WO2022160931A1

WO2022160931A1 - Pyridopyrimidine derivative, preparation method therefor and use thereof

Info

Publication number: WO2022160931A1
Application number: PCT/CN2021/135230
Authority: WO
Inventors: 张盼盼; 周林; 叶成; 钱文建; 陈磊
Original assignee: 浙江海正药业股份有限公司; 上海昂睿医药技术有限公司
Priority date: 2021-01-28
Filing date: 2021-12-03
Publication date: 2022-08-04
Also published as: CN116546985A

Abstract

The present invention relates to a substituted pyridopyrimidine derivative, a preparation method therefor, and the use of a pharmaceutical composition containing the derivative in medicine. In particular, the present invention relates to a substituted pyridopyrimidine derivative as represented by general formula (I), a preparation method therefor, a pharmaceutically acceptable salt thereof, and the use of same as therapeutic agents, in particular as SOS1 inhibitors, wherein the definition of each substituent in the general formula (I) is the same as the definition in the description.

Description

Pyridopyrimidine derivatives and preparation method and use thereof

technical field

The present invention relates to a substituted pyridopyrimidine derivative, its preparation method, a pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as an SOS1 inhibitor.

Background technique

RAS genes are widely present in various eukaryotes such as mammals, fruit flies, fungi, nematodes and yeast, and have important physiological functions in various life systems. The mammalian RAS gene family has three members, namely H- RAS, K-RAS and N-RAS, various RAS genes have similar structures, all composed of four exons, distributed on the DNA of about 30kb in length. Their encoded products are monomeric globular proteins with a relative molecular mass of 21 kDa. The activation and inactivation states of RAS proteins have a significant impact on life processes such as cell growth, differentiation, proliferation and apoptosis. This protein is a membrane-bound guanine nucleotide-binding protein with weak GTPase activity, which regulates RAS through GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) in normal physiological activities In the active state, when RAS protein combines with GTP to form RAS-GTP, it is in the active state. GTPase activating protein can dephosphorylate RAS-GTP into RAS-GDP, and then inactivate; the inactivated RAS-GDP is in guanine. Under the action of nucleotide exchange factors, it is converted into active RAS-GTP, thereby activating a series of downstream pathways such as RAF/MER/ERK and PI3K/AKT/mTOR.

The RAS gene is also closely related to various human diseases, especially in cancer, RAS is an oncogene that frequently mutates, among which KRAS subtype gene mutations account for 86% of the total number of RAS gene mutations, about 90% of pancreatic cancer, Different degrees of KRAS gene mutation occur in 30%-40% of colon cancers and 15-20% of lung cancers. Given the prevalence of KRAS gene mutations, this target has always been the focus of drug development workers. Since the publication of the clinical results of AMG-510, which directly acts on the KRAS-G12C target, the research on KRAS inhibitors has set off a boom at home and abroad.

The SOS (Son of sevenless homolog) protein was originally discovered in Drosophila studies and is a guanosine-releasing protein encoded by the SOS gene. Humans have two SOS homologues, hSOS1 and hSOS2, both of which are members of the guanine nucleotide exchange factor family with 70% homology. Although they are highly similar in structure and sequence, their physiological There are some differences in functionality. hSOS1 protein is 150kDa in size and is a multi-structural protein domain composed of 1333 amino acids, including N-terminal protein domain (HD), multiple homology domains, helical linker (HL), RAS exchange sequence (REM) and rich C-terminal domain of proline. There are two binding sites on hSOS1 with RAS protein, namely catalytic site and allosteric site. The catalytic site binds to the RAS protein on the RAS-GDP complex to promote guanine nucleotide exchange, and the allosteric site binds The RAS protein on the RAS-GTP complex further enhances the catalytic effect, and then participates in and activates the signal transduction of RAS family proteins. Studies have shown that inhibition of SOS1 not only completely inhibited the RAS-RAF-MEK-ERK pathway in wild-type KRAS cells, but also resulted in a 50% reduction in phospho-ERK activity in mutant KRAS cell lines. Therefore, inhibition of SOS1 can also reduce the activity of RAS, thereby treating various cancers caused by RAS gene mutation or RAS protein overactivation, including pancreatic cancer, lung cancer, colorectal cancer, cholangiocarcinoma, multiple myeloma, melanoma tumor, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer , chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma, etc.

There are no drugs selectively targeting SOS1 on the market, but a series of related patents have been published, including BI's WO2018115380A1, WO2019122129A1, Bayer's WO2019201848A1, Revolution's WO2020180768A1, WO2020180770A1, etc., which are currently in clinical trials The drug in stage is BI-1701963. However, these are far from enough for anti-tumor research, and there is still a need to research and develop new selective SOS1 kinase inhibitors to address unmet medical needs.

SUMMARY OF THE INVENTION

In view of the above-mentioned technical problems, the present invention provides a substituted pyridopyrimidine compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

in:

Ring A is selected from C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, 9-10 membered bicyclic heterocyclyl, 9-10 membered bicyclic aryl or 9-10 membered fused ring;

R ¹ are the same or different, each independently selected from hydrogen atom, halogen, cyano, amino, nitro, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-11 membered heterocyclic group, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl; wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further selected from one or more halogens, cyano groups , substituted by substituents of hydroxy, amino, and =O;

R ² is selected from halogen, cyano, C ₁ -C ₆ alkyl, C ₃ -C ₁₀ cycloalkyl, 4-11 membered heterocyclyl, C ₆ -C ₁₀ aryl, 5-10 membered heteroaryl, -OR ⁴ , -C(O)R ⁵ , -NR ⁶ C(O)R ⁷ , -CH ₂ NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ ,

or -NR ⁸ R ⁹ ; wherein, the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more substituents selected from R ¹⁰ ;

R ³ is selected from hydrogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy, C ₃ -C ₁₀ cycloalkyl, 5-10 membered heteroaryl or -C(O)R ⁵ ; wherein , the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are optionally further substituted by one or more substituents selected from R ¹⁰ ;

R ⁴ is selected from a hydrogen atom, a C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkyl group or a 4-11 membered heterocyclic group; wherein the alkyl or cycloalkyl group is optionally further modified by one or more selected from deuterium atom, hydroxyl, halogen, cyano, _C1 - _C6 alkyl, _C1 - _C6 alkoxy, heterocyclyl, =O, -N( _CH3 ) ₂ or -N( _C2H ₅ ) substituted by the substituent of ₂ ; the 4-11-membered heterocyclic group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, C ₁ -C ₆ alkoxy or =O replaced;

R ⁵ is each independently selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, 4-11 membered heterocyclyl, -NR ⁸ R ⁹ ; wherein said alkyl, cycloalkyl or heterocyclyl The cyclic group is optionally further substituted with one or more substituents selected from hydroxy, halogen, cyano, amino, C ₁ -C ₆ alkoxy;

R ⁶ is selected from hydrogen, C ₁ -C ₃ alkyl or C ₃ -C ₆ cycloalkyl;

R ⁷ is selected from C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₆ -C ₁₀ aryl, 5-10-membered heteroaryl or 4-11-membered heterocyclyl; radical, cycloalkyl, aryl or heteroaryl optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, amino, C ₁ -C ₆ alkoxy; the heterocycle is optionally further substituted by one or more substituents selected from hydroxy, halogen, cyano, _C1 - _C6 alkyl, C3 _- _C6 epoxy, _C1 _- C3 alkoxy or =O replace;

R ⁸ and R ⁹ are each independently selected from a hydrogen atom or a C ₁ -C ₆ alkyl group; wherein said alkyl group is optionally further selected from one or more of hydroxyl, halogen, cyano, amino, C ₁ -C ₆ alkoxy, -N(CH ₃ ) ₂ , -N(C ₂ H ₅ ) ₂ , 4-11-membered heterocyclic group or a substituent of =O; the 4-11-membered heterocyclic group is any is further substituted with one or more substituents selected from hydroxyl, halogen, cyano, _C1 - _C6 alkyl, C3 _- _C6 epoxy, _C1 _- C3 alkoxy or =O;

Alternatively, R ⁸ and R ⁹ together with the atoms to which they are attached form an N-containing 4-11 membered heterocyclyl optionally further modified by one or more =O or R ¹⁴ substituted by the substituent;

R ¹⁰ is each independently selected from halogen, cyano, hydroxy, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₃ -C ₆ cycloalkyl , =O, -C(O)R ¹¹ or -CH ₂ C(O)NR ¹² R ¹³ ; wherein said alkyl, alkoxy, hydroxyalkyl or cycloalkyl is optionally further modified by one or more substituted with a substituent selected from halogen, cyano, C ₁ -C ₃ alkoxy, -N(CH ₃ ) ₂ , -N(C ₂ H ₅ ) ₂ or 4-11-membered heterocyclic group; the said The 4-11 membered heterocyclyl is optionally further substituted by one or more C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy substituents;

R ¹¹ is selected from C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected from one or more halogen, cyano, hydroxyl, C ₁ -C ₃ alkoxy, -N(CH ₃ ) ₂ , -N(C ₂ H ₅ ) ₂ or 4-11-membered heterocyclic group substituents; the 4-11-membered heterocyclic group is optional is further substituted by C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

R ¹² and R ¹³ are each independently selected from hydrogen, C ₁ -C ₃ alkyl or C ₃ -C ₆ cycloalkyl;

Alternatively, R ¹² and R ¹³ together with the atoms to which they are attached form an N-containing 4-11 membered heterocyclic group; wherein said heterocyclic group is optionally further selected from one or more groups selected from halogen, cyano, hydroxyl, substituted by C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl, C ₁ -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl or a substituent of =O;

R ¹⁴ is selected from halogen, hydroxy, cyano, amino, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ hydroxyalkyl or -C(O)R ¹⁵ ; wherein said The alkyl, alkoxy or hydroxyalkyl groups are optionally further substituted by one or more selected from halogen, C ₁ -C ₃ alkoxy, -N(CH ₃ ) ₂ , -N(C ₂ H ₅ ) ₂ ,

substituted by the substituent;

R ¹⁵ is selected from C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected by one or more selected from halogen, hydroxyl, cyano, C ₁ - C ₃ alkoxy, -N(CH ₃ ) ₂ , -N(C ₂ H ₅ ) ₂ or substituents of 4-11-membered heterocyclic groups;

m is 1, 2 or 3.

A preferred embodiment of the present invention is a compound represented by the general formula (I) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (II-1), (II- 2) The compound shown in (II-3) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:

wherein: R ¹ , R ² , R ³ and m are defined as described in the general formula (I).

A preferred embodiment of the present invention is a compound represented by general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (III) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

in:

Ring B is selected from C ₃ -C ₁₀ cycloalkyl, 4-11 membered heterocyclyl, C ₆ -C ₁₀ aryl or 5-10 membered heteroaryl;

n is selected from 0, 1, 2, 3 or 4;

Rings A, R ¹ , R ³ , R ¹⁰ and m are as defined in general formula (I).

A preferred embodiment of the present invention is a compound represented by the general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (IV-1), (IV- 2) The compound shown or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

wherein: ring A, R ¹ , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and m are as defined in general formula (I).

A preferred embodiment of the present invention is a compound represented by general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound represented by general formula (V) or its Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

wherein: ring A, R ¹ , R ³ , R ⁴ and m are as defined in general formula (I).

A preferred embodiment of the present invention is a compound represented by the general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (VI-1), (VI- 2), the compound shown in (VI-3) or (VI-4) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:

in:

Rings A, R ¹ , R ³ , R ⁸ , R ⁹ and m are as defined in general formula (I).

A preferred version of the present invention is a compound represented by general formula (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:

selected from the following groups:

wherein: R ¹⁰ and n are as defined in general formula (III).

In a preferred embodiment of the present invention, the compound of general formula (I) is selected from:

or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

NOTE: If there is a discrepancy between the drawn structure and the given name of that structure, the drawn structure will be given greater weight.

Further, the present invention provides a pharmaceutical composition containing effective doses of general formula (I), (II-1), (II-2), (II-3), (III), The compound described in (IV-1), (IV-2), (V), (VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer thereof, Tautomers or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers, excipients or combinations thereof.

The present invention provides a kind of general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V), ( The compound described in VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof Use of compounds in the preparation of SOS1 inhibitors.

The present invention also provides a general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V), The compound described in (VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a drug thereof Use of the composition in the preparation of a medicament for the treatment of diseases mediated by SOS1, wherein the diseases mediated by SOS1 are preferably RAS family protein signaling pathway-dependent related cancers, cancers caused by SOS1 mutations or caused by SOS1 mutations The hereditary disease; wherein said disease mediated by SOS1 is preferably pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute Myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovary cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma.

The present invention further provides a general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V), The compound described in (VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a drug thereof Use of the composition in the preparation of a medicament for treating RAS family protein signal transduction pathway-dependent related cancer, cancer caused by SOS1 mutation or hereditary disease caused by SOS1 mutation.

The present invention provides a kind of general formula (I), (II-1), (II-2), (II-3), (III), (IV-1), (IV-2), (V), ( The compound described in VI-1), (VI-2), (VI-3) or (VI-4) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical combination thereof In preparation for the treatment of pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer , cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma drugs.

Detailed description of the invention

Unless stated to the contrary, some terms used in the specification and claims of the present invention are defined as follows:

"Alkyl" when taken as a group or part of a group is meant to include _C1 - _C20 straight or branched chain aliphatic hydrocarbon groups. Preferably it is a C ₁ -C ₁₀ alkyl group, more preferably a C ₁ -C ₆ alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -Ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait. Alkyl groups can be substituted or unsubstituted.

"Cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged and spirocyclic carbocyclic rings. Preferably it is C ₃ -C ₁₂ cycloalkyl, more preferably C ₃ -C ₈ cycloalkyl, most preferably C ₃ -C ₆ cycloalkyl. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl and cyclohexenyl. Cycloalkyl groups can be substituted or unsubstituted.

"Spirocycloalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and a single carbon atom (called a spiro atom) is shared between the monocyclic rings, and the ring may contain one or more Aromatic systems with multiple double bonds, but none of the rings have fully conjugated pi electrons. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are divided into mono-spiro, double-spiro or poly-spirocycloalkyl groups, preferably mono-spiro and double-spirocycloalkyl groups, preferably 4-membered/5-membered, 4-membered Yuan/6 Yuan, 5 Yuan/5 Yuan or 5 Yuan/6 Yuan. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

"Fused cycloalkyl" refers to a 5- to 18-membered all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain one or more double bonds, But none of the rings have an aromatic system with fully conjugated pi electrons, preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetrahydrophenanthryl.

"Bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other, and one or more rings may contain one or more Aromatic systems in which multiple double bonds, but none of the rings have fully conjugated pi electrons, are preferably 6 to 12 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-dicyclo[3.2.1]octyl Cyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.

"Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclyl in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, Nitrogen, sulfur atoms, etc., including monocyclic, polycyclic, fused, bridged and spirocyclic. It preferably has a 5 to 7 membered monocyclic or 7 to 10 membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulphur.

Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpho Linyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, piperazinyl, hexahydropyrimidinyl,

Monocyclic heterocyclyl groups may be substituted or unsubstituted.

"Spiroheterocyclyl" refers to a 5- to 18-membered polycyclic group with two or more cyclic structures, and the single rings share one atom with each other, and the ring may contain one or more double bonds, but Aromatic systems in which none of the rings has fully conjugated pi electrons, wherein one or more ring atoms are selected from nitrogen, oxygen, or heteroatoms of S(O) _n (wherein n is selected from 0, 1, or 2), and the remaining ring atoms for carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. Spirocycloalkyl groups are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl according to the number of spiro atoms shared between rings, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl group. Non-limiting examples of "spiroheterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[4.4]nonyl Heterospiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

Spiroheterocyclyl can be substituted or unsubstituted.

"Fused heterocyclyl" refers to a polycyclic group containing two or more ring structures that share a pair of atoms with each other, one or more rings may contain one or more double bonds, but none of the rings is fully conjugated A pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) _n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclyl" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1. 0] Hexyl, octahydrobenzo[b][1,4]dioxine.

"Bridged heterocyclyl" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more cyclic structures that share two atoms that are not directly connected to each other, and one or more rings may be Aromatic systems containing one or more double bonds but none of the rings have fully conjugated pi electrons, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) _n (wherein n is selected from 0, 1 or 2), the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo cyclo[3.3.2]decyl,

Bridged heterocyclyl groups can be substituted or unsubstituted.

"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused fashion. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferred aryl groups are _C6 - _C10 aryl groups, more preferred aryl groups are phenyl and naphthyl, and most preferred are phenyl groups. Aryl groups can be substituted or unsubstituted.

"Heteroaryl" refers to an aromatic 5 to 6 membered monocyclic or 8 to 10 membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heteroaryl" include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzom- Dioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzoyl Isothiazolyl, benzoxazolyl, benzisoxazolyl, pyridinone,

Heteroaryl groups can be substituted or unsubstituted.

"Fused ring" refers to a polycyclic group in which two or more ring structures share a pair of atoms with each other, one or more rings may contain one or more double bonds, but at least one ring is not completely conjugated A pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more heteroatoms selected from nitrogen, oxygen or S(O) _r (wherein r is selected from 0, 1 or 2), and the remaining ring atoms are carbon . The condensed ring preferably includes a bicyclic or tricyclic condensed ring, wherein the bicyclic condensed ring is preferably a condensed ring of an aryl group or a heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably it is 7 to 14 yuan, more preferably 8 to 10 yuan. Examples of "fused rings" include, but are not limited to:

"Alkoxy" refers to a group (alkyl-O-). Wherein, alkyl is as defined herein. Ci _- _C6 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

"C ₁ -C ₆ hydroxyalkyl" refers to a hydroxy substituted C ₁ -C ₆ alkyl group.

"C ₁ -C ₆ haloalkyl" refers to a halogen substituted C ₁ -C ₆ alkyl group.

"Hydroxy" refers to the -OH group.

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

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Nitro" refers to _-NO2 .

"Benzyl" refers to _-CH2 -phenyl.

"DMSO" refers to dimethyl sulfoxide.

"DMF" refers to N,N-dimethylformamide.

"BOP" refers to benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate.

"DBU" refers to 1,8-diazabicyclo[5.4.0]undec-7-ene.

"DCC" refers to dicyclohexylcarbodiimide.

"EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.

" _PdCl2 (dppf)" refers to [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride.

"RuPhos-Pd-G ₃ " methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1' - Biphenyl-2-yl)palladium(II).

"Pd( _PPh3 ) _2Cl2 " refers to bis(triphenylphosphine)palladium _dichloride .

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

"XantPhos" refers to 4,5-bisdiphenylphosphino-9,9-dimethylxanthene.

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

"9-BBN" refers to 9-borabicyclo[3.3.1]nonane.

"SPhos-Pd-G3" refers to methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-amino-1,1' - Biphenyl-2-yl)palladium(II).

"Leaving group", or leaving group, is an atom or functional group that is removed from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution and elimination reactions. In the nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that is broken off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to withstand negative charges are good leaving groups. When the pKa of the conjugated acid of the leaving group is smaller, the easier it is for the leaving group to detach from other molecules. The reason is that when the pKa of its conjugated acid is smaller, the corresponding leaving group does not need to be combined with other atoms, and the tendency to exist in the form of an anion (or a neutral leaving group) is also enhanced. Common leaving groups include, but are not limited to, halo, methanesulfonyl, -OTs, or -OH.

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

"Substituted" or "substituted" mentioned in this specification, unless otherwise specified, means that the group may be substituted by one or more substituents.

"Pharmaceutically acceptable salts" refers to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. The pharmaceutically acceptable salt of the compound represented by the general formula (I) may be a metal salt or an amine salt formed with a suitable acid.

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

Synthetic method of the compound of the present invention

In order to accomplish the purpose of the present invention, the present invention adopts following technical scheme:

The present invention provides a preparation method of a compound of general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IA) and compound (IB) undergo condensation reaction under the condition of a condensing agent, preferably BOP condensing agent, DCC condensing agent, EDCI condensing agent and HATU condensing agent, to obtain the compound of general formula (I); when R ¹ When containing a nitro group, it can be further reduced to an amino group;

The definitions of R ¹ , R ² , R ³ and m are as described in the general formula (I).

The present invention provides a preparation method of compounds of general formula (II-1), (II-2), (II-3) or stereoisomers, tautomers or pharmaceutically acceptable salts thereof. The methods described include:

Under the condition of a condensing agent, the compound of general formula (IA) and compound (IIB-1) are respectively subjected to a condensation reaction to obtain general formula (II-1); the compound of (II-1) can be further rationally transformed;

Under the condition of a condensing agent, the compound of general formula (IA) and the compound (IIB-2) are respectively subjected to a condensation reaction to obtain the general formula (II-2); the compound of (II-2) can be further rationally transformed;

Under the condition of a condensing agent, the compound of general formula (IA) and compound (IIB-3) undergo a condensation reaction to obtain general formula (II-1); the compound of (II-2) can be further transformed reasonably;

in:

Described condensing agent is preferably BOP condensing agent, DCC condensing agent, EDCI condensing agent or HATU condensing agent;

The rational transformation includes, when R ¹ contains a nitro group, the nitro group can be further reduced to an amino group;

The definitions of R ¹ , R ² , R ³ and m are as described in the general formulae (II-1), (II-2), (II-3).

The present invention provides a preparation method of a compound of general formula (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:

The compound of general formula (IIIA) and compound (IIIB) are subjected to a cross-coupling reaction under metal catalysis to obtain the compound of general formula (III); when R ¹ contains a nitro group, it can be further reduced to an amino group. Compound (III) can be further rationally transformed. in:

X is selected from halogen, preferably bromine;

M is selected from H, -B(OH) ₂ , _-BF3K , -MgX or

Rings A, R ¹ , R ³ , R ¹⁰ , m and n are as defined in general formula (III).

The present invention provides a preparation method of a compound of general formula (IV-1), (IV-2) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, said method comprising:

The compound of general formula (IIIA) and compound (IVB-1) are subjected to a cross-coupling reaction under metal catalysis to obtain the compound of general formula (IV-1); the compound of (IV-1) can be further rationally transformed;

The compound of general formula (IIIA) and compound (IVB-2) are subjected to a cross-coupling reaction under metal catalysis to obtain compound (IV-2); compound (IV-2) can be further rationally transformed;

in:

X is selected from halogen, preferably bromine;

Ring A, R ¹ , R ³ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and m are as defined in general formulae (IV-1) and (IV-2).

The present invention provides a preparation method of a compound of general formula (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, the method comprising:

Option One:

The compound of general formula (IIIA) and compound (VB) are subjected to a cross-coupling reaction under metal catalysis to obtain the compound of general formula (V); when R ¹ contains a nitro group, it can be further reduced to an amino group.

in:

X is selected from halogen, preferably bromine;

Rings A, R ¹ , R ³ , R ⁴ and m are as defined in general formula (V).

Option II:

The compound of general formula (IIIA) reacts with pinacol biboronate under metal catalysis to obtain the compound of general formula (VC); the compound of general formula (VC) is oxidized to obtain the compound of general formula (VD); the compound of general formula (VD) and The compound of general formula (VE) undergoes a nucleophilic substitution reaction to obtain the compound of general formula (V);

in:

X is selected from halogen, preferably bromine;

L is selected from leaving groups, preferably p-toluenesulfonate and halogen;

Rings A, R ¹ , R ³ , R ⁴ and m are as defined in general formula (V).

The present invention provides a compound of general formula (VI-1), (VI-2), (VI-3), (VI-4) or a stereoisomer, tautomer or pharmaceutically acceptable compound thereof The preparation method of salt, described method comprises:

The compound of general formula (IIIA) is subjected to carbonylation reaction under metal catalysis to obtain the compound of general formula (VIB-1); the compound of general formula (VIB-1) is hydrolyzed to generate carboxylic acid to obtain the compound of general formula (VIC); further react with HNR ⁸ R ⁹ undergoes a condensation reaction under the condition of a condensing agent to obtain a compound of general formula (VI-1);

The compound of the general formula (IIIA) is subjected to a cross-coupling reaction under metal catalysis, and hydrolyzed to obtain the compound of the general formula (VIB-2); the compound of the general formula (VIB-2) undergoes reductive amination reaction with HNR ⁸ R ⁹ , and Through further resolution, compounds (VI-2) and (VI-3) are obtained;

The compound of general formula (VIA) is obtained under metal catalysis to obtain the compound of general formula (VIB-3); the compound of (VIB-3) is subjected to substitution reaction to obtain the compound of general formula (VI-4);

in:

X is selected from halogen, preferably bromine;

Ring A, R ¹ , R ³ , R ⁸ , R ⁹ and m are defined as in the general formula (VI-1).

The present invention provides a kind of preparation method of compound of general formula (IA), described method comprises:

The compound of general formula (SM-1) or the compound of general formula (SM-2) or the compound of general formula (SM-3) undergoes a cyclization reaction to obtain the compound of general formula (IA);

wherein: R ² and R ³ are as defined in the general formula (I).

The present invention provides a preparation method of a compound of general formula (IB), the method comprising:

The bromide (IB-1) compound undergoes a metal-catalyzed cross-coupling reaction (such as Stille coupling reaction) to convert the ethyl ketone intermediate (IB-2) compound; the ethyl ketone intermediate (IB-2) compound is combined with a chiral sulfonic acid The imide undergoes a reduction reaction to form a chiral sulfonimide (IB-3) compound; the chiral sulfonimide (IB-3) compound is reduced by sodium borohydride or 9-BBN to give the separable main product (IB -4) and a diastereomeric mixture of the minor product (IB-5); the enantiomer (IB-4) compound was reacted with HCl/1,4-dioxane solution to remove the sulfinyl group, The chiral benzylamine hydrochloride (IB) compound is obtained.

wherein: R ¹ , ring A and m are as defined in general formula (I).

Detailed ways

The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

Example

The examples give the preparation and related structural identification data of the representative compounds represented by formula (I). It must be noted that the following examples are used to illustrate the present invention rather than limit it. The ¹ H NMR spectrum was measured with a Bruker instrument (400 MHz), and the chemical shifts were expressed in ppm. A tetramethylsilane internal standard (0.00 ppm) was used. ¹ H NMR representation: s=singlet, d=doublet, t=triplet, m=multiplet, br=broadened, dd=doublet of doublet, dt=doublet of triplet. When coupling constants are provided, they are in Hz.

Mass spectrum is obtained by LC/MS instrument, and the ionization mode can be ESI or APCI.

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ~ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ~0.5mm.

Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

In the following examples, all temperatures are in degrees Celsius unless otherwise indicated, and various starting materials and reagents were obtained from commercially available or synthesized according to known methods without further purification. For direct use, unless otherwise specified, commercially available manufacturers include but are not limited to Shanghai Haohong Biomedical Technology Co., Ltd., Shanghai Shaoyuan Reagent Co., Ltd., Shanghai Bide Pharmaceutical Technology Co., Ltd., Saen Chemical Technology (Shanghai) Co., Ltd. and Shanghai Lingkai Pharmaceutical Technology Co., Ltd., etc.

_CD3OD : Deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

Nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon with a volume of about 1 L.

There is no special description in the examples, and the solution in the reaction refers to an aqueous solution.

To purify the compound, use silica gel column chromatography eluent system and thin layer chromatography; the volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or basic reagents can also be added for adjustment, such as acetic acid or Triethylamine, etc.

Synthesis of Intermediate A-1

first step

Synthesis of 2-amino-5-bromo-6-methoxynicotinic acid methyl ester A-1b

2-Amino-6-methoxy-nicotinic acid methyl ester A-1a (1.5g, prepared according to literature Synlett (2011), (2), 203-206), sodium bicarbonate (2.08g) were added to the reaction flask and dichloromethane (20 mL), the temperature was lowered to 0°C, a solution of bromine (1.97 g) in dichloromethane (10 mL) was slowly added dropwise, and the reaction was maintained at 0°C for 1 hour. Complete conversion of starting material was detected by LC-MS. 50 mL of water was added, the reaction was quenched with saturated sodium bisulfite solution, extracted with dichloromethane (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Further separation and purification by chromatography (eluent: petroleum ether/ethyl acetate = 20:1) to obtain methyl 2-amino-5-bromo-6-methoxynicotinate A-1b (2.0 g), yield 93%.

MS m/z(ESI): 261.0[M+1]

second step

Synthesis of 2-acetylimido-5-bromo-6-methoxynicotinic acid methyl ester A-1c

To the reaction flask were added methyl 2-amino-5-bromo-6-methoxynicotinate A-1b (800 mg) and acetonitrile (8 mL), and 4M HCl/1,4-dioxane solution (16 mL) was added , the temperature was raised to 60 °C and the reaction was carried out for 24 hours. Complete conversion of starting material was detected by LC-MS. After concentrating under reduced pressure to remove half of the solvent, add 50 mL of diethyl ether, stir to precipitate a white solid, continue to stir for 1 hour, filter, and dry the solid to obtain 2-acetylimido-5-bromo-6-methoxynicotinic acid Methyl ester A-1c (650 mg), 70% yield.

MS m/z(ESI): 302.0[M+1]

third step

Synthesis of 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1

Into a 100mL reaction flask were sequentially added 2-acetylimido-5-bromo-6-methoxynicotinic acid methyl ester A-1c (500mg), ethanol (20mL) and sodium bicarbonate (695mg), and the reaction was carried out under reflux for 2 Hour. After TLC detected the disappearance of the raw materials, 200 mL of a mixed solvent of dichloromethane/methanol (V:V=10:1) was added, washed once with water (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 6- Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (330 mg), 74% yield. MS m/z(ESI): 270.0[M+1]

Synthesis of Intermediate A-2

Synthesis of 6-bromo-2-methyl-1H-pyrido[2,3-d]pyrimidin-4-one A-2

2-Amino-5-bromo-pyridine-3-carboxylic acid A-2a (2 g) and acetic anhydride (20 mL) were added to a 100 mL flask, and the reaction was carried out at 140° C. for 2 hours. Complete conversion of starting material was detected by TLC. Concentrate under reduced pressure, add 20 mL of ammonia water, and react at 100°C for 6 hours. A large amount of white solid was precipitated in the reaction solution. TLC detected that the intermediate reaction was complete, filtered, and dried the filter cake to obtain 6-bromo-2-methyl-1H-pyrido[2,3-d]pyrimidin-4-one A-2 (1.5g), which was rate 67%.

MS m/z(ESI): 240.0[M+1]

Synthesis of Intermediate A-3

6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (1.00 g, 3.72 mmol), morpholine (647.51 mg, 7.43 mmol), RuPhos-G3 (311 mg, 0.37 mmol), and sodium tert-butoxide (713.50 mg, 7.43 mmol) were successively added to tetrahydrofuran (20 mL), purged with nitrogen three times, and continued to stir the reaction at 100° C. for 12 hours. After returning to room temperature, concentrated under reduced pressure to remove the solvent, added ethyl acetate (100 mL), washed with water (30 mL×3), combined the organic phases, washed with saturated brine solution (30 mL), dried the organic phase with anhydrous sodium sulfate, filtered, and reduced pressure. Concentrated, mixed with silica gel, and separated and purified by column chromatography (eluent: dichloromethane/methanol=20:1) to obtain 7-methoxy-2-methyl-6-morpholine-pyrido[2,3 -d]pyrimidin-4(3H)-one A-3 (800 mg), 78% yield.

MS m/z(ESI): 276.9[M+1]

Synthesis of Intermediate C-1

(R)-6-Bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3 Synthesis of -d]pyrimidin-4-amine C-1

Into a 15mL reaction flask was added 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (300mg), (R)-1- (3-nitro-5-(trifluoromethyl)phenyl)ethan-1-amine B-1 (300 mg, prepared according to published literature Cancer Discov 2021; 11:142-157.), BOP (638.65 mg), DBU (507 mg) and N,N-dimethylformamide (2 mL), and the reaction was stirred at room temperature for 3 hours. After the reaction, 100 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent). : petroleum ether/ethyl acetate=3:1) to obtain (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl) yl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine C-1 (170 mg) in 31% yield.

MS m/z(ESI): 486.0[M+1]

Synthesis of Intermediate C-2

(R)-6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidine-4- Synthesis of Amine A-2

Into a 100 mL flask was added 6-bromo-2-methyl-1H-pyrido[2,3-d]pyrimidin-4-one A-2 (1.5 g), (R)-1-(3-(difluoro) Methyl)-2-fluorophenyl)ethane-1-amine hydrochloride B-2 (1.69g, prepared according to published patent CN 111372932A), BOP (5.53g), DBU (2.85g) and N,N- Dimethylformamide (20 mL) was stirred at room temperature for 5 hours. TLC detected that the reaction of the raw materials was complete. Ethyl acetate and water were added, extracted, and the layers were separated. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: Petroleum ether/ethyl acetate = 3:1) to give (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl Pyrido[2,3-d]pyrimidin-4-amine C-2 (1.7 g), 66% yield.

MS m/z(ESI): 412.1[M+2]

Synthesis of Intermediate C-3

(R)-6-Bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido[2,3- d] Synthesis of Pyrimidine-4-amine C-3

Into a 15 mL reaction flask was added 6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (400 mg, 1.48 mmol), (R) -1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-amine hydrochloride B-2 (501.27 mg, 2.22 mmol), BOP (982.54 mg, 2.22 mmol), DBU ( 676.42 mg, 4.44 mmol) and DMSO (5 mL), and the reaction was stirred at room temperature for 12 hours. 100 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: petroleum ether/ Ethyl acetate = 3:1) to give (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2 -Methylpyrido[2,3-d]pyrimidin-4-amine C-3 (350 mg), 54% yield.

MS m/z(ESI): 441.0[M+1]

Synthesis of Intermediate B-3

Synthesis of (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride B-3

first step

Synthesis of (S,Z)-N-(1-(3-bromo-2-methylphenyl)ethylene)-2-methylpropane-2-sulfonimide

Into a 250 mL flask was added 1-(3-bromo-2-methylphenyl)ethane-1-one (12 g, 56.32 mmol), (R)-2-methylpropane-2-sulfonimide (8.87 g g, 73.22 mmol), tetraethyl titanate (19.27 g, 84.48 mmol), 100 mL of tetrahydrofuran, replaced nitrogen three times, and reacted at 80 degrees for 7 hours. After returning to room temperature, add 30 mL of water, filter through celite, wash with ethyl acetate, wash three times with water, dry over anhydrous sodium sulfate, filter and concentrate, mix with silica gel, and pass through a column machine to obtain (S,Z)-N-(1- (3-Bromo-2-methylphenyl)ethylene)-2-methylpropane-2-sulfonimide 14 g, yield 79%.

MS m/z(ESI): 316.1[M+1]

second step

Synthesis of (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonimide

Into a 250mL reaction flask was added (S,Z)-N-(1-(3-bromo-2-methylphenyl)ethylene)-2-methylpropane-2-sulfonimide (7g, 22.13 g mmol), tetrahydrofuran 30mL), slowly add 0.5M tetrahydrofuran solution 80mL of 9-BBN under ice bath, return to room temperature and continue to react for 5 hours. Send LC-MS to detect the disappearance of raw materials, add saturated ammonium chloride solution to quench, concentrate to remove tetrahydrofuran, add ethyl acetate, wash with water three times, and dry over anhydrous sodium sulfate. Purified by column machine to obtain (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonimide 6.0g , the yield is 85%.

MS m/z(ESI): 318.2[M+1]

third step

Synthesis of (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine hydrochloride

In a 25mL reaction flask was added (S)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfonimide (4g, 12.57 mmol), 10 mL of hydrogen chloride/dioxane solution was added, and the mixture was stirred at room temperature. LC-MS detected that the reaction of the raw materials was complete, the solvent was concentrated, diethyl ether was added to stir, and 1.8 g of (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine hydrochloride was precipitated, with a yield of 58%. . MS m/z(ESI): 214.0[M+1]

the fourth step

Synthesis of tert-butyl (R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamate

Into a 100 mL flask was added (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine hydrochloride (1.3 g, 5.2 mmol) di-tert-butyl dicarbonate (1.19 g, 10.90 g mmol) and dichloromethane 8 mL), slowly added diisopropylethylamine (1.34 g, 10.4 mmol) under ice bath, and reacted at room temperature for 3 hours. 300 mL of dichloromethane was added, washed three times with water, dried over anhydrous sodium sulfate, and purified by passing through a column machine to obtain (R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamic acid tert-butyl ester 3.0 g, 93% yield.

MS m/z(ESI): 314.1[M+1]

the fifth step

Synthesis of tert-butyl (R)-(1-(3-cyano-2-methylphenyl)ethyl)carbamate

In a 50 mL flask was added (R)-(1-(3-bromo-2-methylphenyl)ethyl) tert-butyl carbamate (2 g, 6.37 mmol), Zn(CN) ₂ (1.49 g, 12.73 mmol) ), Pd(PPh ₃ ) ₄ (735.52 mg, 636.50 μmol), DMF (8 mL, nitrogen was replaced three times, and the reaction was carried out at 140 degrees for 8 hours. After returning to room temperature, ethyl acetate was added, washed three times with water, dried over anhydrous sodium sulfate, and passed Column machine was used to obtain tert-butyl (R)-(1-(3-cyano-2-methylphenyl)ethyl)carbamate 0.8 g with a yield of 49%.

MS m/z(ESI): 261.2[M+1]

Step 6

Synthesis of (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride B-3

Into a 100 mL flask were added tert-butyl (R)-(1-(3-cyano-2-methylphenyl)ethyl)carbamate (4.5 g, 17.29 mmol) and 20 mL of 4M hydrogen chloride/dioxane solution , reacted at room temperature for 5 hours, and a white solid was precipitated. Diethyl ether was added and filtered to obtain (R)-3-(1-aminoethyl)-2-methylbenzonitrile hydrochloride 3.0 g with a yield of 89%.

MS m/z(ESI): 161.1[M+1]

Synthesis of Intermediate B-4

Synthesis of (R)-3-(1-aminoethyl)benzonitrile hydrochloride B-4

first step

Synthesis of (R,E)-N-(1-(3-cyanophenyl)ethylene)-2-methylpropane-2-sulfonimide

3-acetylbenzonitrile (1.2g, 8.27mmol), (R)-2-methylpropane-2-sulfonimide (1.80g, 14.88mmol), tetraethyl titanate ( 3.77 g, 16.53 mmol) and tetrahydrofuran 50 mL), replaced with nitrogen 3 times, and reacted at 80 degrees for 7 hours. LC-MS detected that the reaction of the raw materials was complete, water (50 mL) was added for diatomaceous earth filtration, the filter cake was washed with ethyl acetate (50 mL), the filtrate was collected and concentrated under reduced pressure, the obtained residue was added to ethyl acetate (200 mL), washed with water (100 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, the obtained residue was passed through a column machine to obtain (R,E)-N-(1-(3-cyanophenyl)ethylene)-2-methyl Propane-2-sulfonimide 1.8 g, yield 87%.

MS m/z(ESI): 249.2[M+1]

second step

Synthesis of (R)-N-((R)-1-(3-cyanophenyl)ethyl)-2-methylpropane-2-sulfonimide

Into a 50 reaction flask was added (R,E)-N-(1-(3-cyanophenyl)ethylene)-2-methylpropane-2-sulfonimide (1.0g, 4.03mmol) and 20 mL of tetrahydrofuran, 16 mL of 0.5M 9-BBN solution in tetrahydrofuran was slowly added under an ice bath, and the reaction was continued for 5 hours after returning to room temperature. Send LC-MS to detect the disappearance of raw materials, add saturated ammonium chloride solution to quench, concentrate to remove tetrahydrofuran, add ethyl acetate, wash with water three times, and dry over anhydrous sodium sulfate. Purified by column machine to obtain (R)-N-((R)-1-(3-cyanophenyl)ethyl)-2-methylpropane-2-sulfonimide 600mg, yield 60% .

MS m/z(ESI): 251.1[M+1]

third step

Synthesis of (R)-3-(1-aminoethyl)benzonitrile hydrochloride

Into a 25mL reaction flask was added (R)-N-((R)-1-(3-cyanophenyl)ethyl)-2-methylpropane-2-sulfonimide (600mg, 2.40mmol) and 10 mL of 1,4-dioxane was slowly added dropwise with 3 mL of 4M hydrogen chloride/dioxane solution, and the reaction was stirred at room temperature for 3 hours. LCMS showed that the reaction was complete, the reaction solution was concentrated under reduced pressure, diethyl ether (20 mL) was added to the obtained residue, the solid was precipitated by stirring, filtered, and the filter cake was collected and dried to obtain (R)-3-(1-aminoethyl)benzonitrile hydrochloride Salt B-4 (420 mg, 96% yield).

MS m/z(ESI): 147.1[M+1]

Synthesis of Intermediate C-4

(R)-3-(1-((6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-methyl Synthesis of benzonitrile C-4

6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (400 mg, 1.48 mmol), (R) was added to a 25 mL reaction flask -3-(1-Aminoethyl)-2-methylbenzonitrile hydrochloride B-3 (308.5 mg, 1.93 mmol), BOP (982.54 mg, 2.22 mmol), DBU (676.42 mg, 4.44 mmol) and DMSO (5 mL), and the reaction was stirred at room temperature for 12 hours. 100 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: petroleum ether/ Ethyl acetate = 3:1) to give (R)-3-(1-((6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl) Amino)ethyl)-2-methylbenzonitrile C-4 (270 mg), 45% yield.

MS m/z(ESI): 412.1[M+1]

Synthesis of Intermediate C-5

(R)-3-(1-((6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)benzonitrile C- Synthesis of 5

6-Bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4(3H)-one A-1 (400 mg, 1.48 mmol), (R) was added to a 25 mL reaction flask -3-(1-aminoethyl)benzonitrile hydrochloride B-4 (352.4 mg, 1.93 mmol), BOP (982.54 mg, 2.22 mmol), DBU (676.42 mg, 4.44 mmol) and DMSO (5 mL), The reaction was stirred at room temperature for 12 hours. 100 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: petroleum ether/ Ethyl acetate = 3:1) to give (R)-3-(1-((6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl) Amino)ethyl)-2-methylbenzonitrile C-4 (240 mg), 41% yield.

MS m/z(ESI): 398.1[M+1]

Example 1

N-((R)-1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran- Synthesis of 3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1

first step

(R)-7-Methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(4,4,5, Synthesis of 5-Tetramethyl-1,3,2-dioxaboran-2-yl)pyrido[2,3-d]pyrimidin-4-amine 1a

In a 25mL reaction vial, add (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl ) pyrido[2,3-d]pyrimidin-4-amine C-1 (160 mg), pinacol diboronate (125.34 mg), Pd(dppf)Cl ₂ (24 mg) and potassium acetate (64 mg) were added 1,4-dioxane (3 mL) was replaced with nitrogen three times, and the reaction was carried out at 100° C. for 8 hours. After the reaction, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product (R)-7-Methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(4,4,5, 5-Tetramethyl-1,3,2-dioxaboran-2-yl)pyrido[2,3-d]pyrimidin-4-amine 1a (170 mg) was used directly in the next reaction.

second step

(R)-7-Methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3- d] Synthesis of Pyrimidine-6-ol 1b

Add (R)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-( 4,4,5,5-Tetramethyl-1,3,2-dioxaboran-2-yl)pyrido[2,3-d]pyrimidin-4-amine 1a (160 mg), sodium hydroxide (120 mg) and tetrahydrofuran (10 mL), slowly added hydrogen peroxide (102 mg), reacted at room temperature for 1 hour, and LC-MS detected the complete conversion of the raw materials. 10 mL of saturated sodium thiosulfate solution was added to quench the reaction, 1M dilute hydrochloric acid was added dropwise to adjust the pH to neutral, extracted with ethyl acetate (50 mL), the organic phase was washed with water (50 mL), dried over anhydrous sodium sulfate, filtered, Concentration under reduced pressure gave crude (R)-7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyridine and [2,3-d]pyrimidin-6-ol 1b (120 mg) was used directly in the next reaction.

MS m/z(ESI): 424.1[M+1]

third step

7-Methoxy-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(((S)-tetrahydrofuran Synthesis of -3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1d

Add (R)-7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido to the reaction flask [2,3-d]pyrimidin-6-ol 1b (200 mg), (R)-tetrahydrofuran-3-yl p-toluenesulfonate 1c (171.70 mg), potassium carbonate (130.59 mg) and N,N-dimethylformaldehyde formamide (6 mL), the temperature was raised to 60° C. and reacted for 8 hours. The disappearance of starting material was detected by LC-MS. 20 mL of ethyl acetate was added, washed with water (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane). /methanol = 50:1) to give 7-methoxy-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)- 6-(((S)-Tetrahydrofuran-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1d (90 mg), 39% yield.

MS m/z(ESI): 494.2[M+1]

the fourth step

Add 7-methoxy-2-methyl-N-((R)-1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)-6-(( to the reaction flask (S)-Tetrahydrofuran-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1d (100 mg), iron powder (56.59 mg), tetrahydrofuran (3 mL), ethanol (3 mL) and 1M Dilute hydrochloric acid (1 mL) was heated to 100° C. and reacted for 3 hours. Complete conversion of starting material was detected by LC-MS. Sodium bicarbonate solution was added dropwise to adjust the pH to neutral, filtered, the filtrate was concentrated under reduced pressure, 15 mL of ethyl acetate was added, washed with water (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=50:1) to obtain N-((R)-1-(3-amino-5-(trifluoromethyl) )phenyl)ethyl)-7-methoxy-2-methyl-6-(((S)-tetrahydrofuran-3-yl)oxy)pyrido[2,3-d]pyrimidin-4-amine 1 (50 mg), 53% yield.

MS m/z(ESI): 464.2[M+1]

¹ H NMR (400MHz, DMSO-d ₆ )δ8.08(d,J=7.9Hz,1H),8.02(s,1H),6.85(d,J=10.6Hz,2H),6.70(s,1H) ,5.59-5.52(m,3H),5.14(s,1H),3.97(s,3H),3.97-3.95(m,1H),3.93-3.76(m,3H),2.37(s,3H),2.36 -2.28(m,1H),2.07-2.01(m,1H),1.55(d,J=7.0Hz,3H)ppm.

Example 2

(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-morpholinopyrido[2, Synthesis of 3-d]pyrimidin-4-amine 2

first step

(R)-7-Methoxy-2-methyl-6-morpholinyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2 Synthesis of ,3-d]pyrimidin-4-amine 2b

Into a 15mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine [2,3-d]pyrimidin-4-amine C-1 (100 mg), morpholine (21.5 mg), Pd ₂ (dba) ₃ (37.7 mg), XantPhos (47.6 mg), cesium carbonate (134.02 mg) and 1,4-dioxane (3 mL), nitrogen was replaced 3 times, the temperature was raised to 90° C., and the reaction was carried out under nitrogen atmosphere for 5 hours. after the reaction is over. The reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was washed with silica gel Column chromatography was further separated and purified (eluent: dichloromethane/methanol=40:1) to obtain (R)-7-methoxy-2-methyl-6-morpholinyl-N-(1-( 3-Nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 2a (50 mg), 49% yield.

MS m/z(ESI): 493.2[M+1]

second step

Add (R)-7-methoxy-2-methyl-6-morpholinyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl to a 15 mL flask ) pyrido[2,3-d]pyrimidin-4-amine 2a (50mg), iron powder (28.35mg), tetrahydrofuran (2mL), ethanol (2mL) and 1M dilute hydrochloric acid (1mL), the temperature was raised to 100°C for reaction 3 Hour. After the reaction, the pH was adjusted to neutrality with saturated sodium bicarbonate solution, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), and washed with anhydrous sodium sulfate. Dry, filter, and concentrate under reduced pressure, and the obtained residue is further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=40:1) to obtain (R)-N-(1-(3-amino) -5-(Trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-morpholinopyrido[2,3-d]pyrimidin-4-amine 2 (5 mg) , the yield is 10%.

MS m/z(ESI): 463.0[M+1]

¹ H NMR (400MHz, DMSO-d ₆ )δ9.86(d,J=7.8Hz,1H),8.15(s,1H),6.87(d,J=6.0Hz,2H),6.76(s,1H) ,5.69(t,J=7.3Hz,1H),4.11(s,3H),3.79(s,4H),3.14(s,4H),2.57(s,3H),1.62(d,J=7.1Hz, 3H)ppm.

Example 3

(R)-1-(4-((1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2, Synthesis of 3-d]pyrimidin-6-yl)ethan-1-one 3

first step

(R)-6-(1-Ethoxyvinyl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl Synthesis of pyrido[2,3-d]pyrimidin-4-amine 3b

Add (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethane to a 25mL round-bottomed single-necked flask yl)pyrido[2,3-d]pyrimidin-4-amine C-1 (200 mg) and 1,4-dioxane (5 mL), tributyl(1-ethoxyethylene)tin 3a ( 160.4 mg), Pd(PPh ₃ ) ₂ Cl ₂ (26 mg) and triethylamine (93.7 mg), replaced with nitrogen three times, and reacted at 100° C. for 4 hours. After the reaction was completed, it was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL × 3) three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain residual The compound was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=40:1) to obtain (R)-6-(1-ethoxyvinyl)-7-methoxy-2- Methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 3b (150 mg), yield 85 %.

MS m/z(ESI): 478.2[M+1]

second step

(R)-1-(7-Methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2 Synthesis of ,3-d]pyrimidin-6-yl)ethan-1-one 3c

Add (R)-6-(1-ethoxyvinyl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl) into a 25mL reaction flask yl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 3b (150 mg), 1,4-dioxane (2.50 mL) and dilute hydrochloric acid (3M, 2.50 mL), room temperature The reaction was stirred for 3 hours. The disappearance of starting material was detected by LC-MS. 50 mL of ethyl acetate was added, washed three times with water (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain (R)-1-(7-methoxy-2-methyl-4- ((1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)amino)pyrido[2,3-d]pyrimidin-6-yl)ethan-1-one 3c (100 mg) , the yield was 71%, which was directly used in the next reaction.

MS m/z(ESI): 450.1[M+1]

third step

Add (R)-1-(7-methoxy-2-methyl-4-((1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)amino to a 15 mL flask )pyrido[2,3-d]pyrimidin-6-yl)ethan-1-one 3c (100 mg), iron powder (62.1 mg), tetrahydrofuran (2 mL), ethanol (2 mL) and dilute hydrochloric acid (1 M, 1 mL) , and the temperature was raised to 100 °C for 3 hours. After the reaction, the pH was adjusted to neutral with saturated sodium bicarbonate solution, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), and the organic phase was dried with anhydrous dried over sodium sulfate, filtered and concentrated under reduced pressure, the obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=40:1) to obtain (R)-1-(4-(( 1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)ethyl -1-one 3 (40 mg), 43% yield.

MS m/z(ESI): 420.1[M+1]

¹ H NMR (400MHz, DMSO-d ₆ ) δ 9.15(s, 1H), 8.85(d, J=7.9Hz, 1H), 6.88(s, 1H), 6.84(s, 1H), 6.70(s, 1H), 5.55-5.50(m, 1H), 4.05(s, 3H), 2.62(s, 3H), 2.41(s, 3H), 1.53(d, J=7.0Hz, 3H)ppm.

Example 4

(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(1-methyl-1H- Synthesis of Pyrazol-4-yl)pyrido[2,3-d]pyrimidin-4-amine 4

first step

(R)-7-Methoxy-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(1-(3-nitro-5-(trifluoromethyl) Synthesis of yl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 4b

Into a 25mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine Do[2,3-d]pyrimidin-4-amine C-1 (120 mg), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Alk-2-yl)-1H-pyrazole 4a (102.70 mg), RuPhos-Pd-G3 (20.67 mg), sodium carbonate (78.47 mg), dioxane (2 mL) and deionized water (0.2 mL), The nitrogen was replaced three times, and the temperature was raised to 95° C. to react for 5 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=40:1) to obtain (R)-7-methoxy-2-methyl-6-(1-methyl) yl)-1H-pyrazol-4-yl)-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidine-4- Amine 4b (100 mg), 83% yield.

MS m/z(ESI): 488.2[M+1]

second step

Into a 15mL flask was added (R)-7-methoxy-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)-N-(1-(3-nitro-5 -(Trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 4b (100 mg), iron powder (57.29 mg), tetrahydrofuran (2 mL), ethanol (2 mL) and dilute Hydrochloric acid (1M, 1 mL) was heated to 100°C and reacted for 4 hours. After the reaction, the pH was adjusted to neutral with saturated sodium bicarbonate solution, filtered, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), dried with anhydrous sodium sulfate, filtered, and reduced in pressure Concentrated, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=30:1) to obtain (R)-N-(1-(3-amino-5-(trifluoro) Methyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(1-methyl-1H-pyrazol-4-yl)pyrido[2,3-d]pyrimidine-4 - Amine 4 (20 mg), 21% yield.

MS m/z(ESI): 458.2[M+1]

¹ H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.27(d,J=7.9Hz,1H),8.20(s,1H),8.05(s,1H),6.86(d,J =6.2Hz, 2H), 6.71(s, 1H), 5.56(s, 3H), 4.07(s, 3H), 3.92(s, 3H), 2.40(s, 3H), 1.57(d, J=7.0Hz ,3H)ppm.

Example 5

(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,4-dimethoxyphenyl)-7-methoxy- Synthesis of 2-Methylpyrido[2,3-d]pyrimidin-4-amine 5

first step

(R)-6-(3,4-Dimethoxyphenyl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)benzene) Synthesis of yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 5b

Into a 25mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine [2,3-d]pyrimidin-4-amine C-1 (60 mg), (3,4-dimethoxyphenyl)boronic acid 5a (44.91 mg), RuPhos-Pd-G3 (10.33 mg), carbonic acid Sodium (39.24 mg), 1,4-dioxane (2 mL) and deionized water (0.2 mL) were replaced with nitrogen three times, and the temperature was raised to 95° C. to react for 5 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (50 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=40:1) to obtain crude product (R)-6-(3,4-dimethoxyphenyl)-7 -Methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 5b (53.6 mg), 80% yield.

MS m/z(ESI): 544.2[M+1]

second step

Add (R)-6-(3,4-dimethoxyphenyl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-() to a 50 mL reaction flask Trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 5b (67.00 mg), 10% palladium on carbon catalyst (20 mg) and methanol (10 mL), replaced with hydrogen three times, 50 °C reaction overnight. After the reaction, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=30:1) to obtain (R) -N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,4-dimethoxyphenyl)-7-methoxy-2-methyl pyrido[2,3-d]pyrimidin-4-amine 5 (19 mg), 30% yield.

MS m/z(ESI): 514.2[M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.01 (d, J=7.9 Hz, 1H), 8.92 (s, 1H), 7.24 (d, J=2.1 Hz, 1H), 7.19 (dd, J= 8.2, 2.1Hz, 1H), 7.12 (d, J=8.5Hz, 1H), 6.89 (d, J=11.3Hz, 2H), 6.75 (s, 1H), 5.67 (q, J=7.0Hz, 1H) ,4.09(s,3H),3.82(s,3H),3.81(s,3H),2.62(s,3H),1.61(d,J＝7.0Hz,3H)ppm.

Example 6

(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-morpholinepyrido[2,3 Synthesis of -d]pyrimidin-4-amine 6

In a 15 mL flask was added (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido [2,3-d]pyrimidin-4-amine C-3 (150.00 mg, 339.95 μmol), morpholine (59.23 mg, 679.90 μmol), Pd ₂ (dba) ₃ (31.13 mg, 33.99 μmol), XantPhos (39.34 mg, 67.99 μmol), sodium tert-butoxide (97.92 mg, 1.02 mmol) and 1,4-dioxane (2 mL), replaced with nitrogen three times, and heated to 100° C. to react overnight. LC-MS detected that the reaction of the starting materials was complete. Filter through celite, wash with ethyl acetate, collect the filtrate, wash with water three times, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to remove the solvent. The obtained residue is separated and purified by silica gel column chromatography (eluent: dichloromethane). /methanol = 20:1) to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6 - Morpholinepyrido[2,3-d]pyrimidin-4-amine 6 (13 mg), 9% yield.

MS m/z(ESI): 448.2[M+1]

¹ H NMR (400MHz, DMSO-d ₆ )δ8.39-8.24(m,1H),8.00(s,1H),7.67(t,J=7.5Hz,1H),7.50(t,J=7.2Hz, 1H), 7.30(t, J＝7.7Hz, 1H), 7.24(t, J＝54.4Hz, 1H), 5.79(t, J＝7.2Hz, 1H), 3.98(s, 3H), 3.79(t, J=4.5Hz, 4H), 3.11 (q, J=3.3Hz, 4H), 2.32 (s, 3H), 1.60 (d, J=7.0Hz, 3H) ppm.

Example 7

(R)-6-Cyclopropyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3-d]pyrimidine- Synthesis of 4-amine 7

Add (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3- d] Pyrimidine-4-amine C-2 (300 mg) and 1,4-dioxane (10 mL) were added cyclopropylboronic acid 7a (84.6 mg), Pd(dppf)Cl ₂ (48 mg) and cesium carbonate ( 641.8 mg), replaced nitrogen three times, and reacted at 100°C for 4 hours. The reaction solution was filtered through celite, concentrated, added with ethyl acetate, washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane). Methane/methanol=30:1) to give (R)-6-cyclopropyl-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyridine and [2,3-d]pyrimidin-4-amine 7 (80 mg), 33% yield.

MS m/z(ESI): 373.1[M+1]

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.82 (d, J=2.3Hz, 1H), 8.58 (d, J=7.2Hz, 1H), 8.41 (d, J=2.4Hz, 1H), 7.66 (t, J=7.5Hz, 1H), 7.50 (t, J=7.2Hz, 1H), 7.28 (t, J=7.7Hz, 1H), 7.24 (t, J=54.4Hz, 1H), 5.77 (p , J＝7.0Hz, 1H), 2.35(s, 3H), 2.15-2.07(m, 1H), 1.60(d, J＝7.0Hz, 3H), 1.10-1.07(m, 2H), 0.94-0.83( m,2H)ppm.

Example 8

(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-((4-methylpiperazine Synthesis of -1-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine 8

In a 15 mL flask was added (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido [2,3-d]pyrimidin-4-amine C-3 (120.0 mg, 0.27 mmol), ((4-methylpiperazin-1-yl)methyl)potassium trifluoroborate (119.7 mg, 0.54 mmol) , SPhos-Pd-G3 (11.9 mg, 0.014 mmol), tetrahydrofuran (6 mL) and distilled water (0.6 mL), and the temperature was raised to 100° C. to react for 6 hours. Complete conversion of starting material was monitored by LC-MS. Filtered with celite, washed with ethyl acetate, washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, the obtained residue was separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=30:1 ) to get (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-((4-methyl) ylpiperazin-1-yl)methyl)pyrido[2,3-d]pyrimidin-4-amine 8 (47 mg) in 37% yield.

MS m/z(ESI): 475.3[M+1]

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.60 (s, 1H), 8.50 (d, J=7.3Hz, 1H), 7.67 (t, J=7.5Hz, 1H), 7.49 (t, J= 7.2Hz, 1H), 7.29(t, J＝7.7Hz, 1H), 7.23(t, J＝54.4Hz, 1H), 5.77(t, J＝7.2Hz, 1H), 3.95(s, 3H), 3.51 (d, J=5.8Hz, 2H), 2.46-2.39(m, 8H), 2.33(s, 3H), 2.15(s, 3H), 1.59(d, J=7.0Hz, 3H) ppm.

Example 9

(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(pyrrolidin-1-yl)pyrido[2,3-d]pyrimidin- 4-amine

(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(pyrrol-1-yl)pyridine Synthesis of [2,3-d]pyrimidin-4-amine 9

In a 25 mL flask was added (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido [2,3-d]pyrimidin-4-amine C-3 (100 mg, 0.23 mmol), pyrrole (32.2 mg, 0.45 mmol), Pd ₂ (dba) ₃ (41.5 mg, 0.045 mmol), XantPhos (52.5 mg, 0.091 mmol), sodium tert-butoxide (65.3 mg, 0.68 mmol) and 1,4-dioxane (5 mL), nitrogen was replaced three times, the temperature was raised to 95° C. to react overnight. Complete conversion of starting material was monitored by LC-MS. Filter through celite, wash with ethyl acetate, wash three times with water, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography to obtain (R)-N-(1-(3- (Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(pyrrol-1-yl)pyrido[2,3-d]pyrimidine-4- Amine 9 (7.8 mg), 8% yield.

MS m/z(ESI): 432.2[M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (d, J=7.2 Hz, 1H), 7.73 (t, J=7.6 Hz, 1H), 7.65 (s, 1H), 7.57 (t, J= 7.2Hz, 1H), 7.37(d, J=7.0Hz, 1H), 7.24(t, J=54.4Hz, 1H), 5.91(t, J=7.1Hz, 1H), 4.07(s, 3H), 3.55 -3.35(m,7H),1.95(s,4H),1.67(d,J=7.0Hz,3H)ppm.

Example 10

(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6- yl)piperazin-1-yl)ethan-1-one

(R)-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido Synthesis of [2,3-d]pyrimidin-6-yl)piperazin-1-yl)ethan-1-one 10

Add (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido into the reaction flask [2,3-d]pyrimidin-4-amine C-3 (50 mg, 0.11 mmol), 1-(piperazin-1-)ethan-1-one (29.1 mg, 0.23 mmol), Pd ₂ (dba) ₃ (10.4 mg, 0.011 μmol), XantPhos (13.1 mg, 0.022 μmol), sodium tert-butoxide (32.7 mg, 3.4 mmol) and 1,4-dioxane (2 mL), replace nitrogen three times, and heat up to 95 ° C React overnight. LC-MS monitored the complete conversion of the raw materials, filtered through celite, washed with ethyl acetate, washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was mixed with silica gel and separated and purified by column chromatography to obtain (R )-1-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2 ,3-d]pyrimidin-6-yl)piperazin-1-yl)ethan-1-one 10 (35 mg) in 57% yield.

MS m/z(ESI): 489.3[M+1]

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.27 (d, J=7.3 Hz, 1H), 8.02 (s, 1H), 7.66 (t, J=7.4 Hz, 1H), 7.50 (t, J= 7.1Hz, 1H), 7.29(t, J＝7.7Hz, 1H), 7.24(t, J＝54.4Hz, 1H), 5.78(t, J＝7.2Hz, 1H), 3.99(s, 3H), 3.63 (d, J=5.4Hz, 4H), 3.17-2.96(m, 4H), 2.32(s, 3H), 2.06(s, 3H), 1.59(d, J=7.1Hz, 3H) ppm.

Example 11

(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)pyrido[2,3-d ]pyrimidin-4-amine

(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(4-methylpiperazine- Synthesis of 1-yl)pyrido[2,3-d]pyrimidin-4-amine 11

first step

(R)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-(3-nitro-5- (trifluoromethyl)phenyl)ethyl)pyrido[2,3-d ]pyrimidin-4-amine

(R)-7-Methoxy-2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-(3-nitro-5-(trifluoromethyl)benzene) Synthesis of yl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 11a

Into a 25mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine [2,3-d]pyrimidin-4-amine C-1 (100 mg, 0.2 mmol), 1-methylpiperazine (41.20 mg, 0.4 mmol), Pd ₂ (dba) ₃ (37.7 mg, 0.04 mmol) , XantPhos (47.60 mg, 0.08 mmol), cesium carbonate (167.5 mg, 0.5 mmol) and 1,4-dioxane (2 mL), nitrogen was replaced three times, and the temperature was raised to 95° C. to react overnight. LC-MS monitored the complete conversion of the raw materials, filtered through celite, washed with ethyl acetate, washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R)- 7-Methoxy-2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl ) pyrido[2,3-d]pyrimidin-4-amine 11a (25 mg) in 24% yield.

MS m/z(ESI): 506.2[M+1]

second step

Add (R)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl)-N-(1-(3-nitro-5-( Trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 11a (25 mg, 0.05 mmol), 1 M hydrochloric acid (1 mL), iron powder (13.8 mg, 0.25 mmol), tetrahydrofuran (2 mL), reacted at 100°C for 1 hour. Complete conversion of starting material was detected by TLC. The sodium bicarbonate solution was adjusted to neutral pH, filtered, washed with ethyl acetate, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R) -N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(4-methylpiperazin-1-yl) ) pyrido[2,3-d]pyrimidin-4-amine 11 (2.1 mg), 9% yield.

MS m/z(ESI): 475.9[M+1]

Example 12

(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methylpyrido[ 2,3-d]pyrimidin-4-amine

(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7 Synthesis of -methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine 12

first step

(R)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-

(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine

(R)-6-(3,6-Dihydro-2H-pyran-4-yl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(tris) Synthesis of fluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 12a

Into a 25mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine Por[2,3-d]pyrimidin-4-amine C-1 (120 mg, 0.25 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5 -Tetramethyl-1,3,2-pinacolborane (103.7mg, 0.5mmol), RuPhos-Pd-G3 (20.7mg, 0.025mmol), sodium carbonate (78.5mg, 0.75mmol), 1,4 -Dioxane (4 mL) and distilled water (0.4 mL), replaced with nitrogen three times, heated to 95°C and reacted overnight. LC-MS monitored the complete conversion of the raw materials, filtered through celite, washed with ethyl acetate, washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R)- 6-(3,6-Dihydro-2H-pyran-4-yl)-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl) Phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 12a (97 mg) in 81% yield.

MS m/z(ESI): 490.2[M+1]

second step

Add (R)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methyl-N-(1-(3-nitro) to a 10 mL flask -5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 12a (90 mg, 0.18 mmol), iron powder (51.4 mg, 0.92 mmol), 1 M hydrochloric acid ( 1 mL), tetrahydrofuran (2 mL) and ethanol (2 mL), the temperature was raised to 100 degrees and reacted for 2 hours. The complete conversion of the raw materials was detected by TLC, the pH of the sodium bicarbonate solution was adjusted to neutral, filtered, washed with ethyl acetate, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography Purification to give (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl )-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine 12 (18 mg), 22% yield

MS m/z(ESI): 460.2[M+1]

¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.53(s, 1H), 8.38(d, J=7.9Hz, 1H), 6.87(s, 1H), 6.84(s, 1H), 6.70(s, 1H), 6.18(s, 1H), 5.55(s, 2H), 5.51(d, J=7.8Hz, 1H), 4.25(d, J=3.3Hz, 2H), 3.96(s, 3H), 3.82( t, J=5.5Hz, 2H), 2.62-2.46 (m, 2H), 2.39 (s, 3H), 1.53 (d, J=7.0Hz, 3H) ppm.

Example 13

(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[2,3- d]pyrimidin-4-amine

(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methyl-6-(tetrahydro-2H-pyran Synthesis of -4-yl)pyrido[2,3-d]pyrimidin-4-amine 13

first step

(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-2-methylpyrido[2 ,3-d]pyrimidin-4-amine

(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7 Synthesis of -methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine 13a

In a 50 mL flask was added (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido [2,3-d]pyrimidin-4-amine C-3 (100 mg, 0.23 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5- Tetramethyl-1,3,2-pinacolborane (95.2 mg, 0.46 mmol), RuPhos-Pd-G3 (19.0 mg, 0.023 mmol), sodium carbonate (72.1 mg, 0.69 mmol), 1,4- Dioxane (5 mL) and distilled water (0.5 mL) were replaced with nitrogen three times, and the temperature was raised to 95° C. to react overnight. LC-MS monitored the complete conversion of the raw materials, filtered through celite, washed with ethyl acetate, washed with water three times, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R)- N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy -2-Methylpyrido[2,3-d]pyrimidin-4-amine 13a (80 mg), 80% yield.

MS m/z(ESI): 445.2[M+1]

second step

Add (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(3,6-dihydro-2H-pyran- 4-yl)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-amine 13a (80 mg, 0.18 mmol), 10% palladium on carbon catalyst (95 mg) and ethanol (40 mL) , after replacing the hydrogen three times, the reaction was carried out at 40 °C overnight. Celite filtration, washing with ethyl acetate, the obtained residue was separated and purified by preparative HPLC to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)- 7-Methoxy-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[2,3-d]pyrimidin-4-amine 13 (38 mg), 48% yield.

MS m/z(ESI): 447.2[M+1]

Example 14

(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-6-yl)tetrahydro -2H-pyran-4-ol

(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2, Synthesis of 3-d]pyrimidin-6-yl)tetrahydro-2H-pyran-4-ol 14

In a 50 mL flask was added (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-7-methoxy-2-methylpyrido [2,3-d]pyrimidin-4-amine C-3 (100 mg, 0.23 mmol) and tetrahydrofuran (5 mL), replaced nitrogen three times, cooled to -78 °C, and slowly added 2.5 mol/L n-butyllithium/n-hexane dropwise alkane solution (0.5 mL), and the reaction was incubated at -78°C for 1 hour. 1-Methylpiperidin-4-one (38.5 mg, 3.4 mmol) was slowly added, and the reaction was returned to room temperature for 1 hour. Saturated ammonium chloride solution was added to quench the reaction, ethyl acetate was added, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography to obtain ( R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-7-methoxy-2-methylpyrido[2,3 -d]pyrimidin-6-yl)tetrahydro-2H-pyran-4-ol 14 (2 mg), 2% yield.

MS m/z(ESI): 463.2[M+1]

Example 15

(R)-2-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d Synthesis of ]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide 15

(R)-2-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3 ,6-dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide

first step

tert-butyl(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3 ,6-dihydropyridine-1(2H)-carboxylate

(R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidine- Synthesis of 6-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester 15a

In a 25 mL flask, add (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3- d] Pyrimidine-4-amine C-2 (500mg, 1.22mmol), N-Boc-1,2,5,6-tetrahydropyridine-4-boronic acid pinacol ester (751.9mg, 2.43mmol), Pd ( dppf) Cl ₂ (177.9 mg, 0.24 mmol), potassium phosphate (516.2 mg, 2.4 mmol), 1,4-dioxane (8 mL) and distilled water (0.8 mL), reacted under microwave at 110° C. for 4 hours. Complete conversion of starting material was detected by LC-MS. Filter through celite, wash with ethyl acetate, wash the organic phase three times with water, once with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography to obtain (R)-4 -(4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)- 3,6-Dihydropyridine-1(2H)-carboxylate tert-butyl ester 15a (500 mg), 80% yield.

MS m/z(ESI): 514.2[M+1]

second step

(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3- d]pyrimidin-4-amine

(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,2,3,6-tetrahydropyridine-4 Synthesis of -yl)pyrido[2,3-d]pyrimidin-4-amine 15b

In a 50 mL reaction flask, add (R)-4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2 ,3-d]pyrimidin-6-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl ester 15a (500 mg, 0.97 mmol), 1,4-dioxane (10 mL) was added , 4M hydrogen chloride/1,4-dioxane solution (5 mL) was added, and the reaction was carried out at room temperature for 3 hours. The disappearance of starting material was monitored by TLC. At least a small amount of solvent was removed under reduced pressure, diethyl ether was added to separate out the solid, filtered, and the solid was dried to obtain (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2- Methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine 15b hydrochloride salt (400 mg).

MS m/z(ESI): 414.2[M+1]

third step

In a 25mL flask, add (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,2,3,6 - Tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine 15b hydrochloride (50 mg, 0.12 mmol), 2-bromo-N,N-dimethyl-acetamide ( 20.1 mg, 0.12 mmol), potassium carbonate (50.1 mg, 0.36 mmol) and acetonitrile (5 mL) were reacted at 50°C overnight. The reaction solution was added with ethyl acetate, washed with water three times, washed with saturated brine once, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R)-2-(4-( 4-((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3, 6-Dihydropyridin-1(2H)-yl)-N,N-dimethylacetamide 15 (20 mg), 30% yield.

MS m/z(ESI): 499.2[M+1]

Example 16

(R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3 ,6-dihydropyridin-1(2H)-yl)-3-oxopropanenitrile

(R)-3-(4-(4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d Synthesis of ]pyrimidin-6-yl)-3,6-dihydropyridin-1(2H)-yl)-3-oxopropionitrile 16

In a 25mL flask, add (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(1,2,3,6 - Tetrahydropyridin-4-yl)pyrido[2,3-d]pyrimidin-4-amine 15b hydrochloride (50 mg, 0.12 mmol), 2-cyanoacetic acid (20.6 mg, 0.24 mmol), EDCI ( 46.4 mg, 0.24 mmol) and dichloromethane (7 mL), reacted at room temperature for 4 hours. Dichloromethane was added, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography to obtain (R)-3-(4-(4- ((1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-yl)-3,6- Dihydropyridin-1(2H)-yl)-3-oxopropionitrile 16 (20 mg) in 35% yield.

MS m/z(ESI): 481.2[M+1]

Example 17

(R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-morpholinoethoxy)pyrido[2,3-d]pyrimidin-4-amine

(R)-N-(1-(3-(Difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-morpholinoethoxy)pyrido[2 Synthesis of ,3-d]pyrimidin-4-amine 17

first step

(R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-ol(R)-4-((1 Synthesis of -(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-ol 17a

In a 25 mL flask, add (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[2,3- d] Pyrimidine-4-amine C-2 (800mg, 1.95mmol), Pd(dppf)Cl ₂ (317.7mg, 0.39mmol), Biboronate pinacol ester (988.1mg, 3.89mmol), Potassium acetate (381.9mg , 3.89 mmol) and 1,4-dioxane (8 mL), replaced nitrogen three times, and reacted at 100 °C overnight. After cooling to room temperature, celite was filtered, washed with ethyl acetate, the organic phase was washed three times with water, washed with saturated brine once, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and tetrahydrofuran (10 mL), distilled water (3 mL) and 30% hydrogen peroxide were added. The solution (2 mL) and sodium hydroxide (698.26 mg, 17.46 mmol) were reacted overnight at room temperature. Complete conversion of starting material was detected by TLC. Ethyl acetate was added, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and dried in vacuo to obtain crude product (R)-4-((1-(3-(difluoromethyl)-2) -Fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d]pyrimidin-6-ol 17a (650 mg) in 96% yield.

MS m/z(ESI): 349.1[M+1]

second step

In a 25 mL flask, add (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[2,3-d ] Pyrimidine-6-ol 17a (80mg, 0.23mmol), 4-(2-chloroethyl)morpholine (68.7mg, 0.46mmol), potassium iodide (3.8mg, 0.023mmol), potassium carbonate (63.5mg, 0.46mmol) ) and DMF (5 mL) were reacted at 70°C for 3 hours. Complete conversion of starting material was detected by TLC. Ethyl acetate was added, washed three times with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried, and the obtained residue was separated and purified by silica gel column chromatography to obtain (R)-N-(1-(3-(bis). Fluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(2-morpholinoethoxy)pyrido[2,3-d]pyrimidin-4-amine 17 (11 mg) , the yield is 11%.

MS m/z(ESI): 462.2[M+1]

Example 18

(R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3 -yl)pyrido[2,3-d]pyrimidin-4-amine

(R)-N-(1-(3-Amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(9-methyl-3, Synthesis of 9-diazaspiro[5.5]undecan-3-yl)pyrido[2,3-d]pyrimidin-4-amine 18

first step

(R)-7-methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(1-(3-nitro-5-(trifluoromethyl)phenyl) )ethyl)pyrido[2,3-d]pyrimidin-4-amine

(R)-7-Methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(1-(3 -Synthesis of nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 18a

Into a 25mL flask was added (R)-6-bromo-7-methoxy-2-methyl-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyridine [2,3-d]pyrimidin-4-amine C-1 (150 mg), 3-methyl-3,9-diazaspiro[5.5]undecane (102.70 mg), Pd ₂ (dba) ₃ (28.3 mg), XantPhos (35.7 mg), cesium carbonate (301.5 mg) and dioxane (5 mL), nitrogen was replaced three times, and the temperature was raised to 100° C. to react for 6 hours. After the reaction was completed, it was cooled to room temperature, the reaction solution was filtered through celite, the filtrate was concentrated under reduced pressure, 50 mL of ethyl acetate was added, washed with water (25 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was further separated and purified by silica gel column chromatography (eluent: dichloromethane/methanol=9:1) to obtain (R)-7-methoxy-2-methyl-6-(9-methyl) yl-3,9-diazaspiro[5.5]undecan-3-yl)-N-(1-(3-nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[ 2,3-d]pyrimidin-4-amine 18a (50 mg), 29% yield.

MS m/z(ESI): 574.3[M+1]

second step

In a 10 mL flask was added (R)-7-methoxy-2-methyl-6-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-N- (1-(3-Nitro-5-(trifluoromethyl)phenyl)ethyl)pyrido[2,3-d]pyrimidin-4-amine 18a (50mg), iron powder (24mg), 1M hydrochloric acid (1 mL), tetrahydrofuran (2 mL) and ethanol (2 mL), and the temperature was raised to 100 degrees to react for 2 hours. The complete conversion of the raw materials was detected by TLC, the pH of the sodium bicarbonate solution was adjusted to neutral, filtered, washed with ethyl acetate, the organic phase was washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated by silica gel column chromatography Purification to give (R)-N-(1-(3-amino-5-(trifluoromethyl)phenyl)ethyl)-7-methoxy-2-methyl-6-(9-methyl) -3,9-Diazaspiro[5.5]undecan-3-yl)pyrido[2,3-d]pyrimidin-4-amine 18 (17 mg), 36% yield.

MS m/z(ESI): 544.3[M+1]

Example 19

(R)-3-(1-((7-methoxy-2-methyl-6-morpholinopyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-methylbenzonitrile

(R)-3-(1-((7-Methoxy-2-methyl-6-morpholinepyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-methyl Synthesis of Benzonitrile 19

first step

In a 50ml flask was added (R)-3-(1-((6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino)ethyl) -2-methylbenzonitrile C-4 (60 mg, 145.53 μmol), morpholine (43.69 mg, 353.55 μmol), Pd ₂ (dba) ₃ (13.32 mg, 14.55 μmol), BINAP (18.12 mg, 29.11 μmol) With 5m of dioxane, nitrogen was replaced three times, and the temperature was raised to 100 degrees to react for 6 hours. LC-MS showed that the reaction of the raw materials was complete, celite was filtered, concentrated, 100 mL of ethyl acetate was added, washed with water (25 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was further separated and purified by silica gel column chromatography ( Eluent: dichloromethane/methanol=19:1) to give (R)-3-(1-((7-methoxy-2-methyl-6-morpholinopyrido[2,3-d) ]pyrimidin-4-yl)amino)ethyl)-2-methylbenzonitrile 19 26 mg, 43% yield. MS m/z(ESI): 419.2[M+1]

¹ H NMR(400MHz, DMSO-d ₆ )δ8.35(d,J=6.9Hz,1H),7.97(s,1H),7.77(d,J=7.8Hz,1H),7.63(d,J= 7.6Hz, 1H), 7.36(t, J=7.8Hz, 1H), 5.63(t, J=7.0Hz, 1H), 3.97(s, 3H), 3.78(t, J= 4.6Hz, 4H), 3.10 (q, J=3.4Hz, 4H), 2.70 (s, 3H), 2.32 (s, 3H), 1.54 (d, J=7.0Hz, 3H) ppm.

Example 20

(R)-3-(1-((7-methoxy-2-methyl-6-(3-oxa-9-azaspiro[5.5]undecan-9-yl)pyrido[2,3-d]pyrimidin-4- yl)amino)ethyl)-2-methylbenzonitrile

(R)-3-(1-((7-Methoxy-2-methyl-6-(3-oxo-9-azaspiro[5.5]undecan-9-yl)pyrido[2 Synthesis of ,3-d]pyrimidin-4-yl)amino)ethyl)-2-methylbenzonitrile 20

In a 50ml flask was added (R)-3-(1-((6-bromo-7-methoxy-2-methylpyrido[2,3-d]pyrimidin-4-yl)amino)ethyl) -2-methylbenzonitrile C-4 (75.00 mg, 181.91 μmol), 3-oxo-9-azaspiro[5.5]undecane hydrochloride (62.77 mg, 327.45 μmol), Pd ₂ (dba ) ₃ (16.65mg, 18.19μmol), X-PHOS (17.34mg, 36.38μmol), sodium tert-butoxide (69.93mg, 727.66μmol) and dioxane 4mL, replaced nitrogen three times, heated to 100 degrees and reacted for 6 hours . LC-MS showed that the reaction of the raw materials was complete, celite was filtered, concentrated, 100 mL of ethyl acetate was added, washed with water (25 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the obtained residue was further separated and purified by silica gel column chromatography ( Eluent: dichloromethane/methanol=19:1) to obtain (R)-3-(1-((7-methoxy-2-methyl-6-(3-oxo-9-aza) Spiro[5.5]undecan-9-yl)pyrido[2,3-d]pyrimidin-4-yl)amino)ethyl)-2-methylbenzonitrile 20 30 mg, 33% yield.

MS m/z(ESI): 487.3[M+1]

¹ H NMR(400MHz, DMSO-d6)δ8.31(d,J=7.0Hz,1H),7.97(s,1H),7.77(d,J=7.8Hz,

1H), 7.63(d, J=7.7Hz, 1H), 7.36(t, J=7.8Hz, 1H), 5.63(p, J=7.1Hz, 1H), 3.96(s, 3H), 3.60(t, J=5.3Hz, 4H), 3.05(q, J=4.5Hz, 4H), 2.70(s, 3H), 2.32(s, 3H), 1.67(d, J=5.6Hz, 3H),

1.52(t,J=6.6Hz,8H)ppm.

Biological evaluation

Test Example 1. Test that the compound of the present invention blocks the binding of SOS1 to KRAS G12C protein

The following method was used to determine the ability of the compounds of the invention to block the interaction of SOS1 with KRAS G12C protein under in vitro conditions. This method uses the KRAS-G12C/SOS1BINDING ASSAY KITS kit (Cat. No. 63ADK000CB16PEG) from Cisbio Company. For detailed experimental operation, please refer to the kit instructions.

The experimental process is briefly described as follows: Use diluent buffer (Cat. No. 62DLBDDF) to configure the working solution concentration of Tag1-SOS1 and Tag2-KRAS-G12C proteins to 5X for use. Test compounds were dissolved in DMSO to prepare 10 mM stock solutions, which were then diluted with diluent buffer for use. First add 2μL of the test compound to the well (final concentration of the reaction system is 10000nM-0.1nM), then add 4μL of Tag1-SOS1 5X working solution and 4μL of Tag2-KRAS-G12C 5X working solution, centrifuge and mix well, let stand 15 minutes; then add 10 μL of pre-mixed anti-Tag1-Tb ³⁺ and anti-Tag2-XL665, and incubate for 2 hours at room temperature; finally, use a microplate reader to measure at the excitation wavelength of 304nM in TF-FRET mode. Wells emit fluorescence intensities at wavelengths of 620 nM and 665 nM, and the ratio of 665/620 fluorescence intensities for each well is calculated. By comparing the fluorescence intensity ratio with the control group (0.1% DMSO), the percentage inhibition rate of the test compound at each concentration was calculated, and the numerical-inhibition rate was subjected to nonlinear regression analysis with the test compound concentration by GraphPad Prism 5 software. , the _IC50 values of the compounds were obtained, see Table 1.

Table 1 IC ₅₀ data of the compounds of the present invention blocking the interaction between SOS1 and KRAS G12C protein

化合物编号Compound number	SOS1/IC ₅₀(nM) SOS1/ _IC50 (nM)
11	16.716.7
22	12.812.8
33	37.437.4
44	50.150.1
55	30.330.3
66	29.929.9
77	6.56.5
88	24.724.7
99	25.925.9
1111	18.818.8
1212	51.851.8
1313	15.615.6
1515	54.154.1
1616	37.637.6
1919	32.432.4
2020	52.452.4

Conclusion: It can be seen from Table 1 that the compound of the present invention has a strong blocking effect on the interaction between SOS1 and KRAS G12C protein.

Claims

A compound represented by the general formula (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

in:

Ring A is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, 9-10 membered bicyclic heterocyclyl, 9-10 membered bicyclic aryl or 9-10 membered fused ring;

R 1 are the same or different, each independently selected from hydrogen atom, halogen, cyano, amino, nitro, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-11 membered heterocyclic group, C 6 -C 10 aryl, 5-10 membered heteroaryl; wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further selected from one or more halogens, cyano groups , substituted by substituents of hydroxy, amino, and =O;

R 2 is selected from halogen, cyano, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, -OR 4 , -C(O)R 5 , -NR 6 C(O)R 7 , -CH 2 NR 8 R 9 , -C(O)NR 8 R 9 ,
or -NR 8 R 9 ; wherein, the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more substituents selected from R 10 ;

R 3 is selected from hydrogen atom, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 3 -C 10 cycloalkyl, 5-10 membered heteroaryl or -C(O)R 5 ; wherein , the alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group are optionally further substituted by one or more substituents selected from R 10 ;

R 4 is selected from a hydrogen atom, a C 1 -C 6 alkyl group, a C 3 -C 6 cycloalkyl group or a 4-11 membered heterocyclic group; wherein the alkyl or cycloalkyl group is optionally further modified by one or more selected from deuterium atom, hydroxyl, halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxy, heterocyclyl, =O, -N( CH3 ) 2 or -N( C2H 5 ) substituted by the substituent of 2 ; the 4-11-membered heterocyclic group is optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, C 1 -C 6 alkoxy or =O replaced;

R 5 is each independently selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, 4-11 membered heterocyclyl, -NR 8 R 9 ; wherein said alkyl, cycloalkyl or heterocyclyl The cyclic group is optionally further substituted with one or more substituents selected from hydroxy, halogen, cyano, amino, C 1 -C 6 alkoxy;

R 6 is selected from hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl;

R 7 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-10-membered heteroaryl or 4-11-membered heterocyclyl; radical, cycloalkyl, aryl or heteroaryl optionally further substituted by one or more substituents selected from hydroxyl, halogen, cyano, amino, C 1 -C 6 alkoxy; the heterocycle is optionally further substituted by one or more substituents selected from hydroxy, halogen, cyano, C1 - C6 alkyl, C3 - C6 epoxy, C1 - C3 alkoxy or =O replace;

R 8 and R 9 are each independently selected from a hydrogen atom or a C 1 -C 6 alkyl group; wherein said alkyl group is optionally further selected from one or more of hydroxyl, halogen, cyano, amino, C 1 -C 6 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 , 4-11-membered heterocyclic group or a substituent of =O; the 4-11-membered heterocyclic group is any is further substituted with one or more substituents selected from hydroxyl, halogen, cyano, C1 - C6 alkyl, C3 - C6 epoxy, C1 - C3 alkoxy or =O;

Alternatively, R 8 and R 9 together with the atoms to which they are attached form an N-containing 4-11 membered heterocyclyl optionally further modified by one or more =O or R 14 substituted by the substituent;

R 10 is each independently selected from halogen, cyano, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 3 -C 6 cycloalkyl , =O, -C(O)R 11 or -CH 2 C(O)NR 12 R 13 ; wherein said alkyl, alkoxy, hydroxyalkyl or cycloalkyl is optionally further modified by one or more substituted with a substituent selected from halogen, cyano, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or 4-11-membered heterocyclic group; the said The 4-11 membered heterocyclyl is optionally further substituted by one or more C 1 -C 3 alkyl or C 1 -C 3 alkoxy substituents;

R 11 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected from one or more halogen, cyano, hydroxyl, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or 4-11-membered heterocyclic group substituents; the 4-11-membered heterocyclic group is optional is further substituted by C 1 -C 3 alkyl or C 1 -C 3 alkoxy;

R 12 and R 13 are each independently selected from hydrogen, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl;

Alternatively, R 12 and R 13 together with the atoms to which they are attached form an N-containing 4-11 membered heterocyclic group; wherein said heterocyclic group is optionally further selected from one or more groups selected from halogen, cyano, hydroxyl, substituted by C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or a substituent of =O;

R 14 is selected from halogen, hydroxy, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl or -C(O)R 15 ; wherein said The alkyl, alkoxy or hydroxyalkyl groups are optionally further substituted by one or more selected from halogen, C 1 -C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 ,

substituted by the substituent;

R 15 is selected from C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; wherein said alkyl or cycloalkyl is optionally further selected by one or more selected from halogen, hydroxyl, cyano, C 1 - C 3 alkoxy, -N(CH 3 ) 2 , -N(C 2 H 5 ) 2 or substituents of 4-11-membered heterocyclic groups;

m is 1, 2 or 3.
The compound represented by the general formula (I) according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (II-1), (II-2) ), the compound shown in (II-3) or its stereoisomer, tautomer or its pharmaceutically acceptable salt:

wherein: R 1 , R 2 , R 3 and m are as defined in claim 1 .
The compound represented by the general formula (I) according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (III) or a stereoisomer thereof Isomers, tautomers or pharmaceutically acceptable salts thereof:

in:

Ring B is selected from C 3 -C 10 cycloalkyl, 4-11 membered heterocyclyl, C 6 -C 10 aryl or 5-10 membered heteroaryl;

n is selected from 0, 1, 2, 3 or 4;

Rings A, R 1 , R 3 , R 10 and m are as defined in claim 1 .
The compound represented by the general formula (I) according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (IV-1), (IV-2) ) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

wherein: ring A, R 1 , R 3 , R 6 , R 7 , R 8 , R 9 and m are as defined in claim 1 .
The compound represented by the general formula (I) according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (V) or a stereoisomer thereof Isomers, tautomers or pharmaceutically acceptable salts thereof:

wherein: Rings A, R 1 , R 3 , R 4 and m are as defined in claim 1 .
The compound represented by the general formula (I) according to claim 1 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which is the general formula (VI-1), (VI-2) ), (VI-3) or (VI-4) compounds or their stereoisomers, tautomers or their pharmaceutically acceptable salts:

in:

Rings A, R 1 , R 3 , R 8 , R 9 and m are as defined in claim 1 .
The compound represented by the general formula (III) according to claim 3 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein:

selected from the following groups:

wherein: R 10 and n are as defined in claim 1.
The compound according to any one of claims 1 to 7 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is:
A pharmaceutical composition containing an effective dose of the compound according to any one of claims 1 to 8 or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carriers, excipients or their combinations.
The compound according to any one of claims 1 to 8 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of SOS1 inhibitors use in.
The compound according to any one of claims 1 to 8 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 is prepared for the treatment of SOS1 The use in medicine for mediated diseases, wherein the diseases mediated by SOS1 are preferably RAS family protein signaling pathway-dependent related cancers, cancers caused by SOS1 mutations, or genetic diseases caused by SOS1 mutations.
The use according to claim 11, wherein the disease mediated by SOS1 is selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct epithelial cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, Thyroid cancer, acute myeloid leukemia, bladder cancer, urothelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma , breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer and sarcoma.