CN115724841A

CN115724841A - Pyridopyrimidinone derivative, and preparation method and application thereof

Info

Publication number: CN115724841A
Application number: CN202211040465.0A
Authority: CN
Inventors: 程超英; 张盼盼; 林承才; 颜孙力; 叶成; 钱文建; 陈磊
Original assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Current assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Priority date: 2021-08-30
Filing date: 2022-08-29
Publication date: 2023-03-03

Abstract

The invention relates to a substituted pyridopyrimidone derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in medicines. Specifically, the invention relates to substituted pyridopyrimidone derivatives shown as a general formula (I), a preparation method thereof, pharmaceutically acceptable salts thereof and application thereof as a therapeutic agent, particularly an SOS1 inhibitor, wherein the definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Pyridopyrimidinone derivative, preparation method and application thereof

Technical Field

The invention relates to a substituted pyridopyrimidinone derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application thereof as a therapeutic agent, in particular as an SOS1 inhibitor.

Background

RAS genes are widely present in various eukaryotes such as mammals, drosophila, fungi, nematodes and yeasts, and have important physiological functions in various life systems, three members of the mammalian RAS gene family, H-RAS, K-RAS and N-RAS, respectively, and various RAS genes have similar structures, each consisting of four exons, and are distributed on about 30kb DNA. Their encoded product is a monomeric globular protein with a relative molecular mass of 21 kDa. The activated and inactivated state of RAS proteins has a major impact on cell growth, differentiation, proliferation and apoptosis. The protein is membrane-bound guanine nucleotide binding protein, has weak GTP enzyme activity, regulates the activity state of RAS through GTP enzyme activating protein (GAPs) and guanine nucleotide exchange factor (GEFs) in normal physiological activity, is in the activation state when RAS protein is combined with GTP to form RAS-GTP, and can ensure that RAS-GTP is dephosphorylated and converted into RAS-GDP through the GTP enzyme activating protein so as to be inactivated; the inactivated RAS-GDP is converted into active RAS-GTP under the action of guanine nucleotide exchange factors, so that a series of downstream pathways such as RAF/MER/ERK and PI3K/AKT/mTOR are activated.

The RAS gene is also closely related to various diseases of human beings, and particularly in cancer, RAS is an oncogene frequently mutated, in which KRAS subtype gene mutation accounts for 86% of the total RAS gene mutation, and about 90% of pancreatic cancer, 30% -40% of colon cancer, and 15-20% of lung cancer have different degrees of KRAS gene mutation. In view of the universality of KRAS gene mutation, this target has been the direction of attention of drug developers. Starting from the publication of the clinical results of AMG-510 acting directly on the KRAS-G12C target, the studies of KRAS inhibitors have raised a hot tide at home and abroad.

SOS (Son of seven homologes) protein was originally discovered in Drosophila studies and is a guanosine releasing protein encoded by the SOS gene. There are 2 SOS homologues in humans, hSOS1 and hSOS2, both members of the guanine nucleotide exchange factor family, with 70% homology, and although they are highly similar in structure and sequence, there is some difference in their physiological functions. The hSOS1 protein is 150kDa in size, is a multi-structural protein domain consisting of 1333 amino acids, comprising an N-terminal protein domain (HD), multiple homeodomains, a Helical Linker (HL), a RAS exchange sequence (REM), and a proline-rich C-terminal domain. hSOS1 has 2 binding sites with RAS protein, which are catalytic site and allosteric site, the catalytic site combines with RAS protein in RAS-GDP complex to promote guanine nucleotide exchange, and the allosteric site combines with RAS protein in RAS-GTP complex to further strengthen catalytic action and to participate in and activate signal transduction of RAS family protein. It has been shown that SOS1 inhibition not only results in complete inhibition of RAS-RAF-MEK-ERK pathway in wild-type KRAS cells, but also results in a 50% decrease in phospho-ERK activity in mutated KRAS cell lines. Therefore, inhibition of SOS1 can also decrease the activity of RAS, thereby treating various cancers caused by RAS gene mutation or over-activation of RAS protein, including pancreatic cancer, colorectal cancer, bile duct cancer, gastric cancer, non-small cell lung cancer, and the like.

In addition, alterations in SOS1 are also implicated in cancer. Studies have shown that SOS1 mutations are found in embryonal rhabdomyosarcoma, sellery cell orchiema, diffuse large B-cell lymphoma, neurofibroma, cutaneous granulocytic tumors, and lung adenocarcinoma. Meanwhile, studies have described overexpression of SOS1 in bladder and prostate cancer. In addition to cancer, inherited SOS1 mutations are implicated in the pathogenesis of RAS diseases such as Noonan Syndrome (NS), cardio-facial skin syndrome (CFC), and inherited gingival fibromas type i, among others.

SOS1 is also a GEF for activation of the GTPase RAC1 (Ras-related botulinum C3 toxin substrate 1). Like RAS family proteins, RAC1 is involved in the pathogenesis of a variety of human cancers and other diseases.

No drug selectively targeting SOS1 has been marketed in the market, but a series of related patents have been published, including WO2018115380A1, WO2019122129A1, WO2019201848A1, from Bayer, WO2020180768A1, from Revolution, etc., by BI, and BI-1961703 is currently the drug in clinical trials. However, these are far from sufficient for antitumor studies, and there is still a need to study and develop new selective SOS1 kinase inhibitors to address the unmet medical need.

Disclosure of Invention

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

wherein:

x is selected from O, NH, NCH ₃ Or S; x is preferably O;

R ¹ the same or different, each independently selected from hydrogen atom, halogen, nitro, amino, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 3-11 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more deuterium atoms, halogen, hydroxy, amino, cyano, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy or = O substituentGeneration;

R ² is selected from C ₃ -C ₁₁ Cycloalkyl, 3-11 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, 7-to 11-membered fused ring, OR ⁵ or-NR ⁶ R ⁷ (ii) a Wherein said cycloalkyl, heterocyclyl, aryl, heteroaryl or fused ring is optionally further substituted with one or more R ^A Substitution;

R ^A each independently selected from deuterium atom, halogen, nitro group, cyano group, C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, 3-11 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-to 10-membered heteroaryl, = O, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-NHC(O)R ⁵ 、-NHC(O)OR ⁵ 、-NR ⁶ R ⁷ 、-C(O)NR ⁶ R ⁷ 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more alkyl, halogen, nitro, cyano, C ₃ -C ₆ Cycloalkyl, 3-11 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, = O, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-NHC(O)R ⁵ 、-NHC(O)OR ⁵ 、-NR ⁶ R ⁷ 、-C(O)NR ⁶ R ⁷ 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ Substituted with a substituent of (a);

R ³ selected from hydrogen atom, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy or C ₃ -C ₆ A cycloalkyl group; wherein said alkyl, alkoxy or cycloalkyl is optionally further substituted by one or more deuterium atoms, halogen, hydroxy, cyano, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy, C ₃ -C ₆ Cycloalkyl radical, C ₃ -C ₆ Halocycloalkyl or a substituent = O;

R ⁴ selected from hydrogen atom, C ₁ -C ₆ Alkyl, halogen, C ₃ -C ₆ Cycloalkyl or 3-6 membered heterocyclic group, preferably a hydrogen atom.

R ⁵ Selected from the group consisting of hydrogen atom, alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted with one or more groups selected from the group consisting of deuterium atom, hydroxyl group, halogen, nitro group, cyano group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, = O, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Substituted with the substituent(s);

R ⁶ and R ⁷ Each independently selected from the group consisting of hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Substituted with a substituent of (a);

or, R ⁶ And R ⁷ Together with the atoms to which they are attached form a 4-to 8-membered heterocyclic group, wherein the 4-to 8-membered heterocyclic group contains one or more of N, O, or S (O) _r And said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O,-C(O)R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Substituted with the substituent(s);

R ⁸ 、R ⁹ and R ¹⁰ Each independently selected from the group consisting of hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy or carboxylate;

each r is independently selected from 0, 1 or 2;

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

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

wherein: r is ¹ 、R ² 、R ³ 、R ⁴ And m is as defined in formula (I).

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

wherein:

ring B is selected from C ₃ -C ₁₁ Cycloalkyl, 3-10 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroarylOr a 7-11 membered fused ring;

R ^A each independently selected from halogen, cyano, hydroxy, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl or-C (O) R ⁵ ；

n is selected from 0, 1 or 2;

R ⁵ selected from alkyl, preferably methyl;

R ¹ 、R ³ 、R ⁴ and m is as defined in formula (II).

In a preferred embodiment of the present invention, the compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of:

in a preferred embodiment of the present invention, a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein

Selected from the following groups:

in a preferred embodiment of the present invention, the compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ¹ Identical or different, each independently selected from hydrogen atom, halogen, amino, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl group, preferably hydrogen atom, amino group or methyl group.

In a preferred embodiment of the present invention, a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is ³ Is selected from C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy or C ₃ -C ₆ Cycloalkyl, preferably methyl, methoxy or cyclopropyl.

In a preferred embodiment of the present invention, a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R is ⁴ Is selected as a hydrogen atom.

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

or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

Note: if there is a difference between the drawn structure and the name given for that structure, the drawn structure will be given more weight.

Still further, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II) or (III), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

The invention provides an application of a compound shown in a general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing an SOS1 inhibitor.

The invention also provides a use of a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a disease mediated by SOS1, wherein the disease mediated by SOS1 is preferably a RAS family protein signaling pathway dependent related cancer, a SOS1 mutation induced cancer or a SOS1 mutation induced genetic disease; wherein said SOS 1-mediated disease is preferably lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostate cancer, bile duct cancer, stomach cancer, diffuse large B-cell lymphoma, neurofibroma, noonan syndrome, cardio-facio-cutaneous syndrome, type I hereditary gingival fibroma, embryonal rhabdomyosarcoma, seltorit cell orchiema, or cutaneous granulocytic tumor.

The invention further provides an application of the compound of the general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating RAS family protein signal transduction pathway dependence-related cancer, cancer caused by SOS1 mutation or genetic diseases caused by SOS1 mutation.

The invention provides an application of a compound shown in a general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing a medicament for treating lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostatic cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, noonan syndrome, cardio-facio-cutaneous syndrome, I-type hereditary gingival fibroma, embryonal rhabdomyosarcoma, sellergliomas or skin granulomatosis.

Detailed description of the invention

Unless stated to the contrary, some of the 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 means including C ₁ -C ₂₀ Straight-chain or branched aliphatic hydrocarbon groups. Preferably C ₁ -C ₁₀ Alkyl, more preferably C ₁ -C ₆ An 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.

"alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be optionally substituted or unsubstituted.

"alkynyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, and can be straight or branched. Preferably selected is C ₂ -C ₁₀ Alkynyl of (2), more preferably C ₂ -C ₆ Alkynyl, most preferably C ₂ -C ₄ Alkynyl. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-,2-, or 3-butynyl, and the like. Alkynyl groups may be substituted or unsubstituted.

"cycloalkyl" refers to saturated or partially saturated monocyclic, fused, bridged, and spiro carbocyclic rings. Preferably C ₃ -C ₁₂ Cycloalkyl, more preferably C ₃ -C ₈ Cycloalkyl, most preferably C ₃ -C ₆ A cycloalkyl group. Examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like, with cyclopropyl, cyclohexenyl being preferred. Cycloalkyl groups may be substituted or unsubstituted.

"spirocycloalkyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures wherein the individual rings share a common carbon atom (called the spiro atom) and may contain 1 or more double bonds within the ring, but none of the rings have a completely conjugated pi-electron aromatic system. Preferably 6 to 14, more preferably 7 to 10. Spirocycloalkyl groups are classified according to the number of spiro atoms shared between rings into mono-, di-or multi-spiro cycloalkyl groups, preferably mono-and di-spiro cycloalkyl groups, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. 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 cyclic alkyl" 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 has a fully conjugated pi-electron aromatic system, preferably 6 to 12, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicycloalkyl. Non-limiting examples of "fused ring alkyl" 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 tetradecaphenanthryl.

"bridged cycloalkyl" means a 5 to 18 membered, all carbon polycyclic group containing two or more cyclic structures sharing two non-directly attached carbon atoms with each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron aromatic system, preferably 6 to 12, more preferably 7 to 10 membered. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to: (1s, 4s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1s, 5s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, (1r, 5r) -bicyclo [3.3.2] decyl, bicyclo [2.2.1] heptyl, or adamantyl.

"Heterocyclyl," "heterocycle," or "heterocyclic" are used interchangeably herein and all refer to non-aromatic heterocyclic groups in which one or more of the ring-forming atoms is a heteroatom, such as oxygen, nitrogen, sulfur, and the like, including monocyclic, polycyclic, fused, bridged, and spiro rings. Preferably having 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 sulfur.

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

monocyclic heterocyclyl groups may be substituted or unsubstituted.

"spiroheterocyclyl" refers to a 5 to 18 membered polycyclic group having two or more cyclic structures wherein the individual rings share an atom with one another and which may contain 1 or more double bonds within the ring, but none of the rings have a fully conjugated pi-electron aromatic system wherein one or more of the ring atoms is selected from nitrogen, oxygen or S (O) _n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. The spirocycloalkyl group is classified into a single spiroheterocyclic group, a double spiroheterocyclic group or a multiple spiroheterocyclic group, preferably a single spiroheterocyclic group and a double spiroheterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. 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 [3.5]]Nonyl, 5-oxaspiro [2.4]]A heptyl radical,

The spiroheterocyclic group may be substituted or unsubstituted.

"fused heterocyclyl" refers to a polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of which rings may contain one or more double bonds, but none of which rings has a fully conjugated pi-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S (O) _n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5-or 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo [3,4-c ] s]Pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0]Hexyl, octahydrobenzo [ b ]][1,4]Dioxins (dioxines).

"bridged heterocyclyl" means a 5-to 14-membered, 5-to 18-membered polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen, or S (O) _n (wherein n is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10. They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo [2.2.1]Heptyl, 2-azabicyclo [2.2.2]Octyl, 2-azabicyclo [3.3.2]Decyl radical,

The bridged heterocyclic group may 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. Preferably aryl is C ₆ -C ₁₀ Aryl, more preferably aryl is phenyl and naphthyl, most preferably phenyl. The aryl group may be substituted or unsubstituted.

"heteroaryl" refers to an aromatic 5-to 6-membered monocyclic or 8-to 10-membered bicyclic ring, which can contain 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur. <xnotran> " " , ,2- -1,2- , , , , , , , , , , , , , , ,1,2,3- , , , , , ,1,3- - , , , , , , , </xnotran>

Heteroaryl groups may be substituted or unsubstituted.

"fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but at least one of the rings does not have a completely conjugated pi-electron aromatic system, wherein the ring atoms are selected from 0, one or more 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 fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclic group or a monocyclic cycloalkyl group. Preferably 7 to 14, more preferably 8 to 10. Examples of "fused rings" include, but are not limited to:

"alkoxy" refers to a radical of (alkyl-O-). Wherein alkyl is as defined herein. C ₁ -C ₆ Alkoxy groups of (4) are preferred. Examples thereof include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"hydroxyalkyl" refers to a hydroxy-substituted alkyl group.

"haloalkyl" refers to a halogen-substituted alkyl.

"hydroxy" refers to an-OH group.

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

"amino" refers to-NH ₂ 。

"cyano" means-CN.

"nitro" means-NO ₂ 。

"benzyl" means-CH ₂ -a phenyl group.

"DMSO" refers to dimethyl sulfoxide.

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

A "leaving group", or leaving group, an atom or functional group that is removed from a larger molecule in a chemical reaction, is a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called the substrate (substtate), and the atom or group of atoms cleaved from the substrate molecule with a pair of electrons is called the leaving group. Groups that accept electrons easily and have a strong ability to bear negative charges are good leaving groups. The lower the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to be cleaved from other molecules. The reason is that the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced when the pKa of its conjugate acid is smaller, and the corresponding leaving group does not need to be bound to another atom. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -OTs, or-OH.

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

As used herein, "substituted" or "substituted," unless otherwise specified, means that the group may be substituted with one or more substituents.

"pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain their biological activity and which are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds of formula (I) may be metal salts, amine salts with suitable acids.

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

Synthesis of Compounds of the invention

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

the invention relates to a preparation method of a compound shown in a general formula (II) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, which comprises the following steps:

carrying out condensation reaction on a compound with a general formula (IIA) and a compound with a general formula (A-1) to obtain a compound with a general formula (IIB), carrying out ring closure on the compound with the general formula (IIB) under an acidic condition to obtain a compound with a general formula (IIC), and carrying out aryl cyanation reaction on the compound with the general formula (IIC) and a metal cyanide under a palladium catalysis condition to obtain a compound with a general formula (II);

wherein:

X ¹ is halogen, preferably chlorine;

R ¹ 、R ² 、R ³ 、R ⁴ and m is as defined in formula (I).

Detailed Description

The present invention will be further described with reference to the following examples, which are not intended to limit the scope of the present invention.

Examples

The examples show the preparation of representative compounds represented by formula (I) and the associated structural identification data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention. ¹ The H NMR spectrum was measured with a Bruker instrument (400 MHz) and the chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ Presentation of H NMRThe method comprises the following steps: 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.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.

The thin-layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the thin-layer chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4 mm-0.5 mm.

The column chromatography generally uses 200-300 mesh silica gel of the Tibet Huanghai silica gel as a carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, the starting materials and reagents are commercially available or synthesized according to known methods, and are used without further purification, unless otherwise indicated, commercially available manufacturers include, but are not limited to, shanghai haohnhong biomedical science and technology limited, shanghai shaoshimo reagents limited, shanghai beide medical science and technology limited, saen chemical technology (shanghai) limited, shanghai ling medical science and technology limited, and the like.

CD ₃ OD: deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

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

In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.

Purifying the compound using an eluent system for column chromatography and thin layer chromatography, wherein the system is selected from the group consisting of: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: dichloromethane and ethyl acetate system, D: dichloromethane and ethanol system, E: tetrahydrofuran/petroleum ether system, F: tetrahydrofuran and methanol system, wherein the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent, such as acetic acid or triethylamine, can be added for carrying out the conditions.

Example 1

(R)-2-methyl-3-(1-((2-methyl-7-oxo-6-(tetrahydro-2H-pyran-4-yl)-6,7-dihydropyrido[4,3-d]pyrimidin-4-yl)amino)ethyl)benzonitrile

(R) -2-methyl-3- (1- ((2-methyl-7-oxo-6- (tetrahydro-2H-pyran-4-yl) -6, 7-dihydropyrido [4,3-d ] pyrimidin-4-yl) amino) ethyl) benzonitrile

First step of

dimethyl(R)-2-(6-((1-(3-bromo-2-methylphenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)malonate

(R) -2- (6- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) malonic acid dimethyl ester

Dimethyl 2- (6-chloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) malonate 1a (500mg, 1.51mmol, prepared according to publication WO 2020254451), (R) -1- (3-bromo-2-methylphenyl) ethan-1-amine 1b (492.46mg, 1.97mmol, prepared according to publication WO 2013151923), N-diisopropylethylamine (390.78mg, 3.02mmol,499.34 μ L) and dimethyl sulfoxide (7 mL) were added sequentially at room temperature in a 10mL microwave reaction tube and heated to 120 ℃ for reaction for 2 hours. LC-MS detection showed completion of the reaction, the reaction solution was cooled to room temperature, ethyl acetate (100 mL) and water (50 mL) were added, the layers were separated by extraction, the aqueous phase was extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to give dimethyl (R) -2- (6- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) malonate 1c (380mg, 747.50. Mu. Mol) as a yellow solid in 49.44% yield.

MS m/z(ESI):508.1[M+H] ⁺

Second step of

(R)-2-(6-((1-(3-bromo-2-methylphenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)acetic acid

(R) -2- (6- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid

A25 mL reaction flask was charged with dimethyl (R) -2- (6- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) malonate 1c (280mg, 550.79. Mu. Mol), potassium hydroxide (154.51mg, 2.75mmol), methanol (10 mL) and water (1 mL) in that order, and heated to 90 ℃ for 4 hours. The target product formation was detected by LC-MS, and the reaction solution was cooled to room temperature and concentrated under reduced pressure to give (R) -2- (6- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid 1d (230mg, 527.16. Mu. Mol) in 95.71% yield.

MS m/z(ESI):436.1[M+H] ⁺

The third step

(R)-2-(6-((1-(3-bromo-2-methylphenyl)ethyl)amino)-5-(1,3-dioxolan-2-yl)-2-methylpyrimidin-4-yl)-N-(tetrahydro-2H-pyran-4-yl)acetamide

(R) -2- (6- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) -N- (tetrahydro-2H-pyran-4-yl) acetamide

To a 15mL reaction flask were added in this order (R) -2- (6- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) acetic acid 1d (230mg, 527.16. Mu. Mol), tetrahydropyran-4-amine 1e (79.98mg, 790.74. Mu. Mol), dichloromethane (10 mL), 1-propylphosphoric anhydride (335.46mg, 1.05mmol) and triethylamine (160.03mg, 1.58mmol), and the reaction was stirred at room temperature for 4 hours. LC-MS detection indicated complete reaction, ethyl acetate (100 mL) and water (50 mL) were added and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give (R) -2- (6- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) -N- (tetrahydro-2H-pyran-4-yl) acetamide 1f (230mg, 442.79 μmol) in 84% yield.

MS m/z(ESI):519.1[M+H] ⁺

The fourth step

(R)-4-((1-(3-bromo-2-methylphenyl)ethyl)amino)-2-methyl-6-(tetrahydro-2H-pyran-4-yl)pyrido[4,3-d]pyrimidin-7(6H)-one

(R) -4- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -2-methyl-6- (tetrahydro-2H-pyran-4-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one

To a 100mL reaction flask were added in this order (R) -2- (6- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -5- (1, 3-dioxolan-2-yl) -2-methylpyrimidin-4-yl) -N- (tetrahydro-2H-pyran-4-yl) acetamide 1f (240mg, 462.04. Mu. Mol), aqueous hydrochloric acid (1M, 2mL) and isopropanol (20 mL), and the mixture was heated to 50 ℃ for 4 hours. LC-MS detection showed completion of the reaction, and the reaction solution was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate (100 mL) and water (50 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1g (190mg, 415.43. Mu. Mol) of (R) -4- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -2-methyl-6- (tetrahydro-2H-pyran-4-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one (89.91%) in yield.

MS m/z(ESI):457.2[M+H] ⁺

The fifth step

To a 10mL microwave reaction tube were added sequentially (R) -4- ((1- (3-bromo-2-methylphenyl) ethyl) amino) -2-methyl-6- (tetrahydro-2H-pyran-4-yl) pyrido [4,3-d ] pyrimidin-7 (6H) -one 1g (190mg, 415.43. Mu. Mol), N-dimethylformamide (6 mL), tetrakis (triphenylphosphine) palladium (240.02mg, 207.71. Mu. Mol), and zinc cyanide (97.56mg, 830.85. Mu. Mol), with nitrogen protection, and microwave-reacted at 125 ℃ for 2 hours. LC-MS detection showed completion of the reaction, ethyl acetate (100 mL) and water (50 mL) were added for extraction, the organic phase was washed with water (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give (R) -2-methyl-3- (1- ((2-methyl-7-oxo-6- (tetrahydro-2H-pyran-4-yl) -6, 7-dihydropyrido [4,3-d ] pyrimidin-4-yl) amino) ethyl) benzonitrile 1 (32mg, 78. Mu. Mol) in 19% yield.

MS m/z(ESI)：565.2[M+H] ⁺

¹ H NMR(400MHz,DMSO-d ₆ )δ9.09(s,1H),8.84(s,1H),7.77-7.71(m,1H),7.66(d,J＝7.7Hz,1H),7.41(t,J＝7.8Hz,1H),6.10(s,1H),5.61(t,J＝6.8Hz,1H),5.18(s,1H),4.15-3.98(m,2H),3.54(t,J＝11.7Hz,2H),2.67(s,3H),2.20(s,3H),2.04(m,2H),1.79(d,J＝12.0Hz,2H),1.53(d,J＝7.0Hz,3H).

Biological evaluation

Test example 1 test for blocking binding of SOS1 to KRAS G12C protein by Compounds of the invention

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. The method uses KRAS-G12C/SOS1 BINDING ASSAY KITS kit (product number 63ADK000CB16 PEG) of Cisbio company, and the detailed experimental operation can refer to the kit instruction.

The experimental procedure is briefly described as follows: the concentration of the working solution with the protein of Tag1-SOS1 and Tag2-KRAS-G12C of 5X is prepared for later use by using a solvent buffer (the cargo number is 62 DLBDDF). Test compounds were dissolved in DMSO to prepare a 10mM stock solution, which was then diluted with a diluent buffer for use. Firstly, adding 2 mu L of tested compound (the final concentration of a reaction system is 10000nM-0.1 nM) into a hole, then adding 4 mu L of working solution of Tag1-SOS 1X and 4 mu L of working solution of Tag2-KRAS-G12C 5X, centrifuging and uniformly mixing, and standing for 15 minutes; then 10 mu L of premixed anti-Tag1-Tb is added ³⁺ And anti-Tag2-XL665, and incubating for 2 hours at room temperature; finally, the fluorescence intensities of the wells with the emission wavelengths of 620nM and 665nM at the excitation wavelength of 304nM were measured in TF-FRET mode using a plate reader, and the ratio of the fluorescence intensities of 665/620 was calculated for each well. The percent inhibition of the test compound at each concentration was calculated by comparison with the fluorescence intensity ratio of the control group (0.1% DMSO), and the numerical-inhibition was subjected to nonlinear regression analysis by GraphPad Prism 5 software at the test compound concentration to obtain the IC of the compound ₅₀ The value is obtained.

And (4) conclusion: the compound has stronger blocking effect on interaction of SOS1 and KRAS G12C proteinAction, IC of the Compound ₅₀ <1 μ M, IC of preferred compounds ₅₀ <100nM。

Test example 2 inhibition of OCI-AML5 cell proliferation by the Compound of the present invention

The following methods were used to determine the effect of the compounds of the present invention on proliferation of OCI-AML5 cells. OCI-AML5 cells (containing the SOS 1N 233Y mutation) were purchased from Nanjing Ke Bai Biotech, inc. and cultured in MEM α medium containing 10% fetal bovine serum, 100U penicillin and 100. Mu.g/mL streptomycin. Cell viability by

The Luminescent Cell Viability Assay kit (Promega, cat # G7573) was used for the Assay.

The experimental method is operated according to the steps of the kit specification, and is briefly as follows: test compounds were first prepared as 10mM stock solutions dissolved in DMSO and then diluted with culture medium to prepare test samples, with the final concentration of compound ranging from 10000nM to 0.15nM. Cells in logarithmic growth phase were seeded at a density of 1000 cells per well into 96-well cell culture plates, at 37 ℃,5% CO ₂ The incubation in the incubator is carried out overnight, followed by a further 120 hours after addition of the test compound. After the incubation was completed, 50uL volume of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes, and then Luminescence values of each well of the sample were read on a microplate reader using Luminescence mode. The percentage inhibition of the compounds at each concentration point was calculated by comparison with the values of the control (0.3% DMSO), after which non-linear regression analysis was performed in GraphPad Prism 5 software at the log-inhibition of the compound concentration, to obtain the IC of the compounds for inhibition of cell proliferation ₅₀ Values, results are given in the table below.

Claims

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

wherein:

x is selected from O, NH, NCH ₃ Or S; x is preferably O;

R ¹ the same or different, each independently selected from hydrogen atom, halogen, nitro, amino, C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl, 3-11 membered heterocyclyl, C ₆ -C ₁₀ Aryl or 5-10 membered heteroaryl; wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more deuterium atoms, halogen, hydroxy, amino, cyano, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Hydroxyalkyl radical, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy or = O;

R ^A each independently selected from deuterium atom, halogen, nitro group, cyano group, C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, 3-11 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, = O, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-NHC(O)R ⁵ 、-NHC(O)OR ⁵ 、-NR ⁶ R ⁷ 、-C(O)NR ⁶ R ⁷ 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ Wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further providedOne step being substituted by one or more alkyl, halogen, nitro, cyano, C ₃ -C ₆ Cycloalkyl, 3-11 membered heterocyclyl, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, = O, -OR ⁵ 、-C(O)R ⁵ 、-C(O)OR ⁵ 、-NHC(O)R ⁵ 、-NHC(O)OR ⁵ 、-NR ⁶ R ⁷ 、-C(O)NR ⁶ R ⁷ 、-CH ₂ NHC(O)OR ⁵ 、-CH ₂ NR ⁶ R ⁷ or-S (O) _r R ⁵ Substituted with the substituent(s);

R ³ selected from hydrogen atoms, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy or C ₃ -C ₆ A cycloalkyl group; wherein said alkyl, alkoxy or cycloalkyl is optionally further substituted by one or more deuterium atoms, halogen, hydroxy, cyano, C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Haloalkyl, C ₁ -C ₆ Alkoxy radical, C ₁ -C ₆ Haloalkoxy, C ₃ -C ₆ Cycloalkyl radical, C ₃ -C ₆ Halocycloalkyl or a substituent = O;

R ⁴ selected from hydrogen atoms, C ₁ -C ₆ Alkyl, halogen, C ₃ -C ₆ Cycloalkyl or 3-6 membered heterocyclic group, preferably a hydrogen atom.

R ⁶ and R ⁷ Each independently selected from the group consisting of hydrogen, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, whereinSaid alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Substituted with the substituent(s);

or, R ⁶ And R ⁷ Together with the atoms to which they are attached form a 4-to 8-membered heterocyclic group, wherein the 4-to 8-membered heterocyclic group contains one or more of N, O, or S (O) _r And said 4-to 8-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, = O, -C (O) R ⁸ 、-C(O)OR ⁸ 、-OC(O)R ⁸ 、-NR ⁹ R ¹⁰ 、-C(O)NR ⁹ R ¹⁰ 、-SO ₂ NR ⁹ R ¹⁰ or-NR ⁹ C(O)R ¹⁰ Substituted with a substituent of (a);

each r is independently selected from 0, 1 or 2;

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

2. the compound of claim 1, which is a compound of formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, according to formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

wherein: r ¹ 、R ² 、R ³ 、R ⁴ And m is as defined in claim 1.

3. The compound represented by the general formula (II) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to claim 2, which is a compound represented by the general formula (III) or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof:

wherein:

ring B is selected from C ₃ -C ₁₁ Cycloalkyl, 3-to 10-membered heterocyclic group, C ₆ -C ₁₀ Aryl, 5-10 membered heteroaryl, or 7-11 membered fused ring;

n is selected from 0, 1 or 2;

R ⁵ selected from alkyl, preferably methyl;

R ¹ 、R ³ 、R ⁴ and m is as defined in claim 2.

4. A compound according to claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of:

5. a compound according to claim 3, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein

Selected from the following groups:

6. a compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R ¹ Identical or different, each independently selected from hydrogen atom, halogen, amino, C ₁ -C ₆ Alkyl or C ₁ -C ₆ Haloalkyl group, preferably hydrogen atom, amino group or methyl group.

7. A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R ³ Is selected from C ₁ -C ₆ Alkyl radical, C ₁ -C ₆ Alkoxy or C ₃ -C ₆ Cycloalkyl, preferably methyl, methoxy or cyclopropyl.

8. A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R ⁴ Is selected as a hydrogen atom.

9. A compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein the compound is:

10. a pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 9, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or combination thereof.

11. Use of a compound according to any one of claims 1 to 9, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the preparation of an SOS1 inhibitor.

12. Use of a compound according to any one of claims 1 to 9 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10 for the preparation of a medicament for the treatment of a disease mediated by SOS1, wherein said disease mediated by SOS1 is preferably a cancer related to the dependence of the signaling pathway of the proteins of the RAS family, a cancer caused by a mutation in the SOS1 or a genetic disease caused by a mutation in the SOS 1.

13. The use of claim 12, wherein the SOS 1-mediated disease is selected from lung cancer, pancreatic cancer, colon cancer, bladder cancer, prostate cancer, cholangiocarcinoma, gastric cancer, diffuse large B-cell lymphoma, neurofibroma, noonan syndrome, cardio-facio-cutaneous syndrome, hereditary gingival fibroma type I, embryonal rhabdomyosarcoma, sellery cell orchienoma, or cutaneous granulocytic tumor.