WO2023246837A1 - Class of compounds having pyrimido-six-membered ring structure, pharmaceutical compositions comprising same, and use thereof - Google Patents

Abstract

The present invention relates to a class of compounds having a pyrimido-six-membered ring structure, pharmaceutical compositions comprising same, and use thereof. The compounds have a structure represented by formula (I) below. Experiments prove that the compounds of the present application exhibit significantly excellent inhibitory activity against KRAS-G12C/SOS1 interaction. Therefore, the compounds of formula I have the potential to be an SOS1 inhibitor and can be developed into a drug for treating diseases related thereto.

Description

A class of compounds with a pyrimido six-membered ring structure, pharmaceutical compositions containing the same and their applications Technical field

The invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to a class of compounds having a pyrimido six-membered ring structure, their stereoisomers, racemates, geometric isomers, tautomers, prodrugs, hydrates, solvates or their Pharmaceutically acceptable salts, and pharmaceutical compositions containing them, which have SOS1 inhibitor activity.

Background technique

RAS proteins include KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), HRAS (neuroblastoma RAS viral oncogene homolog) and NRAS (Harvey murine sarcoma virus oncogene), of which KRAS has two alternatively spliced isomers KRAS4A and KRAS4B. RAS protein is mainly distributed on the inside of the cell membrane, and membrane localization is a key step in activating RAS. The membrane localization of RAS protein requires prenylation and palmitoylation of its C terminus, but due to the lack of palmitoylation site, the membrane localization of KRAS4B relies on the electrostatic interaction between the polybasic region composed of lysine and the plasma membrane. (Ahearn et al., 2011; Wright and Philips, 2006). RAS protein belongs to the small GTPase family and exists in cells in a GTP-binding or GDP-binding manner. The activation of RAS protein requires its transition from a GDP-bound state to a GTP-bound state. This process is catalyzed by GEFs (guanine nucleotide exchange factors), such as SOS1 (Son of Sevenless 1) (Chardin et al., 1993). RAS activation will promote the activation of downstream effector molecules RAF, PI3K (Phosphoinositide 3-kinase) and RalGDS (Ral guanine nucleotide dissociation stimulator) to affect cell proliferation, growth, metabolism, migration, angiogenesis and other biological processes (Rodriguez-Viciana and McCormick, 2005; Young et al., 2009). RAS proteins have intrinsic hydrolytic activity that converts GTP into GDP. GTPase activating proteins GAPs (GTPase activating proteins), such as NF1, can increase its hydrolysis rate to inactivate RAS. Under normal conditions, GAPs and GEFs strictly regulate the inactivation and activation of RAS protein, but when the RAS protein is mutated, the regulatory mechanism is dysregulated. RAS mutations in tumor cells mainly occur at positions G12, G13 and Q61. Mutations at these sites weaken endogenous and GAPs-mediated hydrolysis activities. Mutations at G13 and Q61 also increase the GTP exchange rate mediated by GEFs (Simanshu et al., 2017; Smith et al., 2013). Biochemical data analysis in recent years has shown that mutated RAS still has a certain intrinsic hydrolytic activity, and the stronger the intrinsic hydrolytic activity of the RAS mutant protein, the stronger the inhibition of its upstream protein SHP2 will hinder its activity (Hunter et al., 2015; Mainardi et al., 2018).

The SOS1 protein has two important motifs, the RAS exchanger motif (REM) and the CDC25 homology domain, which are the allosteric binding site and the catalytic binding site respectively. Among them, CDC25 binds RAS-GDP to promote the exchange of GDP and GTP, and REM binds RAS-GTP to further increase the catalytic activity of SOS1 (Freedman et al., 2006; Pierre et al., 2011). SOS1 plays a key role in KRAS mutant tumors. Knocking down SOS1 will reduce the proliferation and viability of KRAS mutant tumor cells, but has no effect on KRAS wild-type cells (Jeng et al., 2012). SOS1 plays an important role in activating the RAS signaling pathway. After activation of tyrosine kinase receptor RTKs, SHP2 is activated, binding to the adapter protein Grb2, promoting the formation of a complex between Grb2 and SOS1 and activating SOS1, thereby activating the RAS protein (Baltanas et al., 2020). SOS1 mutations exist in tumor cells, such as embryonal rhabdomyosarcoma, lung adenocarcinoma, etc. (Denayer et al., 2010), while SOS1 is highly expressed in bladder cancer and prostate cancer (Timofeeva et al., 2009; Watanabe et al. ,2000). In addition, SOS1 is also present in Noonan syndrome (NS), cardio-facio-cutaneous syndrome (CFC), hereditary gingival fibromatosis and related syndromes. mutation (Pierre et al., 2011).

SOS2, the homolog of SOS1, also acts as a GEF to activate RAS proteins, and there is functional redundancy between the two. Knocking out SOS1 in mice results in embryonic lethality (Qian et al., 2000), while conditional knocking out of SOS1 in adult mice is viable (Baltanas et al., 2013). However, knocking out SOS2 in mice has no obvious phenotype (Esteban et al., 2000). If both SOS1 and SOS2 are knocked out in adult mice, the mice die quickly (Baltanas et al., 2013). Selective inhibition of individual SOS isoforms, such as SOS1, may be more effective in treating SOS1-RAS-activated diseases. Inhibiting the SOS1 catalytic site from binding to RAS can prevent SOS1-mediated RAS-GTP production and inhibit the RAS signaling pathway. In RAS-dependent tumors, such compounds can theoretically disrupt the combination of RAS and SOS, inhibit the phosphorylation of cellular ERK, and have anti-tumor effects. Compounds that inhibit the interaction between SOS1 and RAS can inhibit RAS activity and can be used to treat head and neck cancer, lung cancer, mediastinal tumors, gastrointestinal tumors, prostate cancer, testicular cancer, gynecological tumors, breast cancer, kidney and bladder cancer, and endocrine system tumors. , soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, peripheral nervous system tumors, central nervous system tumors, lymphoma, leukemia, unknown primary cancer, Noonan syndrome, cardiofaciocutaneous syndrome, Hereditary gingival fibromatosis and its associated syndromes.

Contents of the invention

The invention provides a compound of formula (I), its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof:

In formula I, ring A represents a C _6-10 aryl group, a 5-10 membered heteroaryl group or a 4-10 membered saturated or unsaturated heterocyclyl group; in particular, ring A is a phenyl group;

n is an integer from 0 to 5;

Each R ₃ is independently selected from: unsubstituted or substituted C _1-4 alkyl, unsubstituted or substituted C _1-4 alkoxy, unsubstituted or substituted C _2-4 alkynyl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted 4-6 membered saturated or unsubstituted Saturated heterocyclyl, hydroxyl, halogen, cyano, amino, and oxo groups (=O); the substitution refers to one or more substituents selected from halogen, hydroxyl, cyano, and amino. Substitution; when ring A is a C _6-10 aryl group or a 5-10 membered heteroaryl group, R ₃ is not an oxo group (=O);

R ₁ is selected from hydrogen, halogen, hydroxyl, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocycle group, unsubstituted or substituted C _1-6 alkoxy, -CN, -COOH, -CONH ₂ , -CONH-C _1-6 alkyl, amino, -NH-C _1-6 alkyl; in particular, R ₁ is selected from hydrogen, halogen, hydroxyl, unsubstituted or substituted C _1-4 alkyl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _1-4 alkoxy, -CN , -COOH, amino; preferably, R ₁ is selected from hydrogen, halogen, hydroxyl, -CN, methyl, ethyl, methoxy, ethoxy, amino, cyclopropyl;

R ₂ is hydrogen, unsubstituted or substituted C _1-6 alkyl, or unsubstituted or substituted C _3-6 cycloalkyl; in particular, R ₂ is methyl or ethyl;

R ₄ is hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C _{3- 6-} cycloalkyl, unsubstituted or substituted 4-10-membered saturated or unsaturated heterocyclyl, unsubstituted or substituted 5-10-membered heteroaryl and 4-10-membered heterocyclyl, halogen, -CN, -COOH , -OR ₅ , -NH-R ₅ , -CONH-R ₅ , -NHCO-R ₅ , -SO ₂ -R ₅ , or -SO ₂ NH-R ₅ ; preferably, R ₄ is selected from unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted 5-6 membered heteroaryl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted 4-10 membered heterocyclic group;

R ₅ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C _{3 -6} cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclyl;

Substitution in R ₁ , R ₂ , R ₄ and R ₅ means substitution with one or more substituents from the following group A. The substituents in group A include: unsubstituted or one of the substituents in group B. One or more substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, hydroxyl, halogen, cyano, amino, carboxyl, oxo group (=O), -NH-C _1-6 alkyl, -NH-C _3-6 cycloalkyl, unsubstituted or C _6-10 aryl substituted with one or more substituents of Group B, unsubstituted or substituted by Group B 5-10 membered heteroaryl substituted by one or more substituents, C _3-6 cycloalkyl unsubstituted or substituted by one or more substituents of Group B, unsubstituted or substituted by Group B One or more substituted 4-10-membered saturated or unsaturated heterocyclic groups in the substituent, -C(O)-R ₆ , -C(O)-NH-R ₆ , -NH-C(O)- R ₆ , -SO ₂ -R ₆ , -SO ₂ NH-R ₆ ; R ₆ is selected from hydrogen, unsubstituted or C _1-10 alkyl substituted by one or more substituents in Group B, unsubstituted Or a C _6-10 aryl group substituted by one or more substituents in Group B, a 5-10 yuan heteroaryl group that is unsubstituted or substituted by one or more substituents in Group B, none C _3-6 cycloalkyl substituted or substituted by one or more of the substituents of Group B, 4-10 yuan saturated or unsubstituted or unsubstituted or substituted by one or more of the substituents of Group B Saturated heterocyclic group; Group B substituents include: C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, halogen, cyano, amino, and carboxyl.

In specific embodiments, _R2 is methyl or ethyl.

In specific embodiments, Ring A is phenyl.

In specific embodiments, n is 1, 2 or 3; preferably, n is 1 or 2;

Each R ₃ is independently selected from: substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _2-4 alkynyl, substituted Or unsubstituted 4-6 membered saturated or unsaturated heterocyclic group, halogen, cyano group and amino group; the substitution refers to being substituted by one or more substituents selected from halogen, hydroxyl, cyano group and amino group ;Other substituents are as defined above.

In specific embodiments, each R ₃ is independently selected from: halogen, cyano, C _1-2 alkyl, halo C _1-2 alkyl; preferably, each R ₃ is independently methyl, F , CN, CHF ₂ or CF ₃ ; more preferably, each R ₃ is independently F or CHF ₂ .

In specific embodiments, R ₁ is hydrogen, halogen, hydroxyl, unsubstituted or substituted C _1-4 alkyl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _1-4 alkyl Oxygen, -CN, -COOH, or amino; the substitution means substitution with one or more selected from hydroxyl, halogen, cyano, and amino; preferably, R ₁ is hydrogen, halogen, hydroxyl, -CN, methyl, ethyl, methoxy, ethoxy, amino, or cyclopropyl; more preferably, R ₁ is hydrogen, halogen, -CN, methyl, methoxy, or cyclopropyl; Other substituents are as defined above.

In specific embodiments, R ₄ is selected from unsubstituted or substituted C _1-10 alkyl (such as C _1-6 alkyl), unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted 5- 10-membered heteroaryl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted 4-10-membered saturated or unsaturated heterocyclyl; substitution in R ₄ means substitution selected from the following group A Substituted with one or more of the substituents in Group A, group A substituents include: unsubstituted or substituted by one or more of group B substituents, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, hydroxyl, halogen, cyano, amino, carboxyl, oxo group (=O), -C(O)-R ₆ , -C(O)-NH-R ₆ ; choose R ₆ From hydrogen, C _1-10 alkyl unsubstituted or substituted by one or more substituents of Group B, C _3-6 ring unsubstituted or substituted by one or more substituents of Group B Alkyl; Group B substituents include: C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, halogen, cyano, amino, carboxyl;

Preferably, R ₄ is selected from unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted 5-6 membered heteroaryl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted 4-10 membered heterocyclyl;

Wherein, the 5-6 membered heteroaryl group is selected from:
Preferably, the 5-6 membered heteroaryl group is selected from

The 4-10 membered heterocyclic group is selected from: Preferably, the 4-10 membered heterocyclic group is selected from

The substitution in R ₄ means that it is substituted by one or more of the following substituents of Group A. The substituents of Group A include: C ₁ which is unsubstituted or substituted by one or more of the substituents of Group B. _-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, hydroxyl, halogen, cyano, amino, carboxyl, -C(O)-R ₆ , -C(O)-NH-R ₆ ; R ₆ is selected from hydrogen, unsubstituted or C _1-10 alkyl substituted by one or more of the substituents of Group B, unsubstituted or substituted by one or more of the substituents of Group B C _3-6 cycloalkyl; Group B substituents include: C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, halogen, cyano, amino, carboxyl.

More preferably, R ₄ is selected from C _1-10 alkyl which is unsubstituted or substituted by m substituents R ₇ and the following structure:

m is 1, 2 or 3;

R ₇ and R ₈ are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, which is unsubstituted or substituted by one or more of the substituents in Group B. group, hydroxyl, halogen, cyano, amino, carboxyl, -C(O)-R ₉ ; R ₉ is selected from hydrogen, unsubstituted or C _1-10 alkane substituted by one or more of the substituents in Group B group, unsubstituted or C _3-6 cycloalkyl substituted by one or more of the substituents in Group B; Group B substituents include: C _1-6 alkyl, C _1-6 alkoxy, hydroxyl , halogen, cyano, amino, carboxyl;

Preferably,

m is 1 or 2;

R ₇ is selected from H, C _1-6 alkyl, C 1-6 alkoxy, C _3-6 cycloalkyl, _hydroxyl , halogen, which is unsubstituted or substituted by one or more of the substituents of Group B. Cyano group, amino group; Group B substituents include: hydroxyl, halogen, cyano group, amino group;

R ₈ is selected from H, C _1-6 alkyl, C _1-6 alkoxy, -C(O)-R ₉ ; R ₉ is selected from C _1-6 alkyl, C _3-6 cycloalkyl;

More preferably,

m is 1 or 2;

R ₇ is selected from H, C _1-6 alkyl, C 1-6 alkoxy, C _3-6 cycloalkyl, _hydroxyl , halogen, which is unsubstituted or substituted by one or more of the substituents of Group B. Cyano group, amino group; Group B substituents include: hydroxyl, halogen, cyano group, amino group;

R ₈ is selected from H, methyl, ethyl, methoxy, ethoxy, -C(O)-R ₉ ; R ₉ is selected from methyl, ethyl, cyclopropyl;

Other substituents are as defined above.

In specific embodiments, R ₄ is selected from C _1-6 alkyl substituted by hydroxyl and/or C _3-6 cycloalkyl and the following structure:

Among them, R ₇ and R ₇ ' are selected from H, hydroxyl, amino, methyl, ethyl, methoxy, hydroxymethyl, hydroxyethyl, and R ₈ is selected from H, methyl, ethyl, methoxy, -C(O)-R ₉ ; R ₉ is selected from methyl, ethyl, and cyclopropyl;

Other substituents are as defined above.

In a specific embodiment, the compound of formula (I) is represented by the following formula II:

In the above formula II, the definitions of each substituent are as defined above.

In a preferred embodiment, in the compound of formula (II), R ₁ is methyl, methoxy or cyclopropanyl.

In a preferred embodiment, in the compound of formula (II), R ₃ is F, CHF ₂ , CF ₃ or CN.

In specific embodiments, the compound of formula (I) is represented by the following formula III:

In the above formula III, R ₄ is defined as above respectively.

In a specific embodiment, the compound of formula (I) is selected from the following compounds:

Another aspect of the invention provides a pharmaceutical composition comprising:

(1) A therapeutically effective amount of the compound of formula (I), its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable compounds thereof Salt as the active ingredient; and

(2) Pharmaceutically acceptable carrier.

Another aspect of the present invention provides the compound of formula (I), its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable compounds thereof. Acceptable salts, or the use of said pharmaceutical composition in the preparation of SOS1 inhibitors.

Another aspect of the present invention provides the compound of formula (I), its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable compounds thereof. Use of the accepted salts, or the pharmaceutical composition, in the preparation of medicaments for the prevention and/or treatment of diseases related to SOS1 mutations, activity or expression levels.

Among them, the diseases related to SOS1 mutation, activity or expression include head and neck cancer, lung cancer, mediastinal tumors, gastrointestinal tumors, prostate cancer, testicular cancer, gynecological tumors, breast cancer, kidney and bladder cancer, endocrine system tumors, Soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, peripheral nervous system tumors, central nervous system tumors, lymphoma, leukemia, unknown primary cancer, Noonan syndrome, cardiofaciocutaneous syndrome, genetic Gingival fibromatosis and its related syndromes.

beneficial effects

The compound of the present application exhibits significantly excellent KRAS-G12C/SOS1 interaction inhibitory activity. Therefore, it has the potential to be an SOS1 inhibitor and can be developed into a therapeutic drug for diseases related to this.

Detailed ways

It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form new or preferred technical solutions. Each feature disclosed in the specification may be replaced by any alternative feature serving the same, equivalent or similar purpose. Due to space limitations, they will not be described one by one here.

the term

In the present invention, when the group valency has a wavy line when, for example, , the wavy line indicates the point of attachment of the group to the rest of the molecule.

In the present invention, the halogen is F, Cl, Br or I.

In the present invention, unless otherwise specified, the terms used have their ordinary meanings known to those skilled in the art.

In the present invention, the term "C _1-6 " means having 1, 2, 3, 4, 5 or 6 carbon atoms, and "C _1-8 " means having 1, 2, 3, 4, 5, 6 , 7 or 8 carbon atoms, and so on. "3- to 8-membered" heterocyclyl refers to a heterocyclic group with 3-8 ring atoms, and so on, "4- to 10-membered heterocyclyl" and so on.

In the present invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon moiety. For example, the term "C _1-10 alkyl" refers to a linear or branched alkyl group having 1 to 10 carbon atoms, without limitation. Specifically include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably methyl, ethyl, propyl, isopropyl base, butyl, isobutyl, sec-butyl and tert-butyl. In the present invention, unless otherwise specified, the C _1-10 alkyl group is preferably a C _1-6 alkyl group, and more preferably a C _1-4 alkyl group.

In the present invention, the term "alkoxy" means an -O-(C _1-6 alkyl) group. For example, the term "C _1-6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including without limitation methoxy, ethoxy, propoxy, iso Propoxy and butoxy etc.

In the present invention, the term "alkenyl" refers to a linear or branched chain hydrocarbon moiety containing at least one double bond. For example, the term "C _2-6 alkenyl" refers to a hydrocarbon group having 2 to 6 carbon atoms and containing one double bond. Straight-chain or branched alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, isobutenyl, pentenyl, hexenyl, and the like.

In the present invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon moiety. For example, the term "C _3-8 cycloalkyl" refers to a cyclic alkyl group with 3 to 8 carbon atoms in the ring, without limitation. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc.

The term "aryl" as used herein refers to a carbocyclic hydrocarbon group consisting of one ring or more, such as two fused rings, at least one of which is an aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

In the present invention, the term "heterocyclyl" refers to a cyclic group containing at least one carbon atom and at least one (such as 1-3) cyclic heteroatoms selected from N, O, and S, specifically as used in this application. One or more ring carbons on the defined cycloalkyl group are selected from -O-, -N=, -NR-, -C(O)-, -S-, -S(O)- and -S(O ) A group formed by partial replacement of _2- , wherein R is hydrogen, C _1-4 alkyl or nitrogen protecting group (for example, benzyloxycarbonyl, p-methoxybenzylcarbonyl, tert-butoxycarbonyl, acetyl , benzoyl, benzyl, p-methoxy-benzyl, p-methoxy-phenyl, 3,4-dimethoxybenzyl, etc.). "Heterocyclyl" includes monocyclic, bridged, spiro and other bicyclic structures, such as 3- to 8-membered heterocyclyl, 3- to 6-membered heterocyclyl, etc.; such as tetrahydrofuranyl, pyrrolidinyl, oxyheterocycle Butyl, oxanyl, azetidinyl, oxiranyl, aziridinyl, thietanyl, 1,2-dithietanyl, 1,3-di Thietanyl, azepanyl, oxetanyl, etc.

In the present invention, the term "5- to -10-membered heteroaryl" refers to a monomer having 5 to 10 ring atoms, such as 5, 6 or 7 ring atoms (ie, 5- to 7-membered heteroaryl). A cyclic or bicyclic or fused polycyclic cyclic aromatic hydrocarbon group, which contains at least one (such as 1-3) ring heteroatoms independently selected from N, O and S (such as N) in the ring, and the remaining ring atoms Is a carbon atom; such as imidazolyl, pyridyl, pyrrolyl, thiazolyl, furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, pyrimidinyl, 1,2,4-triazolyl, etc. ; Preferred is a five-membered heteroaryl group, such as imidazolyl, isoxazolyl, and 1,2,4-triazolyl. Bicyclic heteroaryl groups include, for example, benzoxazolyl, imidazopyridyl, triazolopyridyl, benzofuryl, pyrazolopyrimidinyl, benzodioxolyl, indolyl , quinolyl, isoquinolyl, etc. In the present invention, the substitution is mono-substitution or poly-substitution, and the poly-substitution is disubstitution, tri-substitution, tetra-substitution or penta-substitution. The disubstituted means having two substituents, and so on. In the case of polysubstitution, the substituents may be the same as or different from each other.

The pharmaceutically acceptable salt described in the present invention may be a salt formed by an anion and a positively charged group on the compound of formula (I). Suitable anions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, tosylate, tartrate, fumarate Acid, glutamate, glucuronate, lactate, glutarate or maleate. Similarly, salts can be formed from cations with negatively charged groups on compounds of formula I. Suitable cations include sodium, potassium, magnesium, calcium and ammonium ions, such as tetramethylammonium.

In another preferred embodiment, "pharmaceutically acceptable salts" refer to salts formed by the compound of formula (I) with an acid selected from the following group: hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, Sulfuric acid, nitric acid, methanesulfonic acid, sulfamic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, wood sorrel Acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid , peptic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or compounds of formula (I) and inorganic Salts formed with bases, such as sodium salts, magnesium salts, potassium salts, calcium salts, aluminum salts, manganese salts or ammonium salts; or salts of compounds of general formula (I) with organic bases, such as methylamine salts, ethylamine salts or Ethanolamine salt.

"Therapeutically effective amount" refers to the amount of active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, pharmaceutical compositions contain 1-2000 mg active ingredient/dose, more preferably, 10-200 mg active ingredient/dose. Preferably, the "dose" is a tablet.

"Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler or gel substances that are suitable for human use and must be of sufficient purity and low enough toxicity. "Compatibility" here refers to the ability of each component of the composition to be blended with the active ingredients of the present invention and with each other without significantly reducing the efficacy of the active ingredients. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearin acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

The administration mode of the active ingredients or pharmaceutical compositions of the present invention is not particularly limited. Representative administration modes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), etc.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active ingredients, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances. Besides these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Suspensions may contain, in addition to the active ingredient, suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these substances and the like.

Compositions for parenteral injection may contain physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

The compounds of the present invention can be administered alone or in combination with other therapeutic drugs (such as anti-tumor drugs).

When using a pharmaceutical composition, a therapeutically effective dose of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, and the dosage when administered is a pharmaceutically effective dosage. For a person weighing 60 kg, the daily dose is The dosage is usually 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the patient's health condition, which are all within the skill of a skilled physician.

The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention. are expressly but not intended to limit the scope of the invention. Experimental methods without specifying specific conditions in the following examples are usually carried out according to conventional conditions (such as the conditions described in Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989)) or according to manufacturing Conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as familiar to one skilled in the art. In addition, any methods and materials similar or equivalent to those described can be used in the method of the present invention. The preferred implementation methods and materials described in this article are for demonstration purposes only.

General synthesis method

The compound of general formula (I) of the present invention can be synthesized through the following synthetic route. In the synthetic route described below, the information involved such as solvents, acids, bases, coupling catalysts and ligands are based on existing organic chemistry knowledge and famous reactions.

In this application, when the name of a compound is inconsistent with its structural formula, the structural formula of the compound shall prevail.

The present invention relates to the synthesis of a class of chiral amine intermediates, and its main synthesis route is as shown in Synthesis Route 1:

Synthesis route 1:

The R ₃ -substituted aromatic bromide (I-a) and the tin reagent are cleaved through Stille coupling reaction under acidic conditions to obtain the compound (I-d). Alternatively, the Weinreb amide (I-c) can be obtained through the condensation reaction of R3 _- substituted aromatic carboxylic acid (I-b) and dimethylhydroxylamine hydrochloride, and then reacted with Grignard reagent to obtain the corresponding ketone (I-d ). Ketone (Ⅰ-d) reacts with (S)-(-)-tert-butylsulfenamide to generate the corresponding ketimine (Ⅰ-e), which is stereoselectively reduced to obtain (Ⅰ-f) . Finally, the sulfinyl group is removed in a hydrogen chloride system to obtain the intermediate chiral amine hydrochloride (I-g).

The synthesis of the target compound is described in detail in Synthetic Route 2.

Synthesis route 2:

The raw material 2-chloro-3-nitro-4-pyridinecarboxylic acid (II-a) and sodium methoxide undergo a substitution reaction to generate a 2-methoxy-substituted compound (II-b). The carboxylic acid reacts with a sulfuric acid methanol system or trimethylsilyl diazomethane to obtain the methyl esterification product (II-c). Through reduction reaction, such as catalytic hydrogenation, iron powder/dilute hydrochloric acid system, the nitro group is reduced to obtain the amino compound (II-d). This compound is halogenated, such as using NCS, to obtain _R1 is methoxy and 6-position is chlorinated. Polysubstituted pyridine compound (II-h). At the same time, 2-chloro-5-amino-4-pyridinecarboxylic acid (II-e) can also be used as the starting material, esterified to obtain the methyl ester (II-f), and then halogenated with NBS to obtain a dihalo-substituted pyridine compound. (II-g). The above halide and the corresponding boron reagent, such as trimethylcyclotriboroxane and cyclopropylboronic acid, are coupled under the catalysis of palladium reagent to obtain compounds (II-h) with different types of R ₁ substituents, such as methyl , cyclopropyl compounds. The multi-substituted pyridine compound (II-h) and formamidine acetate are cyclized to obtain the pyrimidopyridine ring compound (II-i). This compound and the chiral amino compound (II-g) prepared in the synthetic route 1 undergo a condensation reaction to obtain Amino-substituted compound (II-j). Chlorine-containing compound (II-j) undergoes a coupling reaction, such as Suzuki, Buchwald, Stille, etc., to introduce compound (I) with R ₄ substituent. The R ₄ group also involves the introduction of some functional groups, which are specifically explained in subsequent examples.

The abbreviations for the following reagents are as follows:

Diethylamine sulfur trifluoride: DAST; 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate: HATU; dioxane : dixoane; dichloromethane: DCM; N,N-dimethylformamide: DMF; petroleum ether: PE; ethyl acetate: EA.

Example

Example 1: Synthesis of Compound Int-1

Step 1: Add compound Int-1-a (100g, 0.49mol) and dichloromethane 1L) into a dry 3L round-bottomed flask. The solution was cooled to 0°C, and DAST (120g, 0.17mol) was added dropwise under nitrogen protection. After the addition, the mixture was raised to room temperature and reacted for 16 hours. The reaction solution was poured into ice water, extracted with EA (500mL Bromo-3-(difluoromethyl)-2-fluorobenzene Int-1-b (90g, light yellow oil), yield: 82%. ¹ H NMR (CDCl ₃ , 400MHz): δ7.69-7.65(m,1H), 7.56-7.52(m,1H), 7.14(t,J=8.0Hz,1H), 6.88(t,J=54.8Hz ,1H).

Step 2: Add compound Int-1-b (90g, 0.40mol), tributyl (1-ethoxyvinyl) stannane (173g, 0.48mol) and anhydrous to a dry 2L single-neck round-bottomed flask in sequence. Dioxane (900 mL), triethylamine (101 g, 1.0 mol) and bis(triphenylphosphine) palladium (II) chloride (2.8 g, 4.0 mmol) were added under stirring. The reaction was stirred at 80°C for 12 hours under argon protection. Concentrate the reaction solution, add saturated potassium fluoride solution (300mL) to the residue, stir for 1 hour, filter, extract the filtrate with EA (300mL x 3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and use silica gel to obtain the residue Purification by column chromatography (PE/EA=20/1) gave 1-(difluoromethyl)-3-(1-ethoxyvinyl)-2-fluorobenzene Int-1-c (100g, brown oily material), and the crude product is directly used in the next step.

Step 3: Add compound Int-1-c (100g, crude product) and anhydrous dioxane (200mL) into a dry 1L single-neck round-bottom flask in sequence. The solution was cooled to 0°C, and dilute hydrochloric acid (200 mL, 0.40 mol, 2 M) was added dropwise under nitrogen protection. After the dropwise addition, the mixture was raised to room temperature and reacted for 12 hours. The reaction solution was poured into water, and the filtrate was extracted with dichloromethane (300mL 1) Obtain 1-(3-(difluoromethyl)-2-fluorophenyl)ethane-1-one Int-1-d (53g, light yellow oil), yield: 50% in two steps. ¹ H NMR (CDCl ₃ , 400MHz): δ7.69-7.98 (m, 1H), 7.81-7.77 (m, 1H), 7.36-7.33 (m, 1H), 6.95 (t, J = 54.8Hz, 1H) ,2.68(d,J=4.2Hz,3H).

Step 4: Add compound Int-1-d (17g, 90mmol), (S)-2-methylpropane-2-sulfinamide (16g, 0.14mol) and anhydrous to a dry 1L single-neck round-bottomed flask in sequence. To tetrahydrofuran (200 mL), add tetraethyl titanium oxide (62 g, 0.27 mol) under stirring, and stir and react at 80°C for 16 hours under argon protection. Concentrate the reaction solution, add saturated brine (100mL) to the residue, extract with EA (100mL =3/1), obtaining (S,Z)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethylene)-2-methylpropane-2-sulfenamide Int-1-e (23.7g, yellow oil), yield: 90%. LCMS (ESI):m/z 292.1[M+H] ⁺ .

Step 5: In a dry 1L three-necked flask, add dichloro(p-methylcumyl)ruthenium(II) dimer (1.4g, 2.3mmol), (1S,2R)-1-amino-2, 3-Dihydro-1H-inden-2-ol (0.70g, 4.5mmol), 4A molecular sieve (50g) and isopropanol (100mL) were stirred and reacted at 90°C for 20 minutes under argon protection. The reaction temperature was cooled to 40°C, a solution of compound Int-1-e (13g, 45mmol) in isopropyl alcohol (450mL) and a solution of potassium tert-butoxide in isopropyl alcohol (113mL, 11mmol, 0.1M) were added in sequence, and reaction was carried out at 40°C 2 Hour. The reaction solution was concentrated, saturated brine (100 mL) was added to the residue, and extracted with EA (100 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated, and the residue was purified by silica gel column chromatography (PE/EA=1/2) to obtain (S)-N-((R)-1-(3-(difluoromethyl)-2- Fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide Int-1-f (12.5g, yellow oil), yield: 95%. ¹ H NMR (CDCl ₃ , 400MHz): δ7.54-7.51 (m, 2H), 7.24-7.23 (m, 1H), 6.90 (t, J = 54.8Hz, 1H), 4.87-4.80 (m, 1H) , 3.55(d,J＝5.2Hz,1H), 1.55(t,J＝6.4Hz,3H), 1.23(s,9H).

Step 6: Add compound Int-1-f (12.5g, 43mmol) and anhydrous dioxane (100mL) into a dry 1L single-neck round-bottom flask in sequence. The solution was cooled to 0°C, and dilute hydrochloric acid dioxane solution (50 mL, 0.20 mol, 4 M) was added dropwise under nitrogen protection. After the dropwise addition, the mixture was raised to room temperature and stirred for 12 hours. The reaction solution was concentrated, methyl tert-butyl ether (200 mL) was added to the residue, and stirred for 2 hours. The precipitated product was filtered and dried to obtain (R)-1-(3-(difluoromethyl)-2-fluorophenyl). Ethylamine hydrochloride Int-1 (8.7g, white solid), yield: 92%. ¹ H NMR (CDCl ₃ ,400MHz): δ8.87(s,3H),7.98-7.94(m,1H),7.67-7.64(m,1H),7.45-7.41(m,1H),7.25(t, J=54.8Hz, 1H), 4.64 (m, 1H), 1.55 (t, d=6.4Hz, 3H). Chiral HPLC: 98.5%.

Example 2: Synthesis of Compound Int-2

Step 1: Add compound Int-2-a (100g, 465mmol), dry DMF (1.5L) and HATU (195g, 512mmol) into a dry 3L three-necked flask. After stirring at room temperature for 30 minutes, add methoxymethyl. Amine hydrochloride (69g, 512mmol) and N,N-diisopropylethylamine (180g, 1.4mol) were stirred at room temperature for 3 hours. Lower to 0°C, add 2N hydrochloric acid (30mL), water (200mL), EA extraction (500mL×3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the residue The substance was purified by silica gel column chromatography (PE/EA=20/1) to obtain 3-bromo-N-methoxy-N,2-dimethylbenzamide Int-2-b (110g, light yellow oily liquid ), yield: 92%. ¹ H NMR (CD ₃ Cl, 400MHz): δ7.58 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 7.11-7.07 (m, 1H), 3.41 (s, 3H), 3.37(s,3H),2.37(s,3H).

Step 2: Add compound Int-2-b (20g, 77mmol) and anhydrous tetrahydrofuran to a dry 1L three-necked bottle. (300 mL), cooled to 0°C in an ice bath, methylmagnesium bromide (51 mL, 154 mmol, 3.0 M) was added dropwise, and the reaction was slowly raised to room temperature and stirred for 3 hours. Lower to 0°C, add hydrochloric acid solution (75mL, 6N), stir for 30 minutes, add water (200mL) to dilute, extract with EA (200mL×3), combine the organic phases, wash with saturated brine (200mL×3), and use anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate under reduced pressure. The resulting residue is purified by silica gel column chromatography (PE/EA=20/1) to obtain 1-(3-bromo-2-methylphenyl)ethane-1-one. Int-2-c (9.3, orange oily liquid), yield: 56%. ¹ H NMR (CD ₃ Cl, 400MHz): δ7.65 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 2.56 (s,3H), 2.50(s,3H).

Step 3: Add compound Int-2-c (9.3g, 47mmol), anhydrous tetrahydrofuran (250mL), (R)-(+)-tert-butylsulfenamide (6.4g, 52mmol) and titanium tetraethoxide (50g, 218mmol), stirred and reacted at 80°C for 12 hours under argon protection. Dilute with water (200 mL), extract with EA (200 mL (PE/EA=10/1～5/1) Purification gives (R,E)-N-(1-(3-bromo-2-methylphenyl)ethylene)-2-methylpropane-2 - Sulfoxide amide Int-2-d (13 g, yellow oily liquid), yield: 95%. LCMS(ESI):m/z 318[M+H] ⁺ .

Step 4: Add dichloro(p-methylcumyl)ruthenium(II) dimer (0.73g, 1.2mmol) and (1S,2R)-1-amino-2,3 in sequence to a 500mL three-necked flask. -Dihydro-1H-inden-2-ol (0.35g, 2.4mmol), 4A molecular sieve (29g) and isopropyl alcohol (60mL), under argon protection, react at 90°C for 20 minutes, the system changes from yellow to deep red . Cool the temperature to 40°C and add (R,E)-N-(1-(3-bromo-2-methylphenyl)ethylene)-2-methylpropane-2-sulfoxide amide Int-2- in sequence. A solution of d (7.5g, 24mmol) in isopropyl alcohol (250mL) and a solution of potassium tert-butoxide (60mL, 2.4mmol, 0.1M) in isopropyl alcohol were reacted at 40°C for 15 hours under argon protection. The reaction solution was concentrated, the residue was diluted with water (200 mL), extracted with EA (200 mL × 3), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Silica gel column chromatography (PE: EA/dichloromethane=2/1/1) purified to obtain (R)-N-((R)-1-(3-bromo-2-methylphenyl)ethyl) -2-Methylpropane-2-sulfoxide amide Int-2-e (2.0g, brown oily liquid), yield: 27%. LCMS(ESI):m/z 318[M+H] ⁺ .

Step 5: Add compound Int-2-e (6.1g, 19mmol) and dioxane (50mL) into a dry 250mL single-mouth bottle, cool to 0°C in an ice bath, and add hydrochloric acid/1,4 dioxane dropwise. (25 mL, 100 mmol, 4 M) solution, stirred at room temperature for 12 hours. The reaction solution was concentrated, PE (200 mL) was added to the crude product, stirred for 12 hours, filtered, and dried to obtain (R)-1-(3-bromo-2-methylphenyl)ethane-1-amine hydrochloride Int- 2-f (4.8g, dark gray solid), yield: 100%. LCMS(ESI):m/z 214,216[M+H] ⁺ .

Step 6: Add compound Int-2-f (6.5g, 30mmol), di-tert-butyl dicarbonate (1.3g, 33mmol), and N,N-diisopropylethylamine (12g) into a dry 250mL single-mouth bottle in sequence. ,31mmol) and anhydrous dichloromethane (150mL), stir at room temperature for 3 hours. The reaction solution was diluted with water (100 mL), extracted with EA (200 mL × 3), the organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and the resulting residue was layered on a silica gel column Purified by analytical method (PE/EA=5/1) to obtain (tert-butyl (R)-(1-(3-bromo-2-methylphenyl)ethyl) carbamate Int-2-g (7.1 g, white solid), yield: 75%. LCMS (ESI): m/z 316[M+H] ⁺ .

Step 7: Add compound Int-2-g (7.1g, 23mmol) and zinc cyanide into a dry 250mL single-mouth bottle (3.2g, 27mmol), tetrakis triphenylphosphine palladium (2.6g, 2.3mmol) and anhydrous DMF (100mL), stir and react at 110°C for 3 hours under argon protection. Dilute with water (150 mL), extract with EA (200 mL × 3), combine the organic phases, wash with saturated brine (100 mL × 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue obtained is subjected to silica gel column chromatography. (PE/EA=5/1) was purified to obtain (tert-butyl(R)-(1-(3-bromo-2-methylphenyl)ethyl)carbamate Int-2-h (5.0g, White solid), yield: 85%. LCMS (ESI): m/z 261[M+H] ⁺ .

Step 8: Add compound Int-2-h (5.0g, 16mmol) and dioxane (50mL) to a dry 250mL single-mouth bottle, cool to 0°C in an ice bath, and add hydrochloric acid/1,4 dioxane dropwise. (25mL, 100mmol, 4M) solution, warmed to room temperature and stirred for 15 hours. The reaction solution was concentrated, methyl tert-butyl ether (200 mL) was added, stirred for 12 hours, filtered, and dried to obtain (R)-3-(1-aminoethyl)-2-toluonitrile hydrochloride Int-2 (3.0 g , white solid), yield: 80%. LCMS (ESI): m/z 161 [M] ⁺ ; ¹ H NMR (DMSO-d ₆ , 400MHz): δ 8.75 (s, 3H), 8.00 (d, J = 7.6Hz, 1H), 7.80 (d ,J＝7.6Hz,1H), 7.51(t,J＝8.0Hz,1H), 4.67-4.61(m,1H), 2.56(s,3H),1.51(d,J＝6.4Hz,3H).

Example 3: Synthesis of Compound A-1

Step 1: Dissolve compound A-1-a (9.0g, 52.0mmol) in 45mL methanol, slowly add thionyl chloride (12.4g, 104mmol) at room temperature, and then react at 80°C under nitrogen protection 48 Hour. Concentrate under reduced pressure, add water and adjust the pH with sodium bicarbonate solution. The reaction solution is extracted with EA. The organic phase is collected and dried over anhydrous sodium sulfate to obtain compound A-1-b (7.5g, yellow solid). Yield: 77%. LCMS(ESI): m/z=187.0[M+H] ⁺ .

Step 2: Dissolve compound A-1-b (9.0g, 48.1mmol) and N-bromosuccinimide (10.3g, 57.8mmol) in 150mL DMF, and stir at 85°C for 16 hours under nitrogen protection. . The reaction solution was extracted with EA, the organic phase was collected and dried over anhydrous sodium sulfate, then cold water was added to the organic phase at 0°C, filtered and the precipitated product was collected to obtain compound A-1-c (13g, brown solid). Yield: 100%. LCMS(ESI): m/z=265[M+H] ⁺ .

Step 3: Dissolve compound A-1-c (3g, 11.32mmol) and trimethylcyclotriboroxane (50% tetrahydrofuran) (5.8mL, 20.4mmol) in a 40mL dioxane sealed tube, and then Potassium carbonate (4.7g, 34.0mmol) was added in sequence. React with Pd(dppf)Cl ₂ (1.6g, 2.3mmol) at 90°C for 5 hours under nitrogen protection. The reaction solution was extracted with EA, the organic phase was collected and dried over anhydrous sodium sulfate, the organic phase was filtered and concentrated under reduced pressure. The residue was preparatively purified to obtain compound A-1-d (1.2g, yellow solid), yield: 52%. LCMS(ESI):m/z＝201.0[M+H] ⁺ .

Step 4: Dissolve compound A-1-d (300 mg, 1.6 mmol) and formamidine acetate (62 mg, 0.71 mmol) in an eggplant-shaped flask containing 6 mL of ethylene glycol dimethyl ether, under nitrogen protection, at 110°C Stir for 20 hours. The reaction solution was concentrated under reduced pressure. The residue was washed with water and filtered, and the filter cake was dried to obtain compound A-1-e (290 mg, yellow solid), yield: 98%. LCMS(ESI): m/z=196.0[M+H] ⁺ .

Step 5: Dissolve compound A-1-e (250mg, 1.3mmol) and compound Int-1 (226mg, 1.4mmol) in an eggplant-shaped flask filled with 10mL DMF, then add PyBOP (733mg, 1.4mmol), N,N-diisopropylethylamine (3.3g, 25.6mmol) was stirred at 50°C for 10 hours under nitrogen protection. The reaction solution was extracted with EA, the organic phase was collected and dried over anhydrous sodium sulfate, the organic phase was filtered and concentrated under reduced pressure. The residue was purified by normal phase column chromatography to obtain compound A-1-f (180 mg, yellow solid), yield: 39%. LCMS (ESI): m/z=367.1[M+H] ⁺ .

Step 6: Dissolve compound A-1-f (180 mg, 0.14 mmol) and N-Boc-piperazine (275 mg, 1.5 mmol) in a 3 mL dioxane sealed tube, and add cesium carbonate ( 482 mg, 1.5 mmol), Binap (60 mg, 0.1 mmol) and NHC-Pd (34 mg, 0.05 mmol), stirred at 110°C for 8 hours under nitrogen protection. The reaction solution was extracted with EA, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was preparatively purified to obtain compound A-1-g (80 mg, yellow solid), yield: 32%. LCMS (ESI): m/z=517.2[M+H] ⁺ .

Step 7: Dissolve compound A-1-g (80 mg, 0.16 mmol) in 3 mL of methylene chloride, add trifluoroacetic acid (1 mL) to the reaction system, and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound A-1-h (60 mg, yellow oil), yield: 94%. LCMS (ESI): m/z=417.2[M+H] ⁺ .

Step 8: Combine compound A-1-h (60mg, 0.14mmol), acetic acid (13mg, 0.18mmol), HATU (68.5mg, 0.18mmol), N,N-diisopropylethylamine (46.5mg, 0.36mmol) ) was dissolved in 5mL DMF and stirred at room temperature for 2 hours. The reaction solution was extracted with EA, the organic phase was collected and dried over anhydrous sodium sulfate, the organic phase was filtered and concentrated under reduced pressure. The residue was preparatively purified to obtain compound A-1 (60 mg, yellow solid), yield: 88%. LCMS (ESI): m/z＝459.2[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.40-8.42 (d, J＝7.6Hz, 1H), 8.24 (s, 1H ),7.59-7.63(t,J＝7.2Hz,1H),7.49-7.53(t,J＝7.2Hz,1H),7.10-7.34(m,3H),5.74-5.78(m,1H),3.62- 3.65(m,6H),3.56-3.58(m,2H),2.70(s,3H),2.08(s,3H),1.61-1.63(d,J=7.2Hz,3H).

The following compounds were synthesized in a similar manner to A-1:

Example 4: Synthesis of Compound A-10

Step 1: Add Pd(PPh ₃ ) ₄ (126 mg, 0.11 mmol) to compound A-1-f (200 mg, 0.55 mmol), A-10-a (395 mg, 1.1 mmol), TEA (166 mg, 1.7 mmol) and dioxane (10 mL) solution, react overnight at 110°C under nitrogen protection. Cool to room temperature, quench with saturated ammonium chloride solution, dry with EA, filter and concentrate under reduced pressure. The residue is purified by column chromatography to obtain A-10-b (220 mg, crude). LCMS (ESI): m/z=403.2[M+H] ⁺ .

Step 2: Add HCl (5 mL, 2.0 N, aq.) to a solution of compound A-10-b (200 mg, 0.50 mmol) in dioxane (10 mL), and react at room temperature for 4 hours. Adjust the pH to 6 with sodium hydroxide solution (2.0N), extract with EA, filter and concentrate under reduced pressure. The residue (crude product A-10-c) is directly used in the next reaction. LCMS(ESI): m/z=375.1[M+H] ⁺ .

Step 3: Slowly add methylmagnesium bromide (0.32 mL, 0.32 mmol) into a solution of compound A-10-c (60 mg, 0.16 mmol) in THF (3 mL), and react at room temperature overnight. Quenched with saturated ammonium chloride solution, then extracted with ethyl acetate, filtered and concentrated under reduced pressure, the residue was purified by reverse phase preparative purification to obtain A-10 (11.0 mg, yield: 17%). LCMS (ESI): m/z=391.0[M+H] ⁺ ; ¹ H NMR (400MHz, CD ₃ OD) δ8.46 (s, 1H), 8.24 (s, 1H), 7.58-7.46 (m, 2H ),7.22(t,J＝7.2Hz,1H),7.00(t,J＝58.8Hz,1H),5.82(q,J＝6.8Hz,1H),2.84(s,3H),1.69(d,J =7.2Hz,3H),1.63(s,6H).

Example 5: Synthesis of Compound A-11

Step 1: Add compound A-1-f (170mg, 0.46mmol) and borate ester (140mg, 0.56mmol), potassium carbonate (54mg, 1.38mmol), then add 10mL of dioxane and 1mL of water. After the addition is completed, react at 100°C overnight under nitrogen protection. The crude product was separated by silica gel column and eluted with DCM/MeOH (V/V=20/1) to obtain compound A-11-a (150 mg), yield: 71%. LCMS (ESI): m/z=456.2[M+H] ⁺ .

Step 2: Add compound A-11-a (40 mg, 0.09 mmol), palladium on carbon (0.02 mmol) and 10 mL methanol to a single-mouth bottle, stir at room temperature overnight under a hydrogen atmosphere, and perform reverse preparative purification to obtain the target compound A-11 (20 mg ), white solid, yield: 50%. LCMS (ESI): m/z＝458.2[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.68-8.70 (d, J＝7.2Hz, 1H), 8.48 (s, 1H ),8.05(s,1H),7.61-7.65(t,J＝7.6Hz,1H),7.49-7.53(t,J＝7.6Hz,1H),7.27-7.31(t,J＝7.6Hz,1H) ,7.01-7.37(t,J＝54.8Hz,1H),5.77(m,1H),4.57-4.60(m,1H),3.96-3.99(m,1H),3.17-3.23(m,1H),2.99 -3.05(m,1H),2.76(s,3H),2.63-2.69(m,1H),2.05(s,1H),1.93-1.97(m,1H),1.64-1.73(m,2H),1.61 -1.62(d,J＝6.8Hz,3H).

The following compounds were synthesized in a similar manner to A-11.

Example 6: Synthesis of Compound A-12

Step 1: Dissolve compound A-11-a (20 mg, 0.044 mmol) in dichloromethane (0.5 mL) and isopropyl alcohol (5 mL), add manganese tris(dipentanoylmethane) (8 mg, 0.013 mmol), Phenylsilane (14 mg, 0.13 mmol), stirred at room temperature overnight under oxygen protection. The reaction solution was concentrated under reduced pressure, and the target compound A-12 (3.1 mg) was obtained as a white solid by reverse preparative isolation. Yield: 15%. LCMS (ESI): m/z=474.2[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ8.48 (s, 1H), 8.27 (s, 1H), 7.57-7.61 (t, J＝7.2Hz,1H),7.47-7.50(t,J＝7.2Hz,1H),7.21-7.25(t,J＝7.6Hz,1H),6.86-7.14(t,J＝54.8Hz,1H), 5.81-5.87(m,1H),4.47-4.51(m,1H),3.87-3.91(m,1H),3.63-3.70(m,1H),3.13-3.30(m,2H),2.85(s,1H ),2.29-2.36(m,2H),2.76(s,3H),1.63-1.74(m,2H),1.60-1.62(d,J＝6.8Hz,3H).

Example 7: Synthesis of Compound A-13

Step 1: Dissolve compound A-12 (80 mg, 0.17 mmol) in 10 mL dichloromethane, cool the dry ice-EA system to low temperature, and add DAST (1.2 eq). After the addition is completed, the mixture is naturally raised to room temperature and stirred overnight. The reaction was quenched with ammonium chloride, dichloromethane-water system was added, and the layers were separated. The organic phase was collected, dried over anhydrous magnesium sulfate, and concentrated to obtain crude compound A-13-a, which was directly used in the next step.

Step 2: Add the crude compound A-13-a to the sealed tube, dissolve it in 5 mL of methanol, and then slowly add 20 mg of sodium methoxide. Sealed, react at 70°C for 2 hours. Add a small amount of water to quench. The reaction system was prepared by reverse phase to obtain the target compound A-13 (13.2 mg) as a white solid. The two-step yield: 16%. LCMS (ESI): m/z＝488.1[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ8.49 (s, 1H), 8.22 (s, 1H), 7.57-7.60 (t, J＝7.2Hz,1H),7.47-7.50(t,J＝7.2Hz,1H),7.21-7.25(t,J＝7.6Hz,1H),6.87-7.14(t,J＝55.2Hz,1H), 5.82-5.87(m,1H),4.38(m,1H),3.56-3.63(m,2H),3.30-3.31(m,1H),3.14(s,3H),2.85(s,3H),2.17- 2.27(m,3H),2.15(s,3H),2.11-2.13(m,1H),1.70-1.71(d,J＝6.8Hz,3H).

Example 8: Synthesis of Compound A-14

Step 1: Add compound A-13-a (50 mg, 0.11 mmol), 1 mL ammonia water, and dioxane 2 into the sealed tube. mL. Seal and react at 100°C for 2 hours. The reaction solution was prepared by reverse phase to obtain target compound A-14 (8.3 mg) as a white solid, yield: 16%. LCMS (ESI): m/z=473.1[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ.48 (s, 1H), 8.17 (s, 1H), 7.57-7.61 (t, J＝7.2Hz,1H),7.47-7.51(t,J＝7.2Hz,1H),7.21-7.25(t,J＝7.6Hz,1H),6.86-7.14(t,J＝55.2Hz,1H), 5.81-5.86(m,1H),4.04-4.08(m,1H),3.71-3.74(m,2H),3.50-3.71(m,1H),2.85(s,3H),2.31-2.34(m,2H ),2.15(s,1H),1.82-1.91(m,2H),1.70-1.72(d,J＝6.8Hz,3H).

Example 9: Synthesis of Compound A-15

Step 1: Add compound A-1-f (150mg, 0.41mmol), 1-hydroxycyclohex-3-ene-4-borate (110mg, 0.49mmol), and potassium carbonate (48mg, 1.23 mmol), then add 10 mL of dioxane and 1 mL of water. Under nitrogen protection, the reaction was carried out at 100°C overnight. The reaction solution was separated and eluted by silica gel column DCM/MeOH (V/V=20/1～10/1) to obtain compound A-15-a (72 mg), yield: 41%. LCMS (ESI): m/z=429.2[M+H] ⁺ .

Step 2: Dissolve compound A-15-a (60 mg, 0.14 mmol) in dichloromethane (0.5 mL) and isopropanol (5 mL), add manganese tris(dipentanoylmethane) (26 mg, 0.042 mmol), Phenylsilane (45 mg, 0.42 mmol), stirred at room temperature overnight under oxygen protection. The reaction solution was concentrated under reduced pressure, and the target compound A-15 (11 mg) was obtained as a white solid by reverse preparative isolation. Yield: 17%. LCMS (ESI): m/z＝447.1[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ): δ8.93-8.97(m,1H),8.48(1H),8.42-8.45(1H ),7.64-7.68(m,1H),7.49-7.53(m,1H),7.10-7.38(m,2H),5.77-5.84(m,1H),4.97-5.08(1H),4.31-4.51(m ,1H),3.71(m,1H),2.72-2.73(3H),2.32-2.33(m,1H),2.00-2.09(m,1H),1.88-1.94(m,1H),1.71-1.77(m ,3H),1.61-1.69(m,3H),1.52-1.56(m,1H),1.23-1.43(m,1H).

Example 10: Synthesis of Compound A-22

Step 1: Dissolve compound A-1-f (50mg, 0.14mmol) and compound A-22-a (71.7mg, 0.68mmol) into 1,4-dioxane (2mL) in a sealed tube, and then Add NHC-Pd (7.5mg), BINAP (8.5mg, 0.014mmol) and Cs ₂ CO ₃ (134.0 mg, 0.41 mmol), reacted at 110°C for 8 hours under nitrogen protection. The reaction solution was extracted with saturated ammonium chloride solution and EA, the organic phase was backwashed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue was purified by neutral reversed phase preparation to obtain compound A-22 (28.0 mg, Light yellow solid), yield: 45.5%. LCMS (ESI): m/z＝452.0[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD): δ8.38 (s, 1H), 7.59 (dd, J＝16.7, 9.2Hz, 2H) ,7.48(t,J＝6.9Hz,1H),7.22(t,J＝7.7Hz,1H),7.01(t,J＝54.9Hz,1H),5.81(q,J＝7.1Hz,1H),4.07 (t,J＝6.5Hz,2H),3.52(t,J＝7.3Hz,2H),2.80(s,3H),2.56(p,J＝6.9Hz,2H),1.69(d,J＝7.1Hz ,3H).

Example 11: Synthesis of Compound A-33

Step 1: Slowly add cyclopropylmagnesium bromide (0.64 mL, 0.64 mmol, 1.0 N) into a solution of compound A-10-c (120 mg, 0.32 mmol) in THF (8 mL), and react at room temperature overnight. Quenched with saturated ammonium chloride solution, extracted with EA, filtered and concentrated under reduced pressure, the residue was preparatively purified by reverse phase to obtain light yellow solid A-33 (12.6 mg, yield: 9.1%). LCMS (ESI): m/z＝417.1[M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.46 (s, 1H), 8.23 (s, 1H), 7.60-7.46 (m, 2H ),7.25-7.14(m,1H),7.01(t,J＝54.8Hz,1H),5.85-5.82(m,1H),1.69(d,J＝6.8Hz,3H),1.64(s,3H) ,1.46-1.42(m,1H),0.55-0.53(m,1H),0.47-0.42(m,2H),0.27-0.24(m,1H).

Example 12: Synthesis of Compound A-34

Step 1: Add compound A-1-f (50mg, 0.136mmol), A-34-a (48mg, 0.681mmol), NHC-Pd (10mg, 0.014mmol), BINAP (9mg, 0.013mmol), Cs ₂ CO ₃ (139.8mg, 0.404mmol), 1,4-dioxane (5mL). The reaction was stirred at 110°C for 16 hours. The reaction solution was cooled and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure. The residue was purified by prep-HPLC to obtain yellow solid A-34 (40.5 mg, yield: 53%). LCMS (ESI): m/z＝402.1[M+H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.31 (d, J＝7.3Hz, 1H), 8.15 (s, 1H), 7.60 (t,J＝7.3Hz,1H),7.50(t,J＝6.9Hz,1H),7.26(dt,J＝ 63.1,42.4Hz,2H),6.92(s,1H),5.81-5.70(m,1H),3.49(d,J＝3.5Hz,4H),2.67(s,3H),2.00(t,J＝6.5 Hz, 4H), 1.61 (d, J = 7.0Hz, 3H).

Example 13: Synthesis of Compound A-35

Step 1: Add compound A-1-f (50 mg, 0.14 mmol), 1,4-dioxane (5 mL), A-35-a (58 mg, 0.68 mmol), and cesium carbonate in sequence to a dry sealed tube. (137 mg, 0.41 mmol), NHC-Pd (9.3 mg, 0.01 mmol), BINAP (8.5 mg, 0.01 mmol); stir overnight at 110°C under nitrogen protection. Cool, quench the reaction solution with ammonium chloride solution, add EA for extraction, backwash the organic phase with saturated brine, dry over sodium sulfate, and concentrate under reduced pressure. The residue is purified by flash column chromatography to obtain white solid A-35 (21.6 mg, yield: 41%). LCMS (ESI): m/z=416.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.93 (d, J=7.4Hz, 1H), 8.71 (s, 1H), 8.43 (s,1H),7.66(t,J＝7.5Hz,1H),7.50(t,J＝7.1Hz,1H),7.41-7.02(m,2H),5.79-5.82(m,1H),4.21- 3.94(m,2H),2.76(s,3H),2.68-2.56(m,2H),2.20-1.99(m,2H),1.62(d,J＝7.0Hz,3H).

Test Example 1: Detection of the Inhibitory Effect of Compounds on KRAS-G12C/SOS1

Experimental purpose: To detect the inhibitory effect of the test compound on KRAS-G12C/SOS1. IC ₅₀ represents the inhibitory ability of the compound on KRAS-G12C/SOS1. The lower the IC ₅₀ value, the stronger its inhibitory ability. BI-3406 was used as a positive control compound.

Experimental reagents: KRASG12C/SOS Binding kit (Cisbio, cat. 63ADK000CB16PEG); DMSO (Sigma, cat. D8418-1L); 384-well white plate (PerkinElmer, cat. 6007290)

experimental method:

1. Compound preparation: Dissolve in 100% DMSO into 10mM storage solution, and store in the refrigerator away from light.

2. Kinase reaction process:

(1) Preparation of compounds: The concentration of the test compound is 5000nM, dilute it into a 100% DMSO solution of 200 times the final concentration in a 384-well plate, and dilute the compound 3 times to 10 concentrations. Use the dispenser Echo550 to transfer 50 nL of 200 times the final concentration of the compound to the 384-well plate of the destination plate. Add 50nL 100% DMSO to the negative control well and positive control well respectively.

(2) Use Diluent buffer to prepare a Tag1-SOS1 solution with 4 times the final concentration.

(3) Add 2.5 μlL of 4 times the final concentration of Tag1-SOS1 solution to the 384-well plate.

(4) Use Diluent buffer to prepare a Tag2-KRAS-G12C solution with 4 times the final concentration.

(5) Add 2.5 μL of 4 times the final concentration of Tag2-KRAS-G12C solution to the compound wells and positive control wells respectively. solution; add 2.5 μL of diluent buffer to the negative control well.

(6) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake to mix, and incubate at room temperature for 15 minutes.

(7) Use Detection buffer to prepare an Anti-Tag1-TB3+ solution of 1 times the final concentration and an Anti-Tag2-XL665 solution of 1 times the final concentration. Mix the two solutions to obtain a Mix solution. Add 5 μL of the Mix solution to each well.

(8) Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake and mix, and incubate at 4°C for 120 minutes.

(9) Use Envision microplate reader to read Em665/620.

data analysis

Calculation formula: Inhibition% = (Max signal-Compound signal)/(Max signal-Min signal) × 100; where Min signal is the mean value of the negative control wells and Max signal is the mean value of the positive control wells.

Fitted dose-response curve

Taking the log value of the concentration as the X-axis and the percent inhibition rate as the Y-axis, use the log(inhibitor) vs. response-Variable slope of the analysis software GraphPad Prism5 to fit the dose-effect curve to obtain the IC ₅₀ value of each compound on the enzyme activity. The fitting formula is: Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)).

The inhibitory activities of the compounds of Examples on KRAS-G12C/SOS1 interaction are shown in Table 1 below.

Table 1 Inhibitory activity of the examples of compounds on KRAS-G12C/SOS1 interaction

Note: "A" in IC ₅₀ means IC ₅₀ ≤ 200nM, "B" means 200nM < IC ₅₀ ≤ 2000nM, "C" means 2000nM < IC ₅₀ ≤ 5000nM, "D" means IC ₅₀ > 5000nM.

From the data given in Table 1, it can be seen that the compound of the present application exhibits significantly excellent KRAS-G12C/SOS1 interaction inhibitory activity. Therefore, it has the potential to be used as an SOS1 inhibitor and can be developed for use in this regard. drugs for the treatment of diseases.

Claims (10)

1. Compounds of the following formula I, their enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof:
   

   In formula I, ring A represents a C _6-10 aryl group, a 5-10 membered heteroaryl group, or a 4-10 membered saturated or unsaturated heterocyclic group;

   n is an integer from 0 to 5;

   Each R ₃ is independently selected from: unsubstituted or substituted C _1-4 alkyl, unsubstituted or substituted C _1-4 alkoxy, unsubstituted or substituted C _2-4 alkynyl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted 4-6 membered saturated or unsaturated heterocyclic group, hydroxyl, halogen, cyano group, amino, and oxo group (=O); the substitution refers to Substituted with one or more substituents selected from halogen, hydroxyl, cyano and amino; when ring A is a C _6-10 aryl group or a 5-10 membered heteroaryl group, R ₃ is not an oxo group group(=O);

   R ₁ is halogen, hydroxyl, unsubstituted or substituted C _1-6 alkyl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclyl, none Substituted or substituted C _1-6 alkoxy, -CN, -COOH, -CONH ₂ , -CONH-C _1-6 alkyl, amino, or -NH-C _1-6 alkyl;

   R ₂ is hydrogen, unsubstituted or substituted C _1-6 alkyl, or unsubstituted or substituted C _3-6 cycloalkyl;

   R ₄ is hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C _{3- 6-} cycloalkyl, unsubstituted or substituted 4-10-membered saturated or unsaturated heterocyclyl, unsubstituted or substituted 5-10-membered heteroaryl and 4-10-membered heterocyclyl, halogen, -CN, -COOH , -OR ₅ , -NH-R ₅ , -CONH-R ₅ , -NHCO-R ₅ , -SO ₂ -R ₅ , or -SO ₂ NH-R ₅ ;

   R ₅ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted or substituted C _{3 -6} cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclyl;

   Among them, the substitution in R ₁ , R ₂ , R ₄ , and R ₅ means substitution with one or more substituents selected from the following group A substituents. Group A substituents include: unsubstituted or group B substituents. One or more substituted C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, hydroxyl, halogen, cyano, amino, carboxyl, oxo group (=O ), -NH-C _1-6 alkyl, -NH-C _3-6 cycloalkyl, unsubstituted or C _6-10 aryl group substituted by one or more of the substituents in Group B, unsubstituted or 5-10-membered heteroaryl substituted with one or more substituents in Group B, C _3-6 cycloalkyl unsubstituted or substituted with one or more substituents in Group B, unsubstituted or substituted One or more substituted 4-10-membered saturated or unsaturated substituents in Group B and heterocyclyl, -C(O)-R ₆ , -C(O)-NH-R ₆ , -NH-C(O)-R ₆ , -SO ₂ -R ₆ , -SO ₂ NH-R ₆ ; R ₆ is selected from hydrogen, unsubstituted or C _1-10 alkyl substituted by one or more of the substituents of Group B, C unsubstituted or substituted by one or more of the substituents of Group B _6-10 aryl, unsubstituted or substituted by one or more of the substituents of Group B 5-10 membered heteroaryl, unsubstituted or substituted by one or more of the substituents of Group B C _3-6 cycloalkyl, 4-10 membered saturated or unsaturated heterocyclic group that is unsubstituted or substituted by one or more of Group B substituents; Group B substituents include: C _1-6 alkyl , C _1-6 alkoxy, hydroxyl, halogen, cyano, amino, carboxyl.
2. The compound according to claim 1, its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof,

   Wherein, in formula I, R ₂ is methyl or ethyl, and ring A is phenyl;

   n is 1 or 2, and each R ₃ is independently selected from: substituted or unsubstituted C _1-4 alkyl, substituted or unsubstituted C _2-4 alkynyl, substituted or unsubstituted 4-6 membered saturated or Unsaturated heterocyclic group, halogen, cyano group and amino group; the substitution means substitution by one or more substituents selected from halogen, hydroxyl, cyano group and amino group;

   Other substituents are as defined in claim 1.
3. The compound according to claim 1, its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof,

   Wherein, in formula I, R ₁ is selected from halogen, hydroxyl, unsubstituted or substituted C _1-4 alkyl, unsubstituted or substituted C _3-6 cycloalkyl, unsubstituted or substituted C _1-4 alkyl Oxygen, -CN, -COOH, amino; the substitution means substitution with one or more selected from hydroxyl, halogen, cyano, and amino;

   Preferably, R ₁ is selected from halogen, hydroxyl, -CN, methyl, ethyl, methoxy, ethoxy, amino, cyclopropyl;

   More preferably, R ₁ is selected from halogen, -CN, methyl, methoxy, cyclopropyl;

   Other substituents are as defined in claim 1.
4. The compound according to claim 1, its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof,

   Wherein, in formula I, R ₄ is selected from unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted C _6-10 aryl, unsubstituted or substituted 5-10 membered heteroaryl, unsubstituted Or substituted C _3-6 cycloalkyl, unsubstituted or substituted 4-10 membered saturated or unsaturated heterocyclyl; preferably, R ₄ is selected from unsubstituted or substituted C _1-10 alkyl, unsubstituted or Substituted C _6-10 aryl group, unsubstituted or substituted 5-6 membered heteroaryl group, unsubstituted or substituted C _3-6 cycloalkyl group, unsubstituted or substituted 4-10 membered heterocyclyl group;

   The substitution in R ₄ means that it is substituted by one or more of the following substituents of Group A. The substituents of Group A include: C ₁ which is unsubstituted or substituted by one or more of the substituents of Group B. _-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, hydroxyl, halogen, cyano, amino, carboxyl, oxo group (=O), -C(O)-R ₆ , -C(O)-NH-R ₆ ; R ₆ is selected from hydrogen, unsubstituted or C _1-10 alkyl substituted by one or more substituents of group B, unsubstituted or substituent of group B. One or more substituted C _3-6 cycloalkyl groups;

   Group B substituents include: C _1-6 alkyl, C _1-6 alkoxy, hydroxyl, halogen, cyano, amino, carboxyl;

   In particular, the 5-6 membered heteroaryl group is selected from:

   The 4-10 membered heterocyclic group is selected from:

   More preferably, R ₄ is selected from C _1-10 alkyl which is unsubstituted or substituted by m substituents R ₇ and the following structure:
   
   

   m is 1, 2 or 3;

   R ₇ and R ₈ are each independently selected from H, C _1-6 alkyl, C _1-6 alkoxy, C _3-6 cycloalkyl, which is unsubstituted or substituted by one or more of the substituents in Group B. group, hydroxyl, halogen, cyano, amino, carboxyl, -C(O)-R ₉ ; R ₉ is selected from hydrogen, unsubstituted or C _1-10 alkane substituted by one or more of the substituents in Group B group, unsubstituted or C _3-6 cycloalkyl substituted by one or more of the substituents in Group B; Group B substituents include: C _1-6 alkyl, C _1-6 alkoxy, hydroxyl , halogen, cyano, amino, carboxyl;

   Other substituents are as defined in claim 1.
5. The compound according to claim 1, its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof, wherein, formula I The compound is represented by the following formula II:
   

   In the above formula II, the definitions of each substituent are as defined in claim 1 respectively.
6. The compound according to claim 1, its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof, wherein, formula I The compound is represented by the following formula III:
   

   In the above formula III, the definitions of each substituent are as defined in claim 1 respectively.
7. The compound according to claim 1, its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable salts thereof, wherein, formula (I ) compound is selected from the following compounds:
   
   
   
8. A pharmaceutical composition comprising:

   (1) A therapeutically effective amount of the compound of formula I according to any one of claims 1 to 7, its enantiomers, diastereomers, racemates, prodrugs, hydrates, A solvate or a pharmaceutically acceptable salt thereof as the active ingredient; and

   (2) Pharmaceutically acceptable carrier.
9. The compound of formula I according to any one of claims 1 to 7, its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable compounds thereof. Acceptable salts, or use of the pharmaceutical composition according to claim 8 in the preparation of SOS1 inhibitors.
10. The compound of formula I according to any one of claims 1 to 7, its enantiomers, diastereomers, racemates, prodrugs, hydrates, solvates or pharmaceutically acceptable compounds thereof. The salt accepted, or the use of the pharmaceutical composition according to claim 8 in the preparation of a medicament for the prevention and/or treatment of diseases related to SOS1 mutation, activity or expression level,

    Among them, the diseases related to SOS1 mutation, activity or expression include head and neck cancer, lung cancer, mediastinal tumors, gastrointestinal tumors, prostate cancer, testicular cancer, gynecological tumors, breast cancer, kidney and bladder cancer, endocrine system tumors, Soft tissue sarcoma, osteosarcoma, rhabdoid tumor, mesothelioma, skin cancer, peripheral nervous system tumors, central nervous system tumors, lymphoma, leukemia, unknown primary cancer, Noonan syndrome, cardiofaciocutaneous syndrome, genetic Gingival fibromatosis and its related syndromes.