[M+H] ⁺ 。

EXAMPLE 24 Synthesis of 1- (2-chlorophenyl) -3-methoxy-4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 24)

Step 1: synthesis of 1- (2-chlorophenyl) -3-methoxy-4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 24)

Reaction 20-1 (30 mg, 71.67. Mu. Mol) was dissolved in methanol (1.5 mL) and sodium methoxide (23.10 mg, 427.59. Mu. Mol) was added to the solution to give methanesulfonate (tBuBrettPhos Pd G) of (2-di-t-butylphosphino-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2-amino-1, 1-biphenyl-2-yl) palladium (II) ₃ ) (6.12 mg, 7.17. Mu. Mol), 2-di-tert-butylphosphine-2 ',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl (tBuBrettPhos) (3.47 mg, 7.17. Mu. Mol), sodium t-butoxide (13.78 mg, 143.34. Mu. Mol) and dioxane (1.5 mL). The temperature of the reaction system was raised to 80℃under nitrogen protection and the reaction was stirred at 80℃for 16 hours. LC-MS monitored that the starting materials had all reacted completely. The reaction solution was extracted three times with ethyl acetate, the organic layer was concentrated to dryness under reduced pressure, and the residue was purified by high performance liquid chromatography (column: agela DuraShell C, 150, 25mm, 5um; mobile phase: A: water (0.05% ammonia v/v), B: acetonitrile]The method comprises the steps of carrying out a first treatment on the surface of the B%:40% -60%,11 min) to give the title compound (1.6 mg).

¹ H NMR(400MHz,METHANOL-d ₄ )δ8.69(d,J＝8.3Hz,1H),7.67(d,J＝8.3Hz,1H),7.64-7.60(m,1H),7.51-7.48(m,2H),7.38-7.34(m,1H),4.69(s,3H),3.42(s,3H)。

MS m/z(ESI):＝384.0[M+H] ⁺ 。

EXAMPLE 25 Synthesis of 3-bromo-1- (2-chlorophenyl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 25)

Step 1: synthesis of 3-bromo-1- (2-chlorophenyl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 25)

The mixture of intermediates 20-2 and 20-3 was purified by high performance liquid chromatography (column: boston Prime C18. Times.30 mm. Times.5 um; mobile phase: [ A: water (0.05% ammonia v/v), B: acetonitrile ]; B%:30% -60%,9 min) to give the title compound (6.1 mg).

¹ H NMR(400MHz,METHANOL-d ₄ )δ8.84(d,J＝8.3Hz,1H),7.68(d,J＝8.5Hz,1H),7.65-7.60(m,1H),7.55-7.47(m,2H),7.41-7.35(m,1H),3.49(s,3H).

MS m/z(ESI):＝433.9[M+H] ⁺ 。

EXAMPLE 26 Synthesis of ethyl 1- (4- (difluoromethoxy) phenyl) -7-ethoxy-4- (methylamino) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (Compound 26)

Step 1: synthesis of 6-chloro-2- ((4- (difluoromethoxy) phenyl) amino) -3-cyanopyridine (intermediate 26-2)

4- (difluoromethoxy) aniline (9.20 g,57.80 mmol) was dissolved in N, N-dimethylformamide (200 mL) at 25℃and sodium hydride (4.62 g,115.61mmol,60% active content) was slowly added thereto after the temperature of the reaction solution had fallen to 0℃and the reaction was stirred for 30 minutes, then compound 26-1 (10 g,57.80 mmol) was added to the mixture and the reaction solution was stirred under nitrogen for 16 hours at 25 ℃. LCMS showed complete reaction of the starting material. After completion of the reaction, the reaction mixture was quenched by adding an aqueous solution (10 mL), to which were added ethyl acetate (200 mL) and water (400 mL), extracted 2 times with water (400 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent to give the title compound (17 g).

MS m/z(ESI):＝296.0[M+H] ⁺ 。

Step 2: synthesis of ethyl 4-amino-1- (4- (difluoromethoxy) phenyl) -7-ethoxy-2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 26-3)

Dimethyl malonate (22.52 g,170.46 mmol) was dissolved in ethanol (100 mL) at 20deg.C, sodium ethoxide (15.47 g,227.28 mmol) was added to the mixture, and after 30 minutes of reaction, intermediate 26-2 (16.8 g,56.82 mmol) was added thereto. The reaction mixture was stirred at 90℃for 16 hours under nitrogen protection. LCMS showed complete reaction of starting material with formation of target product. After the reaction was completed, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. To this was added ethyl acetate (200 mL) and water (400 mL), extracted 2 times with water (400 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by column chromatography (silica, dichloromethane/methanol=9/1) to give the title compound (7 g).

MS m/z(ESI):＝420.1[M+H] ⁺ 。

Step 3: synthesis of ethyl 1- (4- (difluoromethoxy) phenyl) -7-ethoxy-4- (methylamino) -2-oxo-1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (Compound 26)

Intermediate 26-3 (100 mg, 238.45. Mu. Mol) was dissolved in N, N-dimethylformamide (1 mL) at 20℃and sodium hydride (14.31 mg, 357.67. Mu. Mol,60% effective content) and methyl iodide (27.08 mg, 190.76. Mu. Mol) were slowly added to the mixture. The reaction mixture was stirred at 40℃for 16 hours under nitrogen protection. LCMS showed complete reaction and formation of the target product. After completion of the reaction, the reaction mixture was quenched by adding an aqueous solution (1 mL), to which were added ethyl acetate (5 mL) and water (10 mL), extracted 2 times with water (10 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure (0.01 MPa) to remove the solvent. The residue was purified by high performance liquid chromatography (acidic conditions, column: waters Xbridge BEH C, 100 x 25mm x 5um; mobile phase: [ A: water (0.225% formic acid v/v), B: acetonitrile ]; B%:30% -60%,12 min) to give the title compound (3.6 mg).

¹ H NMR(400MHz,METHANOL-d ₄ )δ8.28(d,J＝8.8Hz,1H),7.34-7.25(m,4H),6.93(t,J＝73.8Hz,1H),6.64(d,J＝8.8Hz,1H),4.34(q,J＝7.0Hz,2H),3.96(q,J＝7.0Hz,2H),3.06(s,3H),1.37(t,J＝7.2Hz,3H),1.12(t,J＝7.0Hz,3H).

MS m/z(ESI):＝434.1[M+H] ⁺ 。

Example 27 Synthesis of 3- (azetidin-1-yl) -1- (2-chlorophenyl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 27)

Step 1: synthesis of 3- (azetidin-1-yl) -1- (2-chlorophenyl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 27)

Compound 25 (30 mg, 69.34. Mu. Mol) and azetidine (11.88 mg, 208.03. Mu. Mol) were dissolved in dioxane (2 mL) and (2-dicyclohexylphosphino-3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) methanesulfonate (Brettphos Pd G) was added at 25 ℃ ₃ ) (6.29 mg, 6.93. Mu. Mol) and cesium carbonate (45.19 mg, 138.69. Mu. Mol). The reaction mixture was reacted at 60℃for 1.5 hours under nitrogen atmosphere. LC-MS monitored complete reaction of starting material. The reaction solution was concentrated to dryness under reduced pressure, and the residue was purified by high performance liquid chromatography (column: YMC-Actus Triart C18. Times.30 mm. Times.5 um; mobile phase: [ A: water (0.05% ammonia v/v), B: acetonitrile)]The method comprises the steps of carrying out a first treatment on the surface of the B%:60% -80%,11 min)) to give the title compound (4.4 mg).

¹ H NMR(400MHz,METHANOL-d ₄ )δ8.53(d,J＝8.2Hz,1H),7.65-7.60(m,1H),7.58(d,J＝8.3Hz,1H),7.50(dd,J＝3.5,5.9Hz,2H),7.36(dd,J＝3.6,5.8Hz,1H),4.12(t,J＝7.3Hz,4H),3.16(s,3H),2.24(q,J＝7.3Hz,2H).

MS m/z(ESI):＝409.1[M+H] ⁺ 。

Example 28, 4- (methylamino) -1- (2-methylpyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 28)

Step 1: synthesis of 2- ((2-methylpyridin-3-yl) amino) -6- (trifluoromethyl) -3-cyanopyridine (intermediate 28-2)

Intermediate 28-1 (3.14 g,29.05 mmol) was dissolved in anhydrous N, N-dimethylformamide (50 mL) at 25℃and the temperature was lowered to 0℃to which NaH (1.94 g,48.41mmol,60% active content) was slowly added, and after stirring for 30 minutes, intermediate 3-1 (5 g,24.21 mmol) was dissolved in anhydrous N, N-dimethylformamide (50 mL) and then added to the reaction system, and the reaction mixture was stirred under nitrogen for 16 hours at 25 ℃. After completion of the reaction, ethyl acetate (100 mL) and water (200 mL) were added to the reaction solution, extracted 2 times with an ethyl acetate solution (100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative column chromatography (0.about.20% ethyl acetate/petroleum ether, flow rate: 50 ml/min) to give the title compound (4.3 g).

MS m/z(ESI):＝279.0[M+H] ⁺ 。

Step 2: synthesis of methyl 4-amino-1- (2-methylpyridin-3-yl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 28-3).

Intermediate 28-2 (200 mg, 718.82. Mu. Mol) was dissolved in 1, 2-dichloroethane (2 mL) at 20deg.C, the temperature was reduced to 0deg.C, and tin tetrachloride (374.54 mg,1.44 mmol) and dimethyl malonate (284.90 mg,2.16 mmol) were slowly added thereto. The reaction mixture was stirred at 70℃for 16 hours under nitrogen protection. After completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate (5 mL), dichloromethane (10 mL) and water (20 mL) were added, the mixture was extracted 2 times with dichloromethane (10 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin layer chromatography (ethyl acetate 100%) to give the title compound (60 mg).

MS m/z(ESI):＝379.1[M+H] ⁺ 。

Step 3: synthesis of methyl 4-chloro-1- (2-methylpyridin-3-yl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 28-4).

Intermediate 28-3 (60 mg, 158.60. Mu. Mol) was dissolved in acetonitrile (1 mL) at 20deg.C, the temperature was lowered to 0deg.C, and t-butyl nitrite (3.60 mg, 713.71. Mu. Mol) and cuprous chloride (31.40 mg, 317.20. Mu. Mol) were slowly added thereto. The reaction mixture was stirred at 20℃for 4 hours under nitrogen protection. After completion of the reaction, ethyl acetate (10 mL) and water (20 mL) were added to the reaction solution, and extraction was performed 2 times with ethyl acetate (10 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=1/1) to give the title compound (10 mg).

MS m/z(ESI):＝398.0[M+H] ⁺ 。

Step 4: synthesis of methyl 4- (methylamino) -1- (2-methylpyridin-3-yl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (Compound 28-5).

Intermediate 28-4 (10 mg, 25.14. Mu. Mol) was dissolved in tetrahydrofuran (0.5 mL) at 20℃to which was added an ethanol solution of methylamine (23.66 mg, 251.42. Mu. Mol, mass fraction 33%). The reaction solution was stirred at 20℃for 3 hours under nitrogen protection. After the reaction was completed, the organic phase was concentrated under reduced pressure to remove the solvent. The title compound (10 mg) was obtained.

MS m/z(ESI):＝393.1[M+H] ⁺ 。

Step 5: synthesis of 4- (methylamino) -1- (2-methylpyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 28).

Intermediate 28-5 (10 mg, 25.49. Mu. Mol) was dissolved in anhydrous methanol (0.5 mL) at 20deg.C, and lithium hydroxide monohydrate (53.48 mg,1.27 mmol) was dissolved in water (0.5 mL) and added to the reaction solution. The reaction mixture was stirred at 20℃for 16 hours under nitrogen protection. After the reaction was completed, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by high performance liquid chromatography (column: waters Xbridge BEH C, 100 x 25mm x 5um; mobile phase: a: water (formic acid), B: acetonitrile; B%:8% -28%,22 min) to give the title compound (2.4 mg).

¹ H NMR(400MHz,DMSO-d ₆ )δ8.73(d,J＝8.0Hz,1H),8.59(d,J＝3.8Hz,1H),7.83-7.77(m,2H),7.74(d,J＝4.8Hz,1H),7.52(dd,J＝5.0,7.8Hz,1H),5.59(s,1H),2.91(d,J＝4.3Hz,3H),2.14(s,3H).

MS m/z(ESI):＝335.1[M+H] ⁺ 。

Compound 28 (15 mg) was purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 um), mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia; B%:30% -30%; flow rate: 70 ml/min), to give compound 28 Iosmer 1 (3.2 mg, RT:1.076 min) and compound 28 Iosmer 2 (2.7 mg, RT:1.423 min).

Compound 28 Iosmer 1:

¹ H NMR(400MHz,Methanol-d ₄ )δ8.62(d,J＝8.0Hz,1H),8.55(dd,J＝1.3,5.0Hz,1H),7.73-7.65(m,2H),7.48(dd,J＝4.9,7.9Hz,1H),5.75(s,1H),3.04(s,3H),2.21(s,3H).

MS m/z(ESI):＝335.1[M+H] ⁺ 。

compound 28 Iosmer 2:

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.62(d,J＝8.3Hz,1H),8.55(dd,J＝1.4,4.9Hz,1H),7.74-7.65(m,2H),7.48(dd,J＝5.0,7.8Hz,1H),5.75(s,1H),3.04(s,3H),2.21(s,3H).

MS m/z(ESI):＝335.1[M+H] ⁺ 。

example 29, 4- ((methyl-d) ₃ ) Amino) -1- (2-methylpyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 29)

Step 1:4- ((methyl-d) ₃ ) Synthesis of methyl amino) -1- (2-methylpyridin-3-yl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 29-1).

Intermediate 28-3 (200 mg, 528.67. Mu. Mol) was dissolved in anhydrous N, N-dimethylformamide (3 mL) at 25℃and the temperature was lowered to 0℃to which NaH (42.29 mg,1.06mmol,60% effective content) was slowly added, and after stirring for 30 minutes, deuterated iodomethane (61.31 mg, 422.94. Mu. Mol) was dissolved in anhydrous N, N-dimethylformamide (1 mL) and then added to the reaction system, and the reaction mixture was stirred under nitrogen at 25℃for 16 hours. After completion of the reaction, ethyl acetate (10 mL) and water (20 mL) were added to the reaction solution, extracted 2 times with an ethyl acetate solution (10 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin layer chromatography (dichloromethane/tetrahydrofuran=5/1) to give the title compound (110 mg).

MS m/z(ESI):＝396.1[M+H] ⁺ .

Step 2:4- ((methyl-d) ₃ ) Synthesis of amino) -1- (2-methylpyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 29)

Intermediate 29-1 (110 mg, 278.23. Mu. Mol) was dissolved in anhydrous methanol (5 mL) at 20℃and lithium hydroxide monohydrate (350.24 mg,8.35 mmol) was dissolved in water (5 mL) and added to the reaction solution. The reaction mixture was stirred at 20℃for 16 hours under nitrogen protection. After completion of the reaction, methylene chloride (20 mL) and water (40 mL) were added to the reaction mixture, the mixture was extracted 2 times with methylene chloride (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by thin layer chromatography (dichloromethane/methanol=10/1) to give the title compound (30 mg, racemate);

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.74(d,J＝5.1Hz,1H),8.67(d,J＝7.6Hz,1H),8.19(d,J＝7.6Hz,1H),7.83(d,J＝5.9Hz,1H),7.76(d,J＝7.9Hz,1H),5.76(s,1H),2.40(s,3H).

MS m/z(ESI):＝338.1[M+H] ⁺ .

step 3:4- ((methyl-d) ₃ ) Synthesis of amino) -1- (2-methylpyridin-3-yl) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compounds Isomer 1 and Isomer 2)

Compound 29 racemate (27.2 mg remaining) was further purified by supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 um), mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia; B%:30% -30%) to give compound 29 Isomer 1 (11.6 mg, RT:3.231 min) and compound 29 Isomer 2 (12.2 mg, RT:4.317 min).

¹ H NMR(400MHz,Methanol-d ₄ )δ8.61(d,J＝8.3Hz,1H),8.54(d,J＝3.5Hz,1H),7.73-7.65(m,2H),7.48(dd,J＝4.9,7.9Hz,1H),5.74(s,1H),2.21(s,3H).

MS m/z(ESI):＝338.1[M+H] ⁺ .

¹ H NMR(400MHz,Methanol-d ₄ )δ8.61(d,J＝8.3Hz,1H),8.54(d,J＝5.0Hz,1H),7.73-7.65(m,2H),7.48(dd,J＝4.9,7.9Hz,1H),5.74(s,1H),2.21(s,3H).

MS m/z(ESI):＝338.1[M+H] ⁺ .

Example 30, 1- (2-chloro-3-fluorophenyl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 30)

Step 1: synthesis of 2- ((2-chloro-3-fluorophenyl) amino) -6- (trifluoromethyl) -3-cyanopyridine (intermediate 30-2)

Intermediate 30-1 (3.52 g,24.21 mmol) was dissolved in N, N dimethylformamide (20 mL) at 25℃and NaH (1.94 g,48.41mmol,60% active content) was added to the reaction solution after the temperature had dropped to 0 ℃. The reaction was stirred at 0deg.C for 0.5 hr under nitrogen protection, and intermediate 3-1 (5 g,24.21 mmol) was added to the reaction. The reaction solution was stirred at 25℃for 16 hours under nitrogen protection. After the reaction was completed, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (100 ml×2), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative column chromatography (petroleum ether/ethyl acetate=0 to 100%; flow rate: 80 ml/min) to give the title compound (5 g).

MS m/z(ESI):＝316.0[M+H] ⁺ 。

Step 2: synthesis of methyl 4-amino-1- (2-chloro-3-fluorophenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 30-3)

Intermediate 30-2 (5 g,15.84 mmol) and dimethyl malonate (6.28 g,47.52 mmol) were dissolved in 1, 2-dichloroethane (80 mL) at 25℃and anhydrous tin tetrachloride (8.25 g,31.68 mmol) was added to the reaction solution. The reaction solution was stirred at 70℃for 16 hours under nitrogen protection. After the reaction was completed, saturated sodium bicarbonate (200 mL) was added to the reaction solution, extracted with ethyl acetate (500 ml×2), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative column chromatography (petroleum ether/ethyl acetate=0 to 100%; flow rate: 60 ml/min) to give the title compound (1.56 g).

MS m/z(ESI):＝415.9[M+H] ⁺ 。

Step 3: synthesis of methyl 4-chloro-1- (2-chloro-3-fluorophenyl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 30-4)

Intermediate 30-3 (1 g,2.41 mmol) was added to anhydrous acetonitrile (15 mL) at 25deg.C, tert-butyl nitrite (1.24 g,12.03 mmol) was added to the reaction solution, copper chloride (646.83 mg,4.81 mmol) was added to the reaction solution, and the reaction solution was reacted at 50deg.C under nitrogen for 16 hours. After the reaction was completed, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (100 ml×2), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative column chromatography (petroleum ether/ethyl acetate=0 to 40%; flow rate: 60 ml/min) to give the title compound (900 mg).

MS m/z(ESI):＝434.7[M+H] ⁺ 。

Step 4 Synthesis of 1- (2-chloro-3-fluorophenyl) -4- (methylamino) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylic acid methyl ester (intermediate 30-5)

Intermediate 30-4 (500 mg,1.15 mmol) was dissolved in anhydrous tetrahydrofuran (5 mL) at 25℃and a solution of methylamine in ethanol (2.16 g,22.98mmol,33% active content) was added to the reaction solution. The reaction solution was stirred at 20℃for 0.5 h under nitrogen protection. After the reaction was completed, the temperature was lowered to 25℃and the organic phase was concentrated under reduced pressure to remove the solvent to give the title compound (472 mg).

MS m/z(ESI):＝430.0[M+H] ⁺ 。

Step 5 Synthesis of 1- (2-chloro-3-fluorophenyl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 30)

Intermediate 30-5 (235 mg, 546.83. Mu. Mol) was dissolved in anhydrous methanol (2 mL) at 25℃and lithium hydroxide monohydrate (688.40 mg,16.40 mmol) was added to the reaction solution. The reaction solution was stirred at 50℃for 16 hours under nitrogen protection. After the reaction was completed. After the temperature was reduced to 25 ℃, water (200 mL) was added, extracted with ethyl acetate (50 mL x 2), the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent, and the residue was purified by preparative high performance liquid chromatography (column: waters Xbridge BEH C, 100 x 25mm x 5um; mobile phase: A: water (0.025% formic acid; B: acetonitrile, 22% -42%;12 min) to give the title compound (21.2 mg, racemate).

MS m/z(ESI):＝372.0[M+H] ⁺

¹ H NMR(400MHz,Methanol-d ₄ )δ8.60(d,J＝8.3Hz,1H),7.69(d,J＝8.3Hz,1H),7.56-7.47(m,1H),7.45-7.36(m,1H),7.23(d,J＝7.8Hz,1H),5.72(s,1H),3.04(s,4H).

Compound 30 (140 mg) was purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm. Times. 30mm,10 um), mobile phase: A: carbon dioxide; B:35% isopropyl alcohol (0.1% ammonia; flow rate: 70 ml/min) to give compound 30 Isomer 1 (29.5 mg, RT:3.683 min) and compound 30 Isomer 2 (24.2 mg, RT: 4.924).

Compound 30 Isomer 1:

MS m/z(ESI):＝372.0[M+H] ⁺ 。

¹ H NMR(400MHz,Methanol-d ₄ )δ8.59(d,J＝8.3Hz,1H),7.69(d,J＝8.3Hz,1H),7.55-7.49(m,1H),7.47-7.38(m,1H),7.23(d,J＝8.0Hz,1H),5.72(s,1H),3.04(s,3H).

compound 30 Isomer 2:

MS m/z(ESI):＝372.0[M+H] ⁺ 。

¹ H NMR(400MHz,Methanol-d ₄ )δ8.59(d,J＝8.0Hz,1H),7.69(d,J＝8.3Hz,1H),7.60-7.46(m,1H),7.45-7.39(m,1H),7.23(d,J＝8.0Hz,1H),5.72(s,1H),3.04(s,3H).

example 31, 4- (methylamino) -7- (trifluoromethyl) -1- (2- (trifluoromethyl) pyridin-3-yl) -1, 8-naphthyridin-2 (1H) -one (Compound 31)

Step 1: synthesis of 6- (trifluoromethyl) -2- ((2- (trifluoromethyl) pyridin-3-yl) amino) -3-cyanopyridine (intermediate 31-2).

Intermediate 31-1 (1.65 g,10.17 mmol) was dissolved in anhydrous N, N-dimethylformamide (40 mL) at 25℃and the temperature was lowered to 0℃to which NaH (813.28 mg,20.33mmol,60% active content) was slowly added, and after stirring for 30 minutes, intermediate 3-1 (2.1 g,10.17 mmol) was dissolved in anhydrous N, N-dimethylformamide (10 mL) and then added to the reaction system, and the reaction mixture was stirred under nitrogen for 16 hours at 25 ℃. After completion of the reaction, ethyl acetate (50 mL) and water (100 mL) were added to the reaction solution, extracted with an ethyl acetate solution (50 ml×2), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative column chromatography (0.about.10% ethyl acetate/petroleum ether, flow rate: 60 ml/min) to give the title compound (2.4 g).

MS m/z(ESI):＝332.9[M+H] ⁺ 。

Step 2: synthesis of methyl 4-amino-2-oxo-7- (trifluoromethyl) -1- (2- (trifluoromethyl) pyridin-3-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 31-3).

Intermediate 31-2 (2.4 g,7.22 mmol) was dissolved in 1, 2-dichloroethane (30 mL) at 20deg.C, the temperature was reduced to 0deg.C, and anhydrous tin tetrachloride (3.76 g,14.45 mmol) and dimethyl malonate (2.86 g,21.67 mmol) were slowly added thereto. The reaction mixture was stirred at 70℃for 16 hours under nitrogen protection. After the reaction was completed, it was quenched with saturated sodium bicarbonate (30 mL), dichloromethane (50 mL) and water (100 mL) were added to the reaction solution, extracted with dichloromethane (50 ml×2), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative column chromatography (0.about.100% ethyl acetate/petroleum ether, flow rate: 60 ml/min) to give the title compound (1.35 g).

MS m/z(ESI):＝433.0[M+H] ⁺ 。

Step 3: synthesis of methyl 4-chloro-2-oxo-7- (trifluoromethyl) -1- (2- (trifluoromethyl) pyridin-3-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 31-4).

Intermediate 31-3 (1 g,2.31 mmol) was dissolved in acetonitrile (12 mL) at 20deg.C, the temperature was lowered to 0deg.C, and tert-butyl nitrite (1.07 g,10.41 mmol) and copper chloride (622.07 mg,4.63 mmol) were slowly added thereto. The reaction solution was stirred at 20℃for 16 hours under nitrogen protection. After completion of the reaction, ethyl acetate (30 mL) and water (60 mL) were added to the reaction solution, extracted with ethyl acetate (30 ml×2), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin layer chromatography (0 to 30% ethyl acetate/petroleum ether, flow rate: 60 ml/min) to give the title compound (900 mg).

MS m/z(ESI):＝452.0[M+H] ⁺ 。

Step 4: synthesis of methyl 4- (methylamino) -2-oxo-7- (trifluoromethyl) -1- (2- (trifluoromethyl) pyridin-3-yl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 31-5).

Intermediate 31-4 (500 mg,1.11 mmol) was dissolved in tetrahydrofuran (5 mL) at 20deg.C, to which was added a solution of methylamine in ethanol (5.21 g,55.35mmol,33% effective). The reaction solution was stirred at 20℃for 3 hours under nitrogen protection. After the reaction was completed, the organic phase was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative thin layer chromatography (ethyl acetate 100%) to give the title compound (310 mg).

MS m/z(ESI):＝447.1[M+H] ⁺ 。

Step 5: synthesis of 4- (methylamino) -7- (trifluoromethyl) -1- (2- (trifluoromethyl) pyridin-3-yl) -1, 8-naphthyridin-2 (1H) -one (Compound 31).

Intermediate 31-5 (150 mg, 336.09. Mu. Mol) was dissolved in anhydrous methanol (5 mL) at 20℃and lithium hydroxide monohydrate (423.11 mg,10.08 mmol) was dissolved in water (5 mL) and added to the reaction solution. The reaction mixture was stirred at 20℃for 16 hours under nitrogen protection. To the reaction solution were added dichloromethane (20 mL) and water (40 mL), and the mixture was extracted 2 times with dichloromethane (20 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration, the organic phase was concentrated under reduced pressure to remove the solvent. The title compound (5.0 mg) was obtained.

¹ H NMR(400MHz,Methanol-d ₄ )δ8.83(d,J＝3.8Hz,1H),8.61(d,J＝8.3Hz,1H),7.96-7.92(m,1H),7.89-7.85(m,1H),7.69(d,J＝8.0Hz,1H),5.71(s,1H),3.04(s,3H).

MS m/z(ESI):＝389.0[M+H] ⁺ 。

Compound 31 (30 mg) was purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 um), mobile phase: A: carbon dioxide; B: ethanol (0.1% ammonia; B%:30% -30%; flow rate: 70 ml/min) to give compound 31 Isomer 1 (6.8 mg, RT:2.752 min) and compound 31 Isomer 2 (6.4 mg, RT:3.579 min).

Compound 31 Isomer 1:

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.83(d,J＝4.3Hz,1H),8.61(d,J＝8.0Hz,1H),7.97-7.92(m,1H),7.90-7.84(m,1H),7.69(d,J＝8.3Hz,1H),5.71(s,1H),3.04(s,3H)

MS m/z(ESI):＝389.1[M+H] ⁺ 。

compound 31 Isomer 2:

¹ H NMR(400MHz,Methanol-d ₄ )δ＝8.83(d,J＝3.8Hz,1H),8.61(d,J＝8.3Hz,1H),7.97-7.91(m,1H),7.90-7.84(m,1H),7.69(d,J＝8.3Hz,1H),5.71(s,1H),3.04(s,3H)

MS m/z(ESI):＝389.1[M+H] ⁺ 。

example 32, 1- (2-Cyclopropylpyridin-3-yl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 32)

Step 1: synthesis of 2-cyclopropyl-3-nitropyridine (intermediate 32-2)

The reaction 32-1 (5 g,31.54 mmol) and cyclopropylboronic acid (4.06 g,47.31 mmol) were dissolved in dioxane (80 mL) and PdCl was added under nitrogen at 25 ℃ ₂ (dppf) (1.15 g,1.58 mmol), potassium phosphate (13.39 g,63.07 mmol) and water (20 mL) were reacted under nitrogen at 90℃for 16 hours. After the reaction, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (200 mL 3 times), and the residue was concentrated under reduced pressure and purified by column chromatography

120g

Silica Flash Column gradient 0-2% ethyl acetate/Petroleum ether @100 mL/min) to give the title compound (2.24 g).

MS m/z(ESI):＝165.0[M+H] ⁺ 。

Step 2: synthesis of 2-cyclopropylpyridin-3-amine (intermediate 32-3)

Intermediate 32-2 (2.24 g,13.65 mmol) was dissolved in methanol (40 mL), ammonium chloride (7.30 g,136.45 mmol), iron powder (3.81 g,68.23 mmol) and water (10 mL) were added at 25℃and the reaction stirred under nitrogen at 50℃for 16 h. Iron powder (3.81 g,68.23 mmol) was added thereto at 25℃and the reaction mixture was stirred under nitrogen at 80℃for 6 hours. After the reaction was completed, the reaction mixture was filtered, concentrated under reduced pressure to remove methanol, extracted with ethyl acetate (200 ml×3 times), and the organic phase was concentrated under reduced pressure to give the title compound (1.19 g).

¹ H NMR(400MHz,DMSO-d ₆ )δ＝7.67(s,1H),6.92-6.79(m,2H),5.15(s,2H),2.06(s,1H),0.88-0.77(m,4H)

Step 3: synthesis of 2- ((2-cyclopropylpyridin-3-yl) amino) -6- (trifluoromethyl) -3-cyanopyridine (intermediate 32-4)

Intermediate 32-3 (1.19 g,8.87 mmol) was dissolved in N, N-dimethylformamide (30 mL). Sodium hydride (709.44 mg,17.74mmol,60% active content) was added to the reaction solution under nitrogen at 0deg.C, and stirred for 30 minutes. The reaction mixture was stirred at 0deg.C for 16 hours with the addition of intermediate 3-1 (1.83 g,8.87 mmol). After the reaction, the reaction mixture was quenched with 50mL of water, extracted with ethyl acetate (100 mL 3 times), the organic phase was concentrated under reduced pressure and the residue was purified by column chromatography

40g

Silica Flash Column gradient 0-12% ethyl acetate/Petroleum ether @100 mL/min) to give the title compound (1.03 g).

MS m/z(ESI):＝305.2[M+H] ⁺ 。

Step 4: preparation of methyl 4-amino-1- (2-cyclopropylpyridin-3-yl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 32-5)

Intermediate 32-4 (480 mg,3.22 mmol) and dimethyl malonate (1.28 g,9.66mmol,1.11 mL) were dissolved in dichloroethane (19 mL). Tin tetrachloride (1.68 g,6.44mmol,752.55 uL) was added to the reaction solution under nitrogen at 25 ℃. The reaction mixture was stirred at 70℃for 16 hours. After the reaction was completed, the reaction solution was diluted with water (30 mL), extracted with ethyl acetate (50 mL 3 times), the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography

40g

Silica Flash Column gradient 0-7% methanol/dichloromethane @100 mL/min) to give the title compound (1.13 g).

MS m/z(ESI):＝405.2[M+H] ⁺ 。

Step 5: preparation of methyl 4-chloro-1- (2-cyclopropylpyridin-3-yl) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 32-6)

Intermediate 32-5 (1.13 g,2.79 mmol) was dissolved in acetonitrile (19 mL). The reaction mixture was added t-butyl nitrite (1.30 g,12.58mmol,1.50 mL) and copper chloride (751.50 mg,5.59 mmol) under nitrogen at 0deg.C. The reaction mixture was stirred at 25℃for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure to remove acetonitrile, diluted with water (20 mL), extracted with ethyl acetate (20 mL. Times.3), the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography

40g

Silica Flash Column gradient 0 ～ 21 ～ 56 ～ 94% tetrahydrofuran/petroleum ether @100 mL/min) to give the title compound (1.12 g).

MS m/z(ESI):＝424.1[M+H] ⁺ 。

Step 6: preparation of methyl 1- (2-cyclopropylpyridin-3-yl) -4- (methylamino) -2-oxo-7- (trifluoromethyl) -1, 2-dihydro-1, 8-naphthyridine-3-carboxylate (intermediate 32-7)

Intermediate 32-6 (500 mg,1.18 mmol) was dissolved in tetrahydrofuran (5 mL). The reaction mixture was added with a solution of methylamine in ethanol (1.11 g,11.80mmol,33% strength) under nitrogen at 25 ℃. The reaction mixture was stirred at 25℃for 0.5 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure to give the title compound (587 mg).

MS m/z(ESI):＝419.0[M+H] ⁺ 。

Step 7: preparation of 1- (2-cyclopropylpyridin-3-yl) -4- (methylamino) -7- (trifluoromethyl) -1, 8-naphthyridin-2 (1H) -one (Compound 32)

Intermediate 32-7 (300 mg, 717.07. Mu. Mol) was dissolved in methanol (5 mL) and lithium hydroxide monohydrate (902.73 mg,21.51 mmol) and water (2.5 mL) were added at 25 ℃. The reaction was stirred at 25℃for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (30 mL), extracted with ethyl acetate (30 ml×3 times), and the organic phase was concentrated under reduced pressure to give 260mg of the crude title compound. 140mg of the crude title compound was further purified by high performance liquid chromatography (column: YMC-acts Triart C18. Times.30 mm. Times.5 um; mobile phase: [ A: water (ammonia), B: acetonitrile ]; B%:37% -57%,11 min) to give the title compound (8.5 mg).

¹ H NMR(400MHz,DMSO-d ₆ )δ＝8.70(d,J＝8.2Hz,1H),8.46(dd,J＝1.4,4.7Hz,1H),7.78(d,J＝8.2Hz,1H),7.66(d,J＝4.6Hz,1H),7.56(dd,J＝1.5,7.8Hz,1H),7.27(dd,J＝4.8,7.8Hz,1H),5.59(s,1H),2.90(d,J＝4.5Hz,3H),1.56-1.41(m,1H),1.08-0.97(m,1H),0.76-0.66(m,2H),0.61-0.51(m,1H)

MS m/z(ESI):＝361.1[M+H] ⁺ 。

Compound 32 (110 mg) was purified by preparative supercritical fluid chromatography (column: DAICEL CHIRALPAK AD (250 mm. Times.30 mm,10 um); mobile phase: [ A: carbon dioxide, B: ethanol (0.1% ammonia) ]; B%:30% -30%) to give crude compound 32 Isomer 1 (29.1 mg) and crude compound 32 Isomer 2 (22.3 mg). The crude two isomers were further purified by high performance liquid chromatography (column: YMC-acts Triart C18 150X 30mm X5 um; mobile phase: [ A: water (ammonia), B: acetonitrile ]; B%:35% -55%,11 min.) to give title compound 32 Isomer 1 (9.8 mg, RT:3.211 min) and compound 32 Isomer 2 (8.3 mg, RT:3.833 min), respectively.

¹ H NMR(400MHz,DMSO-d ₆ )δ8.70(d,J＝8.0Hz,1H),8.46(dd,J＝1.5,4.8Hz,1H),7.78(d,J＝8.0Hz,1H),7.67(d,J＝4.5Hz,1H),7.56(dd,J＝1.5,7.8Hz,1H),7.27(dd,J＝4.8,7.8Hz,1H),5.59(s,1H),2.90(d,J＝4.5Hz,3H),1.57-1.42(m,1H),1.09-0.97(m,1H),0.77-0.64(m,2H),0.62-0.51(m,1H)

MS m/z(ESI):＝361.1[M+H] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ8.70(d,J＝8.0Hz,1H),8.46(dd,J＝1.4,4.6Hz,1H),7.78(d,J＝8.3Hz,1H),7.67(d,J＝4.5Hz,1H),7.56(dd,J＝1.4,7.9Hz,1H),7.27(dd,J＝4.8,7.8Hz,1H),5.59(s,1H),2.90(d,J＝4.5Hz,3H),1.54-1.44(m,1H),1.07-0.97(m,1H),0.76-0.65(m,2H),0.61-0.50(m,1H)

MS m/z(ESI):＝361.1[M+H] ⁺ 。

Biological Activity and related Property test cases

Test example 1, biochemical test

Brief description of the test principle: l-methionine and ATP can be converted to SAM, inorganic phosphates and inorganic bisphosphates under MAT2A enzymatic conditions. The amount of inorganic phosphate in the sample can be quantitatively detected by adding a color-developing agent such as ammonium molybdate or the like to the enzymatic reaction mixture, thereby reacting the enzymatic activity of MAT 2A.

Materials: MAT2A screening kit was purchased from BPS bioscience (USA); 384 well plates were purchased from corning corporation (usa).

MAT2A protein (Kang Long chemical (Beijing) New pharmaceutical technology Co., ltd.)

L-methionine (Sigma#M 9625-5G)

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)。

The detection method comprises the following steps: DMSO dissolved compound, compounds were diluted to final concentration of 10 μm, 3-fold dilution, and transferred into 80nL to 384 well plates using Echo.

Preparation of experiment buffer (50mM Tris,50mM KCl,15mM MgCl) ₂ 100. Mu.M EDTA,0.005% BSA). MAT2a protein (final concentration 4. Mu.g/mL) was diluted with assay buffer. 40. Mu.L of 2 XMAT 2a solution was added to 384-well plates, centrifuged at 1000rpm for 1 min and incubated at room temperature for 120 min.

L-methionine and ATP (final L-methionine concentration of 200. Mu.M and ATP final concentration of 400. Mu.M) were diluted with assay buffer. The reaction was started by adding 40. Mu.L of 2X L-methionine and ATP solution, centrifuging at 1000rpm for 1 minute and incubating at room temperature for 90 minutes.

Picolorlock is to be used according to the specification ^TM Reaction catalyst and PicolorLock ^TM Buffer 1:100 was mixed and added to each well with 20. Mu.L and then shaken for 30 seconds. Add 8. Mu.L of stabilizing reagent and shake for 30 seconds. After incubation at room temperature for 30 minutes, the signal value was measured.

Data analysis:

calculate% Compound inhibition and fit to IC to give compound ₅₀ 。

％Compound inhibition＝(100-100*(Signal-Bottom)/(Top-Bottom))％

Experimental results:

under the experimental conditions, the inhibition of MAT2A by the compound to be tested can be achieved by IC inhibiting the level of phosphoric acid produced during the enzymatic reaction ₅₀ The value represents. The MAT2A inhibitory activity of the test compounds is specifically shown in table 1.

TABLE 1

Test example 2, human colon cancer HCT116 cell proliferation inhibition test

Brief description of the test principle: after incubating the MAT2A inhibitor to be tested with cancer cells for a period of time, the effect of the test compound on cell proliferation is measured by using a cell proliferation counting method based on ATP content.

Materials and cells: HCT116WT cells and HCT116 MTAP ^-/- Cells were purchased from Kang Yuanbo; fetal bovine serum, mcCoy's 5a medium, and penicillin-streptomycin were purchased from Gibco corporation (usa), 96-well plates were purchased from corning corporation (usa), and Cell-Titer Glo reagent was purchased from plagmatog corporation (usa).

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

Cell proliferation activity assay: detection of compound pairs with Cell-Titer Glo reagent HCT116 WT and HCT116 MTAP ^-/- Inhibitory Activity of proliferation of both cell lines. Adjusting cell concentration to 400 cells per well, inoculating 96-well plate, placing at 37deg.C and 5% CO ₂ The culture was carried out overnight under the conditions.

The compound was dissolved in DMSO, diluted in DMSO and medium sequentially and transferred to the cell plate at a final concentration of 10 μm, 3-fold dilution. Placing at 37deg.C and 5% CO ₂ Culturing was continued for 6 days under the conditions. Cell-Titer Glo reagent was added to detect Cell activity.

Data analysis:

calculate% Compound inhibition and fit to IC to give compound ₅₀ 。

％Compound inhibition＝1-100％*(Signal-Bottom)/(Top-Bottom)

The experimental results are shown in table 2.

TABLE 2

The compounds 28, 29, 30, 31 and the like have good antiproliferative activity on HCT116 MTAP-/-cells (MTAP-deleted tumor cells), and can be expected to have therapeutic effects on MTAP-deleted tumors, and simultaneously have good selectivity and low side effects.

Claims (15)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

   

   wherein,

   L ₁ selected from N or O;

   when L ₁ When selected from N, R ¹ Selected from H or optionally R ^1a The substituted following groups: c (C) ₁ -C ₁₀ Alkyl, C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, R ² Selected from optionally R ^2a The substituted following groups: c (C) ₁ -C ₁₀ Alkyl, C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, or R ¹ 、R ² Together with the N atoms to which they are attached form a 4-7 membered heterocyclic group, said 4-7 membered heterocyclic group optionally being R ^1a Substitution;

   when L ₁ When selected from O, R ² Is absent and R ¹ Selected from optionally R ^1a The substituted following groups: c (C) ₁ -C ₁₀ Alkyl, C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl;

   L ₂ selected from a bond, NH, or O;

   R ³ selected from halogen or optionally R ^3a The substituted following groups: c (C) ₁ -C ₁₀ Alkyl, C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl;

   X ₁ 、X ₃ selected from N or CH;

   X ₂ selected from N or CR ⁴ ；

   Y is selected from O or S, and when X ₂ When N, Y is selected from S only;

   R ⁴ selected from H, halogen, OH, CN, COOH or optionally R ^4a The substituted following groups: c (C) ₁ -C ₁₀ Alkyl, C (=o) -O- (C) ₁ -C ₆ Alkyl), C (=O) -NH (C) ₁ -C ₆ Alkyl), C (=O) -N (C) ₁ -C ₆ Alkyl group ₂ 、C ₃ -C ₁₀ Cycloalkyl, 3-10 membered heterocyclyl, C ₁ -C ₁₀ Alkoxy, C ₃ -C ₁₀ Cycloalkyloxy, 3-to 10-membered heterocyclyloxy, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ Aryloxy, 5-to 10-membered heteroaryloxy, C ₂ -C ₁₀ Alkenyl, C ₂ -C ₁₀ Alkynyl;

   ring Q is selected from C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl, said C ₆ -C ₁₀ Aryl or 5-to 10-membered heteroaryl optionally substituted with R ⁵ Substitution;

   R ⁵ Selected from halogen, =o, OH, CN or optionally R ^5a Substituted with the following groups: NH (NH) ₂ 、C ₁ -C ₁₀ Alkyl, C ₃ -C ₁₀ Cycloalkyl, C ₁ -C ₁₀ Alkoxy, C ₃ -C ₁₀ Cycloalkyloxy, 3-10 membered heterocyclyloxy;

   each R is ^1a 、R ^2a 、R ^3a 、R ^4a 、R ^5a Independently selected from deuterium, F, cl, br, I, OH, CN, =o or optionally R ^b Substituted with the following groups: NH (NH) ₂ 、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyloxy, 4-7 membered heterocyclyloxy, C ₂ -C ₆ Alkenyl, C ₂ -C ₆ Alkynyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, C ₆ -C ₁₀ Aryloxy, 5-10 membered heteroaryloxy;

   each R is ^b Independently selected from F, cl, br, I, OH, CN, = O, NH ₂ 、SH、C ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl;

   with the proviso that the compound of formula (I) does not comprise

   
2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein L ₁ Selected from N, R ¹ Selected from H or optionally R ^1a Substituted C ₁ -C ₆ Alkyl, R ² Selected from optionally R ^2a The substituted following groups: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, or R ¹ 、R ² And the N atoms to which they are attached together formAzetidinyl or pyrrolidinyl, optionally substituted with R ^1a And (3) substitution.
3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein L ₁ Selected from N, R ¹ Selected from H or methyl, R ² Selected from methyl, CD ₃ 、

   

   Cyclopropyl group,

   

   Or R is ¹ 、R ² And the N atoms to which they are attached together form

   
4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ Selected from halogen or optionally R ^3a Substituted C ₁ -C ₃ An alkyl group.
5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit

   

   Selected from Cl, CF ₃ Or OCH (optical wavelength) ₂ CH ₃ 。
6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1Characterized in that when X ₂ When selected from N, Y is selected from S, when X ₂ Selected from CR ⁴ When Y is selected from O.
7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ Selected from H, F, cl, br, I, CN, COOH or optionally R ^4a The substituted following groups: c (C) ₁ -C ₃ Alkyl, C (=o) -O- (C) ₁ -C ₄ Alkyl), CONHMe, cyclopropyl, 4-6 membered heterocyclyl, C ₁ -C ₃ Alkoxy, cyclopropyloxy, 5-6 membered heteroaryl, 9 membered heteroaryl.
8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁴ Selected from H, F, br, CN, COOMe, CONHMe,

   

   Cyclopropyl, methoxy, cyclopropyloxy,

   

   
9. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring Q is selected from phenyl or pyridinyl, optionally substituted by R ⁵ And (3) substitution.
10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ⁵ Selected from halogen,CN or optionally R ^5a Substituted with the following groups: c (C) ₁ -C ₆ Alkyl, C ₃ -C ₆ Cycloalkyl, 4-7 membered heterocyclyl, C ₁ -C ₆ Alkoxy, C ₃ -C ₆ Cycloalkyloxy, 4-7 membered heterocyclyloxy.
11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring Q is selected from the group consisting of

    
12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of the compound of formula (II):

    

    wherein R is ¹ 、R ² 、R ³ 、R ⁴ 、X ₁ 、L ₂ And ring Q is as defined in claim 1.
13. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following structures:

    

    

    
14. a pharmaceutical composition comprising a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant.
15. Use of a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the prevention or treatment of MTAP-deficient tumors.